437 results on '"Wraith, David C"'
Search Results
152. Inhibition of experimental autoimmune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity
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Metzler, Barbara, primary and Wraith, David C., additional
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- 1993
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153. Peptide-MHC interaction in autoimmunity
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Fairchild, Paul J., primary and Wraith, David C., additional
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- 1992
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154. MHC-binding peptides for immunotherapy ofexperimental autoimmune disease
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Wraith, David C., primary, Smilek, Dawn E., additional, and Webb, Sandra, additional
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- 1992
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155. Enhanced selection of FoxP3+ 1-regulatory cells protects CTLA-4-deficient mice from CNS autoimmune disease.
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Verhagen, Johan, Gabryšová, Leona, Minaee, Sophie, Sabatos, Catherine A., Anderson, Graham, Sharpe, Arlene H., and Wraith, David C.
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CELLS ,AUTOIMMUNE diseases ,LABORATORY mice ,LYMPHOPROLIFERATIVE disorders ,BASIC proteins ,PEPTIDES - Abstract
it is generally acknowledged that cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4/CD152) plays a pivotal role in the regulation of T-cell activation and the establishment of self-tolerance in the periphery. CTLA-4-deficient (CTLA-4KO) mice develop a lymphoproliferative disorder and die within 4 weeks of birth, suggesting a role for CTLA-4 in T-cell homeostasis or the development and activity of T-regulatory (Treg) cells. To study the role of CTLA-4 in the control of experimental autoimmune encephalomyelitis (EAE), we have generated a CTLA-4KO mouse in which >90% of all CD4
+ cells bear a Vβ8.2 transgenic T-cell receptor that is specific for myelin basic protein peptide Ac1-9 (ASQKRPSQR). These mice do not develop spontaneous lymphoproliferative disease or EAE and are resistant to disease induction. This correlates with a higher frequency of functional FoxP3+ Treg cells in the spleen and thymus of CTLA-4KO mice. The absence of CTLA-4-mediated suppression of CD28 signaling resulted in the early expression of FoxP3 on double-positive cells in the thymic cortex. We conclude that CTLA-4 is not essential for the peripheral function of FoxP3+ Treg cells but plays a pivotal role in their thymic selection. [ABSTRACT FROM AUTHOR]- Published
- 2009
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156. T Cell Recognition in Experimental Autoimmune Encephalomyelitis: Prospects for Immune Intervention with Synthetic Peptides
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Wraith, David C., primary, Smilek, Dawn E., additional, Mitchell, Dennis J., additional, Steinman, Lawrence, additional, and McDevitt, Hugh O., additional
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- 1990
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157. Regulatory CD4+ T cells and the control of autoimmune disease
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Wraith, David C, Nicolson, Kirsty S, and Whitley, Nathaniel T
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CD4 antigen , *T cells , *AUTOIMMUNE diseases , *VIRAL receptors - Abstract
The immune system is a delicately balanced network of interacting cells. In recent years, the concept of immune regulation/suppression has been firmly established, and both natural and induced regulatory cells play vital roles in protection from autoimmune disease. Recent work has revealed the diverse nature of regulatory CD4+ T (Treg) cells and the molecules involved in their function. Innate and adaptive responses to infection are able to override the suppressive properties of such regulatory cells, whereas several reports point to deficiencies in regulatory cell function in autoimmune disease. Protocols have been developed that allow the expansion of Treg cells in vitro and their antigen-specific induction in vivo. A full understanding of Treg differentiation and function will facilitate the development of improved strategies for prevention and treatment of autoimmune diseases. [Copyright &y& Elsevier]
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- 2004
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158. CD4+T-cell epitopes associated with antibody responses after intravenously and subcutaneously applied human FVIII in humanized hemophilic E17 HLA-DRB1*1501 mice
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Steinitz, Katharina N., van Helden, Pauline M., Binder, Brigitte, Wraith, David C., Unterthurner, Sabine, Hermann, Corinna, Schuster, Maria, Ahmad, Rafi U., Weiller, Markus, Lubich, Christian, de la Rosa, Maurus, Schwarz, Hans Peter, and Reipert, Birgit M.
- Abstract
Today it is generally accepted that B cells require cognate interactions with CD4+T cells to develop high-affinity antibodies against proteins. CD4+T cells recognize peptides (epitopes) presented by MHC class II molecules that are expressed on antigen-presenting cells. Structural features of both the MHC class II molecule and the peptide determine the specificity of CD4+T cells that can bind to the MHC class II–peptide complex. We used a new humanized hemophilic mouse model to identify FVIII peptides presented by HLA-DRB1*1501. This model carries a knockout of all murine MHC class II molecules and expresses a chimeric murine-human MHC class II complex that contains the peptide-binding sites of the human HLA-DRB1*1501. When mice were treated with human FVIII, the proportion of mice that developed antibodies depended on the application route of FVIII and the activation state of the innate immune system. We identified 8 FVIII peptide regions that contained CD4+T-cell epitopes presented by HLA-DRB1*1501 to CD4+T cells during immune responses against FVIII. CD4+T-cell responses after intravenous and subcutaneous application of FVIII involved the same immunodominant FVIII epitopes. Interestingly, most of the 8 peptide regions contained promiscuous epitopes that bound to several different HLA-DR proteins in in vitro binding assays.
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- 2012
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159. Loss of serological determinants does not affect recognition of H-2K.
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Wraith, David C., Holtkamp, Bodo, and Askonas, Brigitte A.
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- 1983
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160. IDENTIFICATION OF AN INDIRECTLY PRESENTED EPITOPE IN A MOUSE MODEL OF SKIN ALLOGRAFT REJECTION1.
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Maceachern, Mary C., Burkhart, Christoph, Lowrey, Pauline A., and Wraith, David C.
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- 1998
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161. Natural and Induced Regulatory T Cells: Targets for Immunotherapy of Autoimmune Disease and Allergy
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Nicolson, Kirsty S. and Wraith, David C.
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Recent advances in immunology have greatly increased our understanding of immunological tolerance. In particular, there has been a resurgence of interest in mechanisms of immune regulation. Immune regulation refers to the phenomenon, previously known as immune suppression, by which excessive responses to infectious agents and hypersensitivities to otherwise innocuous antigens such as self antigens and allergens are avoided. We now appreciate that various distinct cell types mediate immune suppression and that some of these may be induced by appropriate administration of antigens, synthetic peptides and drugs of various types. The induction of antigen specific immunotherapy for treatment of autoimmune and allergic diseases remains the 'holy grail' for treatment of these diseases. This goal comes ever closer as understanding of the mechanisms of immune suppression and in particular antigen specific immunotherapy increases. Here we review evidence that immune suppression is mediated by various different subsets of CD4 T cells.
- Published
- 2006
162. Blockade of LFA-1 augments in vitro differentiation of antigen-induced Foxp3+ Treg cells
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Verhagen, Johan and Wraith, David C.
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Immunology ,Cell Differentiation ,Forkhead Transcription Factors ,Mice, Transgenic ,hemic and immune systems ,chemical and pharmacologic phenomena ,Autoimmunity ,Adoptive Transfer ,T-Lymphocytes, Regulatory ,Lymphocyte Function-Associated Antigen-1 ,Treg cell ,Autoimmune Diseases ,Mice ,Transforming Growth Factor beta ,Foxp3 ,Technical Note ,Animals ,Interleukin-2 ,Immunology and Allergy ,CTLA-4 Antigen ,Immunotherapy ,Cells, Cultured ,Signal Transduction ,LFA-1 - Abstract
Adoptive transfer of antigen-specific, in vitro-induced Foxp3+ Treg (iTreg) cells protects against autoimmune disease. To generate antigen-specific iTreg cells at high purity, however, remains a challenge. Whereas polyclonal T cell stimulation with anti-CD3 and anti-CD28 antibody yields Foxp3+ iTreg cells at a purity of 90–95%, antigen-induced iTreg cells typically do not exceed a purity of 65–75%, even in a TCR-transgenic model. In a similar vein to thymic Treg cell selection, iTreg cell differentiation is influenced not only by antigen recognition and the availability of TGF-β but also by co-factors including costimulation and adhesion molecules. In this study, we demonstrate that blockade of the T cell integrin Leukocyte Function-associated Antigen-1 (LFA-1) during antigen-mediated iTreg cell differentiation augments Foxp3 induction, leading to approximately 90% purity of Foxp3+ iTreg cells. This increased efficacy not only boosts the yield of Foxp3+ iTreg cells, it also reduces contamination with activated effector T cells, thus improving the safety of adoptive transfer immunotherapy., Highlights • iTreg cells can be generated in an antigen-specific manner, even if specific Tconv cells are present at low frequency. • Blockade of anti-LFA-1 during iTreg cell differentiation augments Foxp3 induction. • The blockade of LFA-1 alters the iTreg cell phenotype but does not impair stability or function.
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163. Cytotoxic T-cell recognition of influenza-infected target cells varies in different H-2k mouse strains
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Stringfellow, Margaret, Wraith, David C., and Askonas, Brigitte A.
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- 1983
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164. A role for major histocompatibility complex-binding peptides in the immunotherapy of autoimmune disease
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Wraith, David C. and Smilek, Dawn E.
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In conclusion, rapid advances in our understanding of the molecular basis of T cell recognition have revealed a number of approaches for immune intervention in autoimmune disease. Each procedure has been tried and tested in experimental models. Characterization of T cell recognition in human autoimmune disease is a step behind. However, their success in experimental models indicates that MHC-blocking peptides will find use both in identification of restriction elements for disease and in the prevention and treatment of human autoimmune conditions.
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- 1992
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165. Nr4a1 and Nr4a3 Reporter Mice Are Differentially Sensitive to T Cell Receptor Signal Strength and Duration
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Jennings, Emma, Elliot, Thomas A.E., Thawait, Natasha, Kanabar, Shivani, Yam-Puc, Juan Carlos, Ono, Masahiro, Toellner, Kai-Michael, Wraith, David C., Anderson, Graham, and Bending, David
- Abstract
Nr4areceptors are activated by T cell receptor (TCR) signaling and play key roles in T cell differentiation. Which TCR signaling pathways regulate Nr4a receptors and their sensitivities to TCR signal strength and duration remains unclear. Using Nr4a1/Nur77-GFP and Nr4a3-Timer of cell kinetics and activity (Tocky) mice, we elucidate the signaling pathways governing Nr4a receptor expression. We reveal that Nr4a1–Nr4a3are Src family kinase dependent. Moreover, Nr4a2and Nr4a3are attenuated by calcineurin inhibitors and bind nuclear factor of activated T cells 1 (NFAT1), highlighting a necessary and sufficient role for NFAT1 in the control of Nr4a2and Nr4a3,but redundancy for Nr4a1. Nr4a1-GFP is activated by tonic and cognate signals during T cell development, whereas Nr4a3-Tocky requires cognate peptide:major histocompatibility complex (MHC) interactions for expression. Compared to Nr4a3-Tocky, Nr4a1-GFP is approximately 2- to 3-fold more sensitive to TCR signaling and is detectable by shorter periods of TCR signaling. These findings suggest that TCR signal duration may be an underappreciated aspect influencing the developmental fate of T cells in vivo.
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- 2020
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166. Chromatin Priming Renders T Cell Tolerance-Associated Genes Sensitive to Activation below the Signaling Threshold for Immune Response Genes
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Bevington, Sarah L., Ng, Sky T.H., Britton, Graham J., Keane, Peter, Wraith, David C., and Cockerill, Peter N.
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Immunological homeostasis in T cells is maintained by a tightly regulated signaling and transcriptional network. Full engagement of effector T cells occurs only when signaling exceeds a critical threshold that enables induction of immune response genes carrying an epigenetic memory of prior activation. Here we investigate the underlying mechanisms causing the suppression of normal immune responses when T cells are rendered anergic by tolerance induction. By performing an integrated analysis of signaling, epigenetic modifications, and gene expression, we demonstrate that immunological tolerance is established when both signaling to and chromatin priming of immune response genes are weakened. In parallel, chromatin priming of immune-repressive genes becomes boosted, rendering them sensitive to low levels of signaling below the threshold needed to activate immune response genes. Our study reveals how repeated exposure to antigens causes an altered epigenetic state leading to T cell anergy and tolerance, representing a basis for treating auto-immune diseases.
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- 2020
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167. Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy
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Wraith, David C., primary, Smilek, Dawn E., additional, Mitchell, Dennis J., additional, Steinman, Lawrence, additional, and McDevitt, Hugh O., additional
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- 1989
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168. The recognition of influenza A virus- infected cells by cytotoxic T lymphocytes
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Wraith, David C., primary
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- 1987
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169. T cell recognition as the target for immune intervention in autoimmune disease
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Wraith, David C., primary, McDevitt, Hugh O., additional, Steinman, Lawrence, additional, and Acha-Orbea, Hans, additional
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- 1989
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170. CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire.
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Verhagen, Johan, Genolet, Raphaël, Britton, Graham J., Stevenson, Brian J., Sabatos-Peyton, Catherine A., Dyson, Julian, Luescher, Immanuel F., and Wraith, David C.
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THYMUS physiology ,CYTOTOXIC T cells ,T cell receptors ,IMMUNE response ,THYMIC hormones ,ANIMAL models of immunology ,LABORATORY mice - Abstract
The article discusses a study on role of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) in the thymic development of conventional and regulatory T cells (Tconv and Treg). It examines the mechanism of the immunological process of central tolerance in the thymus, such as the selection of T-cell receptor (TCR) and negative selection. It states that the location of CTLA-4 in the corticomedullary region in mice suggests that it influences thymic development of Tconv and Treg cells.
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- 2013
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171. HSP60 as an autoantigen in obesity.
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Emrah Şelli, M., Newby, Andrew C., and Wraith, David C.
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AUTOANTIGENS ,ANIMAL models in research ,OBESITY ,IMMUNOTHERAPY ,AUTOIMMUNITY ,EFFECT of drugs on T cells ,MITOCHONDRIAL proteins - Abstract
Although the association of a chronic low-grade inflammation with obesity has long been appreciated, its molecular basis is yet to be defined. The proven involvement of adaptive immunity, coupled with a phenotypic switch from autoimmune suppressive tolerogenic Treg to pro-inflammatory CD4+ Th1 and CD8+ T cells, during progression of obesity necessitates the presence of a triggering antigen as an activator of T and B cells. Not surprisingly in this context, it is found that visceral adipose tissue-specific T cells show severely biased T cell receptor Vα repertoires in diet induced obese mice (Winer et al. 2009), implying an antigen-specific clonal expansion of T cells during obesity. HSP60 is an evolutionary conserved mitochondrial chaperonin that assists the correct folding of other mitochondrial proteins. However, its occurrence is not restricted to mitochondria and it can be located in the cytosol or exposed on the cell membrane also. An increase in cell membrane HSP60, which may be accompanied by HSP60 release into circulation, is especially considered a signal of autoimmunity. HSP60 has been associated with a broad range of diseases so far, particularly those with an autoimmune component. More recently, HSP60 is also linked to obesity as a mediator of adipose tissue inflammation and insulin resistance. Moreover, circulating HSP60 levels are found to be higher in obese individuals than lean controls (Märker et al. 2012). We observed an adaptive immune response against HSP60 at both T cell and B cell (antibody) levels during continuous high fat feeding of C57bl6 mice. Hence HSP60 appears to be one of the mystery auto-antigens triggering the early T and B cell responses during obesity. Furthermore, we attempted a peptide therapy in a dose escalation protocol aiming to down-regulate the inflammatory related adverse effects of obesity by achieving tolerance in T cell populations and suppressing the pathogenic antibody response. Treatment with a mixture of three proven immunomodulatory HSP60 peptides did not reduce weight but completely reversed the increase in VLDL/LDL levels and partially reversed the glucose intolerance in obese mice, which encourages further research to improve peptide therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2016
172. A new humanized mouse model for autoimmune cardiomyopathy and its use to devise immunomodulation therapy.
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Emrah Şelli, M., Newby, Andrew C., and Wraith, David C.
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CARDIOMYOPATHIES ,IMMUNOREGULATION ,MYOSIN ,LABORATORY mice ,HLA histocompatibility antigens - Abstract
Myocarditis is the principal cause of heart failure in young adults. Frequently triggered acutely by an episode of viral infection, its progression to dilated cardiomyopathy is associated with the development of auto-immunity, especially to human cardiac α-myosin (hCAM). Consistent with this, HLA genotype influences prevalence of the disease. Previous studies showed that humanised DQ8 transgenic non-obese diabetic mice spontaneously developed autoimmune cardiomyopathy, whereas the DR4 allele is over represented in patients and there is no association with diabetes. We therefore attempted to induce experimental autoimmune myocarditis in DR4 transgenic mice (DR4 mice) as a more relevant model of the human disease. DR4 mice were injected with purified hCAM or vehicle subcutaneously in complete Freund's adjuvant (CFA). After 3 weeks, anesthetized mice were subjected to cardiac ultrasonography, following which blood was obtained from the abdominal aorta under terminal anaesthesia. The hearts were then perfused fixed for histology and spleens were harvested for proliferation assay. Potential immunomodulatory peptides were predicted in silico. Peptides were then proven water soluble and effective in T-cell proliferation assays. For immunotherapy, mice were pre-dosed with escalating doses of mixtures of 3 each of 6 soluble hCAM-derived peptides (pools 1 and 2) according to an established protocol. DR4 mice did not develop spontaneous myocarditis. However, all mice immunized with hCAM developed high titres of both IgG1 and IgG2c antibodies. Consistent with this, splenic T-cell proliferation responses to hCAM significantly increased compared to un-immunized mice. DR4 mice immunized with hCAM failed to gain weight and by echocardiography showed a significant decline in cardiac output and fractional shortening and increase in diastolic dimension compared to those injected with PBS in CFA alone. 5/5 immunized vs 0/5 control mice showed cardiac inflammation based on histology. 3/5 immunized mice died if the experiment was prolonged for 6 weeks. Pre-treatment with hCAM derived peptide pools 1 or 2 blunted the T-cell proliferation response and pool 2 also decreased both IgG1 and IgG2c levels. Pools 1 and 2 significantly improved the left ventricular cardiac function by increasing the percentage of ejection fraction and fractional shortening. Pool 2 also significantly reduced cardiac inflammation. We have developed a novel, more relevant humanized mouse model of autoimmune cardiomyopathy and demonstrated its ability to validate the immunomodulatory activity of hCAM derived peptides. Further use of our approach should prove valuable in developing optimized, clinically applicable peptide cocktails to prevent the progression of myocarditis to dilated cardiomyopathy. [ABSTRACT FROM AUTHOR]
- Published
- 2016
173. SARS-CoV-2 infection is associated with anti-desmoglein 2 autoantibody detection.
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Ward, Kerensa E, Steadman, Lora, Karim, Abid R, Reynolds, Gary M, Pugh, Matthew, Chua, Winnie, Faustini, Sian E, Veenith, Tonny, Thwaites, Ryan S, Openshaw, Peter J M, Drayson, Mark T, Shields, Adrian M, Cunningham, Adam F, Wraith, David C, and Richter, Alex G
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AUTOANTIBODIES , *CONVALESCENT plasma , *COVID-19 , *SARS-CoV-2 , *BLOOD proteins , *AUTOIMMUNE diseases - Abstract
Post-acute cardiac sequelae, following SARS-CoV-2 infection, are well recognized as complications of COVID-19. We have previously shown the persistence of autoantibodies against antigens in skin, muscle, and heart in individuals following severe COVID-19; the most common staining on skin tissue displayed an inter-cellular cement pattern consistent with antibodies against desmosomal proteins. Desmosomes play a critical role in maintaining the structural integrity of tissues. For this reason, we analyzed desmosomal protein levels and the presence of anti-desmoglein (DSG) 1, 2, and 3 antibodies in acute and convalescent sera from patients with COVID-19 of differing clinical severity. We find increased levels of DSG2 protein in sera from acute COVID-19 patients. Furthermore, we find that DSG2 autoantibody levels are increased significantly in convalescent sera following severe COVID-19 but not in hospitalized patients recovering from influenza infection or healthy controls. Levels of autoantibody in sera from patients with severe COVID-19 were comparable to levels in patients with non-COVID-19-associated cardiac disease, potentially identifying DSG2 autoantibodies as a novel biomarker for cardiac damage. To determine if there was any association between severe COVID-19 and DSG2, we stained post-mortem cardiac tissue from patients who died from COVID-19 infection. This confirmed DSG2 protein within the intercalated discs and disruption of the intercalated disc between cardiomyocytes in patients who died from COVID-19. Our results reveal the potential for DSG2 protein and autoimmunity to DSG2 to contribute to unexpected pathologies associated with COVID-19 infection. We find raised levels of anti-DSG2 autoantibodies in sera from individuals following severe COVID-19. Staining of post-mortem cardiac tissue from individuals that died from COVID-19 with an anti-DSG2 antibody revealed disruption of the intercalated disc between cardiomyocytes that was consistent with separation of the DSG2 protein homodimer. Our results reveal the potential for DSG2 protein and autoimmunity to DSG2 to contribute to unexpected pathologies associated with COVID-19 infection. [ABSTRACT FROM AUTHOR]
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- 2023
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174. Human Mesenchymal Stem Cells Infiltrate the Spinal Cord, Reduce Demyelination, and Localize to White Matter Lesions in Experimental Autoimmune Encephalomyelitis
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Gordon, David, Pavlovska, Gordana, Uney, James B., Wraith, David C., and Scolding, Neil J.
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Mesenchymal stem cells (MSCs) can abrogate the animal model ofmultiple sclerosis, experimental autoimmune encephalomyelitis (EAE), but whether this therapeutic effect occurs entirely through systemic immune modulation and whether CNS infiltration occurs after peripheral delivery are uncertain. We studied the clinical and neuropathologic effects of intravenously administered human MSCs (hMSCs) in C57BL/6 mice with EAE. Human MSCs significantly reduced the clinical disease severity, particularly in later disease. Large numbers of hMSCs migrated into gray and white matter at all levels of the spinal cord in both naive mice and mice with EAE. In the latter, hMSCs accumulated over time in demyelinated areas. There were 2 distinct morphological appearances of the hMSCs in the tissue, that is, rounded and less numerous process-bearing forms; very few expressed neural markers. The number of spinal cord white matter lesions and areas of white matter demyelination were reduced after hMSC treatment compared with control treatment. These findings show that central nervous system infiltration occurs after peripheral delivery of hMSCs, that they accumulate where there is myelin damage, and that they are associated with a reduced extent ofdemyelination. These data support a potential role for hMSCs in autologous cell therapy in multiple sclerosis.
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- 2010
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175. Human CD4+CD25+CD127−T Cells Show Potent Dose-Dependent Inhibition of Allogeneic DC-Driven MLRs.
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Protheroe, Rachel E., Steward, Colin G., Mazza, Graziella, and Wraith, David C.
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Graft versus host disease (GVHD) is the primary cause of transplant related morbidity and mortality, limiting the widespread application of haemopoietic stem cell transplantation (HSCT). Evidence from murine models supports the role of CD4+CD25+regulatory T cells in the suppression of GVHD. Human evidence regarding the role of regulatory T cells in alloresponses is conflicting and may reflect the difficulty in defining and isolating the regulatory T cell population in humans. We have investigated the use of peripheral blood monocyte-derived dendritic cells (DCs) as stimulator cells in allogeneic mixed lymphocyte reactions (MLRs), as a means of assessing the in vitrosuppressive function of regulatory T cells in human alloresponses. Peripheral blood mononuclear cells (PBMCs) were obtained from healthy adult volunteers. Magnetically isolated CD4+CD25+T cells were combined with 50×103autologous PBMCs or 20×103autologous CD4+T cells as responders, and 5×103allogeneic irradiated DCs. Proliferation was assessed by tritiated thymidine incorporation. The CD4+CD25+cells were anergic and demonstrated dose-dependent suppression of responder cell proliferation in the DC-driven allogeneic MLR. Greater than 50% suppression was seen with CD4+CD25+T cells co-cultured with responder PBMCs at ratios of 1:4 to 1:32. Furthermore, depletion of CD4+CD25+T cells from whole CD4+responder cells resulted in enhanced proliferation and an increase in the amplitude of the MLR. Flow cytometry indicated that the majority of the magnetically isolated CD4+CD25+T cells were FoxP3+on intracellular staining and demonstrated down-regulation of cell surface expression of the IL-7 receptor (CD127). The potent suppression demonstrated here by CD4+CD25+CD127−T cells at ratios of 1:32 responder cells, suggests that these cells have a potential role for suppressing alloresponses at physiological levels. Moreover, this assay provides the basis for future investigation into regulatory T cell function in patients post-HSCT.
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- 2006
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176. Extra-thymically induced T regulatory cell subsets: the optimal target for antigen-specific immunotherapy.
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Verhagen, Johan, Wegner, Anja, and Wraith, David C.
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IMMUNOTHERAPY , *AUTOIMMUNE diseases , *ALLERGIES , *IMMUNOSUPPRESSION , *IMMUNOSPECIFICITY , *INTERLEUKIN-10 - Abstract
Antigen-specific immunotherapy aims to selectively restore tolerance to innocuous antigens in cases of autoimmune or allergic disease, without the need for general immune suppression. Although the principle of antigen-specific immunotherapy was discovered more than a century ago, its clinical application to date is limited, particularly in the control of autoimmunity. This has resulted mainly from a lack of in-depth understanding of the underlying mechanism. More recently, the differentiation of extra-thymically induced T regulatory ( Treg) cell subsets has been shown to be instrumental in peripheral tolerance induction. Two main types of inducible Treg cells, interleukin-10-secreting or Foxp3+, have now been described, each with distinct characteristics and methods of therapeutic induction. It is crucial, therefore, to identify the suitability of either subset in the control of specific immune disorders. This review explores their natural function, the known mechanisms of therapeutic differentiation of either subset as well as their in vivo functionality and discusses new developments that may aid their use in antigen-specific immunotherapy, with a focus on autoimmune disease. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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177. Antigen-specific immunotherapy of autoimmune and allergic diseases
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Sabatos-Peyton, Catherine A, Verhagen, Johan, and Wraith, David C
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IMMUNOTHERAPY , *AUTOIMMUNE disease treatment , *ALLERGY treatment , *BIOCHEMICAL mechanism of action , *GENETIC regulation , *IMMUNOLOGICAL tolerance , *ANTIGENS - Abstract
Nearly a century has passed since the first report describing antigen-specific immunotherapy (antigen-SIT) was published. Research into the use of antigen-SIT in the treatment of both allergic and autoimmune disease has increased dramatically since, although its mechanism of action is only slowly being unravelled. It is clear though, from recent studies, that success of antigen-SIT depends on the induction of regulatory T (T reg) cell subsets that recognise potentially disease-inducing epitopes. The major challenge remaining for the widespread use of antigen-SIT is to safely administer high doses of immunodominant and potentially pathogenic epitopes in a manner that induces T cell tolerance rather than activation. This review illustrates that intelligent design of treatment agents and strategies can lead to the development of safe and effective antigen-SIT. [ABSTRACT FROM AUTHOR]
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- 2010
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178. IL-10 is essential for disease protection following intranasal peptide administration in the C57BL/6 model of EAE
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O’Neill, Emma J., Day, Michael J., and Wraith, David C.
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CENTRAL nervous system diseases , *PEPTIDE drugs , *HISTOPATHOLOGY , *MICE - Abstract
Abstract: We have shown previously that intranasal administration of encephalitogenic peptides in soluble form to H-2u and H-2s mice affords protection from experimental autoimmune encephalomyelitis (EAE). Here we demonstrate that this method of disease protection can be induced in C57BL/6 mice by administration of the soluble peptide 35–55 from myelin oligodendrocyte glycoprotein. This protective effect was demonstrated by the evaluation of both clinical EAE scores and central nervous system histopathology; the latter showing minimal inflammatory infiltrates in treated mice. The employment of an IL-10−/− congenic strain allowed an appraisal of the involvement of IL-10 in this process. The lack of disease protection in these mice clearly demonstrates the non-redundant role of IL-10 in this process. [Copyright &y& Elsevier]
- Published
- 2006
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179. Activation thresholds determine susceptibility to peptide-induced tolerance in a heterogeneous myelin-reactive T cell repertoire
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McCue, David, Ryan, Kelli R., Wraith, David C., and Anderton, Stephen M.
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T cells , *CYTOCHROMES , *LYMPHOCYTES , *CENTRAL nervous system diseases , *BASIC proteins - Abstract
Altered peptide ligands (APL) with increased MHC-binding properties are highly effective at inducing T cell tolerance after systemic administration in soluble form, preventing experimental autoimmune encephalomyelitis (EAE) induced with the myelin basic protein (MBP) Ac1-9 peptide. We have previously described a diverse Ac1-9-reactive T cell repertoire with differing TCR affinities. A remaining question is what proportion of this repertoire is silenced by peptide therapy? Here, we show that the sensitivity of a T cell to peptide-induced tolerance is related to its avidity for native Ac1-9. These data provide new evidence that self-reactive T cells bearing low-affinity TCRs are able to escape therapeutic induction of tolerance. [Copyright &y& Elsevier]
- Published
- 2004
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180. Development of a high‐sensitivity ELISA detecting IgG, IgA and IgM antibodies to the SARS‐CoV‐2 spike glycoprotein in serum and saliva.
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Faustini, Sian E., Jossi, Sian E., Perez‐Toledo, Marisol, Shields, Adrian M., Allen, Joel D., Watanabe, Yasunori, Newby, Maddy L., Cook, Alex, Willcox, Carrie R., Salim, Mahboob, Goodall, Margaret, Heaney, Jennifer L., Marcial‐Juarez, Edith, Morley, Gabriella L., Torlinska, Barbara, Wraith, David C., Veenith, Tonny V., Harding, Stephen, Jolles, Stephen, and Ponsford, Mark J.
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IMMUNOGLOBULIN G , *SARS-CoV-2 , *IMMUNOGLOBULIN A , *SALIVA , *IMMUNOGLOBULINS - Abstract
Detecting antibody responses during and after SARS‐CoV‐2 infection is essential in determining the seroepidemiology of the virus and the potential role of antibody in disease. Scalable, sensitive and specific serological assays are essential to this process. The detection of antibody in hospitalized patients with severe disease has proven relatively straightforward; detecting responses in subjects with mild disease and asymptomatic infections has proven less reliable. We hypothesized that the suboptimal sensitivity of antibody assays and the compartmentalization of the antibody response may contribute to this effect. We systematically developed an ELISA, optimizing different antigens and amplification steps, in serum and saliva from non‐hospitalized SARS‐CoV‐2‐infected subjects. Using trimeric spike glycoprotein, rather than nucleocapsid, enabled detection of responses in individuals with low antibody responses. IgG1 and IgG3 predominate to both antigens, but more anti‐spike IgG1 than IgG3 was detectable. All antigens were effective for detecting responses in hospitalized patients. Anti‐spike IgG, IgA and IgM antibody responses were readily detectable in saliva from a minority of RT‐PCR confirmed, non‐hospitalized symptomatic individuals, and these were mostly subjects who had the highest levels of anti‐spike serum antibodies. Therefore, detecting antibody responses in both saliva and serum can contribute to determining virus exposure and understanding immune responses after SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]
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- 2021
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181. Establishing the prevalence of common tissue‐specific autoantibodies following severe acute respiratory syndrome coronavirus 2 infection.
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Richter, Alex G., Shields, Adrian M., Karim, Abid, Birch, David, Faustini, Sian E., Steadman, Lora, Ward, Kerensa, Plant, Timothy, Reynolds, Gary, Veenith, Tonny, Cunningham, Adam F., Drayson, Mark T., and Wraith, David C.
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COVID-19 , *AUTOANTIBODIES , *VIRUS diseases , *RESPIRATORY infections , *SARS-CoV-2 - Abstract
Summary: Coronavirus 19 (COVID‐19) has been associated with both transient and persistent systemic symptoms that do not appear to be a direct consequence of viral infection. The generation of autoantibodies has been proposed as a mechanism to explain these symptoms. To understand the prevalence of autoantibodies associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, we investigated the frequency and specificity of clinically relevant autoantibodies in 84 individuals previously infected with SARS‐CoV‐2, suffering from COVID‐19 of varying severity in both the acute and convalescent setting. These were compared with results from 32 individuals who were on the intensive therapy unit (ITU) for non‐COVID reasons. We demonstrate a higher frequency of autoantibodies in the COVID‐19 ITU group compared with non‐COVID‐19 ITU disease control patients and that autoantibodies were also found in the serum 3–5 months post‐COVID‐19 infection. Non‐COVID patients displayed a diverse pattern of autoantibodies; in contrast, the COVID‐19 groups had a more restricted panel of autoantibodies including skin, skeletal muscle and cardiac antibodies. Our results demonstrate that respiratory viral infection with SARS‐CoV‐2 is associated with the detection of a limited profile of tissue‐specific autoantibodies, detectable using routine clinical immunology assays. Further studies are required to determine whether these autoantibodies are specific to SARS‐CoV‐2 or a phenomenon arising from severe viral infections and to determine the clinical significance of these autoantibodies. [ABSTRACT FROM AUTHOR]
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- 2021
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182. SARS‐CoV‐2‐specific IgG1/IgG3 but not IgM in children with Pediatric Inflammatory Multi‐System Syndrome.
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Perez‐Toledo, Marisol, Faustini, Sian E., Jossi, Sian E., Shields, Adrian M., Marcial‐Juarez, Edith, Kanthimathinathan, Hari Krishnan, Allen, Joel D., Watanabe, Yasunori, Goodall, Margaret, Willcox, Benjamin E., Willcox, Carrie R., Salim, Mahboob, Wraith, David C., Veenith, Tonny V., Syrimi, Eleni, Drayson, Mark T., Jyothish, Deepthi, Al‐Abadi, Eslam, Chikermane, Ashish, and Welch, Steven B.
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COVID-19 , *CHILD patients , *TOXIC shock syndrome , *MEDICAL personnel , *VIRAL antibodies - Abstract
Although anti-S IgA and IgG were more similar in children and adult COVID-19 patients, anti-N IgA and IgG antibodies were higher in ITU patients (Figure 1C,D). Since antibody isotypes can reflect recent infection (IgM), or more historic infections (IgG and IgA), we examined individual antibody isotypes and presented these results as area under the curve (AUC). Therefore, children with Kawasaki-like inflammatory syndrome, negative by PCR, can have IgG1, IgG3, and IgA antibody levels to SARS-CoV-2 in the absence of maintained IgM responses. Screening of sera, diluted 1:40, to detect IgG, IgA, and IgM demonstrated that all children had antibodies against the SARS-CoV-2 S glycoprotein (Figure 1A). [Extracted from the article]
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- 2021
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183. Nanoparticle-based autoantigen delivery to Treg-inducing liver sinusoidal endothelial cells enables control of autoimmunity in mice.
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Carambia, Antonella, Freund, Barbara, Schwinge, Dorothee, Bruns, Oliver T., Salmen, Sunhild C., Ittrich, Harald, Reimer, Rudolph, Heine, Markus, Huber, Samuel, Waurisch, Christian, Eychmüller, Alexander, Wraith, David C., Korn, Thomas, Nielsen, Peter, Weller, Horst, Schramm, Christoph, Lüth, Stefan, Lohse, Ansgar W., Heeren, Joerg, and Herkel, Johannes
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LIVER disease treatment , *NANOMEDICINE , *AUTOANTIGENS , *ENDOTHELIAL cells , *AUTOIMMUNITY , *LABORATORY mice - Abstract
Background & Aims It is well-known that the liver can induce immune tolerance, yet this knowledge could, thus far, not be translated into effective treatments for autoimmune diseases. We have previously shown that liver sinusoidal endothelial cells (LSECs) could substantially contribute to hepatic tolerance through their ability to induce CD4+ Foxp3+ regulatory T cells (Tregs). Here, we explored whether the Treg-inducing potential of LSECs could be harnessed for the treatment of autoimmune disease. Methods We engineered a polymeric nanoparticle (NP) carrier for the selective delivery of autoantigen peptides to LSECs in vivo . In the well-characterized autoimmune disease model of experimental autoimmune encephalomyelitis (EAE), we investigated whether administration of LSEC-targeting autoantigen peptide-loaded NPs could protect mice from autoimmune disease. Results We demonstrate that NP-based autoantigen delivery to LSECs could completely and permanently prevent the onset of clinical EAE. More importantly, in a therapeutic approach, mice with already established EAE improved rapidly and substantially following administration of a single dose of autoantigen peptide-loaded NPs, whereas the control group deteriorated. Treatment efficacy seemed to depend on Tregs. The Treg frequencies in the spleens of mice treated with autoantigen peptide-loaded NPs were significantly higher than those in vehicle-treated mice. Moreover, NP-mediated disease control was abrogated after Treg depletion by repeated administration of Treg-depleting antibody. Conclusion Our findings provide proof of principle that the selective delivery of autoantigen peptides to LSECs by NPs can induce antigen-specific Tregs and enable effective treatment of autoimmune disease. These findings highlight the importance of Treg induction by LSECs for immune tolerance. [ABSTRACT FROM AUTHOR]
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- 2015
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184. TGF-β-dependent induction of CD4+CD25+Foxp3+ Tregs by liver sinusoidal endothelial cells.
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Carambia, Antonella, Freund, Barbara, Schwinge, Dorothee, Heine, Markus, Laschtowitz, Alena, Huber, Samuel, Wraith, David C., Korn, Thomas, Schramm, Christoph, Lohse, Ansgar W., Heeren, Joerg, and Herkel, Johannes
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TRANSFORMING growth factors , *CD4 antigen , *T cells , *ENDOTHELIAL cells , *IMMUNE response , *LIVER cells , *ANTIGEN presenting cells - Abstract
CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) have a profound ability to control immune responses. We have previously shown that the liver is a major source of peripherally induced Tregs. Here, we investigate the liver cell types and molecular mechanisms responsible for hepatic Treg induction. Methods To assess the Treg-inducing potential of liver resident antigen-presenting cell types, we studied the conversion of Foxp3− non-Tregs into Foxp3+ Tregs induced by liver dendritic cells (DCs), liver sinusoidal endothelial cells (LSECs), or Kupffer cells (KCs). The dependency of Treg induction on TGF-β was tested in Treg conversion assays using T cells with reduced TGF-β sensitivity. The suppressive potential of liver cell-induced Tregs was assessed by an in vitro suppression assay and in vivo, in the model of experimental autoimmune encephalomyelitis (EAE). Results All tested liver cell types were capable of inducing Foxp3+ Tregs; however, LSECs were most efficient in inducing Tregs. Treg-induction was antigen-specific and depended on TGF-β. LSECs featured membrane-bound LAP/TGF-β and the anchor molecule GARP, which is required for tethering LAP/TGF-β to the cell membrane. LSEC-induced Tregs suppressed proliferation and cytokine secretion of effector T cells in vitro. LSEC-induced Tregs were also functional suppressors in vivo, as neuroantigen-specific Tregs induced by LSECs were able to suppress EAE. Conclusions We demonstrate that LSECs are the major liver cell type responsible for TGF-β dependent hepatic Treg induction. The extraordinary capacity of LSECs to induce Tregs was associated with their unique ability to tether TGF-β to their membrane. [ABSTRACT FROM AUTHOR]
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- 2014
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185. CD4+ T-cell epitopes associated with antibody responses after intravenously and subcutaneously applied human FVHI in humanized hemophilic E17 HLA-DRB1*1501 mice.
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Steinitz, Katharina N., van Helden, Pauline M., Binder, Brigitte, Wraith, David C., Unterthumer, Sabine, Hermann, Corinna, Schuster, Maria, Ahmad, Rati U., Weiller, Markus, Lubich, Christian, de la Rosa, Maurus, Schwarz, Hans Peter, and Reipert, Birgit M.
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CD4 antigen , *EPITOPES , *T cells , *IMMUNOGLOBULINS , *IMMUNE response , *LABORATORY mice - Abstract
Today it is generally accepted that B cells require cognate interactions with CD4+ T cells to develop high-affinity antibodies against proteins. CD4+ T ceils recognize peptides (epitopes) presented by MHC class II molecules that are expressed on antigen-presenting cells. Structural features of both the MHC class II molecule and the peptide determine the specificity of CD4+ T cells that can bind to the MHC class ll-peptide complex. We used a new humanized hemophilic mouse model to identify FVIII peptides presented by HLA-DRB1*1501. This model carries a knockout of all murine MHC class II molecules and expresses a chimeric murine-human MHC class II complex that contains the peptide-binding sites of the human HLA-DRB1*1501. When mice were treated with human FVIII, the proportion of mice that developed antibodies depended on the application route of FVIII and the activation state of the innate immune system. We identified 8 FVIII peptide regions that contained CD4+ T-ceil epitopes presented by HLA-DRB1*1501 to CD4+ T cells during immune responses against FVIII. CD4+ T-cell responses after intravenous and subcutaneous application of FVIII involved the same immunodominant FVIII epitopes. Interestingly, most of the 8 peptide regions contained promiscuous epitopes that bound to several different HLA-DR proteins in in vitro binding assays. [ABSTRACT FROM AUTHOR]
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- 2012
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186. Antigen and checkpoint receptor engagement recalibrates T cell receptor signal strength.
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Elliot, Thomas A.E., Jennings, Emma K., Lecky, David A.J., Thawait, Natasha, Flores-Langarica, Adriana, Copland, Alastair, Maslowski, Kendle M., Wraith, David C., and Bending, David
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T cell receptors , *ANTIGEN receptors , *IMMUNE checkpoint proteins , *CELL communication , *T cells - Abstract
How T cell receptor (TCR) signal strength modulates T cell function and to what extent this is modified by immune checkpoint blockade (ICB) are key questions in immunology. Using Nr4a3 -Tocky mice, we characterized early quantitative and qualitative changes that occur in CD4+ T cells in relation to TCR signaling strength. We captured how dose- and time-dependent programming of distinct co-inhibitory receptors rapidly recalibrates T cell activation thresholds and visualized the immediate effects of ICB on T cell re-activation. Our findings reveal that anti-PD1 immunotherapy leads to an increased TCR signal strength. We defined a strong TCR signal metric of five genes upregulated by anti-PD1 in T cells (TCR.strong), which was superior to a canonical T cell activation gene signature in stratifying melanoma patient outcomes to anti-PD1 therapy. Our study therefore reveals how analysis of TCR signal strength—and its manipulation—can provide powerful metrics for monitoring outcomes to immunotherapy. [Display omitted] • TCR signal strength drives dynamic and time-dependent changes in CD4+ T cells • Inhibitory receptor expression recalibrates T cell activation thresholds • PD1 blockade leads to a strong TCR signal signature in T cells (TCR.strong) • TCR.strong can stratify melanoma patient responses to anti-PD1 therapy How antigen and immune checkpoint engagement regulate T cell function is not completely understood. Elliot et al. reveal how antigen abundance regulates immune checkpoint expression and recalibrates T cell activation thresholds. PD1 blockade lowers the T cell activation threshold, resulting in a transcriptional signature that stratifies responses to immunotherapy. [ABSTRACT FROM AUTHOR]
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- 2021
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187. Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs.
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Lüth, Stefan, Huber, Samuel, Schramm, Christoph, Buch, Thorsten, Zander, Stefan, Stadelmann, Christine, Brück, Wolfgang, Wraith, David C., Herkel, Johannes, Lohse, Ansgar W., Lüth, Stefan, and Brück, Wolfgang
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IMMUNOLOGICAL tolerance , *ANTIGENS , *AUTOIMMUNE diseases , *IMMUNOTHERAPY , *LIVER , *MYELIN basic protein , *MICE , *GENETIC transformation , *LIVER cells , *ANIMAL experimentation , *BRAIN , *COMPARATIVE studies , *DEMYELINATION , *GENES , *RESEARCH methodology , *MEDICAL cooperation , *NERVE tissue proteins , *NEURONS , *RESEARCH , *RESEARCH funding , *T cells , *THYMUS , *TIME , *EVALUATION research , *PREVENTION - Abstract
Tregs are important mediators of immune tolerance to self antigens, and it has been suggested that Treg inactivation may cause autoimmune disease. Therefore, immunotherapy approaches that aim to restore or expand autoantigen-specific Treg activity might be beneficial for the treatment of autoimmune disease. Here we report that Treg-mediated suppression of autoimmune disease can be achieved in vivo by taking advantage of the ability of the liver to promote immune tolerance. Expression of the neural autoantigen myelin basic protein (MBP) in the liver was accomplished stably in liver-specific MBP transgenic mice and transiently using gene transfer to liver cells in vivo. Such ectopic MBP expression induced protection from autoimmune neuroinflammation in a mouse model of multiple sclerosis. Protection from autoimmunity was mediated by MBP-specific CD4+CD25+Foxp3+ Tregs, as demonstrated by the ability of these cells to prevent disease when adoptively transferred into nontransgenic mice and to suppress conventional CD4+CD25- T cell proliferation after antigen-specific stimulation with MBP in vitro. The generation of MBP-specific CD4+CD25+Foxp3+ Tregs in vivo depended on expression of MBP in the liver, but not in skin, and occurred by TGF-beta-dependent peripheral conversion from conventional non-Tregs. Our findings indicate that autoantigen expression in the liver may generate autoantigen-specific Tregs. Thus, targeting of autoantigens to hepatocytes may be a novel approach to prevention or treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]
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- 2008
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188. A LAT-Based Signaling Complex in the Immunological Synapse as Determined with Live Cell Imaging Is Less Stable in T Cells with Regulatory Capability.
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Li, Yikui, Tunbridge, Helen M., Britton, Graham J., Hill, Elaine V., Sinai, Parisa, Cirillo, Silvia, Thompson, Clare, Fallah-Arani, Farnaz, Dovedi, Simon J., Wraith, David C., Wülfing, Christoph, Schütz, Gerhard J., and Huppa, Johannes
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SUPPRESSOR cells , *CELL imaging , *MYELIN basic protein , *T cells , *T cell receptors , *ANTIGEN presenting cells , *ADAPTOR proteins , *SYNAPSES - Abstract
Peripheral immune regulation is critical for the maintenance of self-tolerance. Here we have investigated signaling processes that distinguish T cells with regulatory capability from effector T cells. The murine Tg4 T cell receptor recognizes a peptide derived from the self-antigen myelin basic protein. T cells from Tg4 T cell receptor transgenic mice can be used to generate effector T cells and three types of T cells with regulatory capability, inducible regulatory T cells, T cells tolerized by repeated in vivo antigenic peptide exposure or T cells treated with the tolerogenic drug UCB9608 (a phosphatidylinositol 4 kinase IIIβ inhibitor). We comparatively studied signaling in all of these T cells by activating them with the same antigen presenting cells presenting the same myelin basic protein peptide. Supramolecular signaling structures, as efficiently detected by large-scale live cell imaging, are critical mediators of T cell activation. The formation of a supramolecular signaling complex anchored by the adaptor protein linker for activation of T cells (LAT) was consistently terminated more rapidly in Tg4 T cells with regulatory capability. Such termination could be partially reversed by blocking the inhibitory receptors CTLA-4 and PD-1. Our work suggests that attenuation of proximal signaling may favor regulatory over effector function in T cells. [ABSTRACT FROM AUTHOR]
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- 2021
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189. Regulatory T Cell Migration Is Dependent on Glucokinase-Mediated Glycolysis
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Alberico L. Catapano, Maryam Jangani, Veronica De Rosa, Eleanor J. Ward, Andrea Baragetti, Guosu Wang, David C. Wraith, Claudio Mauro, Fabrizia Bonacina, Federica M. Marelli-Berg, Robert Haas, Klaus Okkenhaug, Madhav Kishore, Kenneth C. P. Cheung, David Coe, Giuseppe Danilo Norata, David M. Smith, Hongmei Fu, Giuseppe Matarese, Alessandra Colamatteo, Okkenhaug, Klaus [0000-0002-9432-4051], Apollo - University of Cambridge Repository, Kishore, Madhav, Cheung, Kenneth C. P., Fu, Hongmei, Bonacina, Fabrizia, Wang, Guosu, Coe, David, Ward, Eleanor J., Colamatteo, Alessandra, Jangani, Maryam, Baragetti, Andrea, Matarese, Giuseppe, Smith, David M., Haas, Robert, Mauro, Claudio, Wraith, David C., Okkenhaug, Klau, Catapano, Alberico L., De Rosa, Veronica, Norata, GIUSEPPE DANILO, and Marelli-Berg, Federica M.
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0301 basic medicine ,regulatory T cell ,Glycolysi ,migration ,Mice, Inbred Strain ,T-Lymphocytes, Regulatory ,regulatory T cells ,Mice ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Cell Movement ,Glucokinase ,Immunology and Allergy ,CTLA-4 Antigen ,Glycolysis ,Cytoskeleton ,Cells, Cultured ,Regulation of gene expression ,CD28 ,hemic and immune systems ,glycolysis ,Cell biology ,Infectious Diseases ,medicine.anatomical_structure ,Biochemistry ,030220 oncology & carcinogenesis ,mTOR ,Human ,Regulatory T cell ,Immunology ,Mice, Inbred Strains ,chemical and pharmacologic phenomena ,Mechanistic Target of Rapamycin Complex 2 ,Mechanistic Target of Rapamycin Complex 1 ,Biology ,Article ,03 medical and health sciences ,CD28 Antigens ,medicine ,Animals ,Humans ,CD28 Antigen ,PI3K/AKT/mTOR pathway ,Adaptor Proteins, Signal Transducing ,Animal ,030104 developmental biology ,CTLA-4 ,Phosphatidylinositol 3-Kinase ,Proto-Oncogene Proteins c-akt ,metabolism - Abstract
Summary Migration of activated regulatory T (Treg) cells to inflamed tissue is crucial for their immune-modulatory function. While metabolic reprogramming during Treg cell differentiation has been extensively studied, the bioenergetics of Treg cell trafficking remains undefined. We have investigated the metabolic demands of migrating Treg cells in vitro and in vivo. We show that glycolysis was instrumental for their migration and was initiated by pro-migratory stimuli via a PI3K-mTORC2-mediated pathway culminating in induction of the enzyme glucokinase (GCK). Subsequently, GCK promoted cytoskeletal rearrangements by associating with actin. Treg cells lacking this pathway were functionally suppressive but failed to migrate to skin allografts and inhibit rejection. Similarly, human carriers of a loss-of-function GCK regulatory protein gene—leading to increased GCK activity—had reduced numbers of circulating Treg cells. These cells displayed enhanced migratory activity but similar suppressive function, while conventional T cells were unaffected. Thus, GCK-dependent glycolysis regulates Treg cell migration., Graphical Abstract, Highlights • Migration of regulatory T (Treg) cells requires glycolysis • This is mediated by the enzyme glucokinase induced by a PI3K-mTORC2 pathway • Treg cells lacking this pathway are unable to localize to inflammatory sites • A loss-of-function GCK regulator gene causes enhanced motility of human Treg cells, Regulatory T cell localization to inflammatory sites is key to their homeostatic function. Kishore and colleagues demonstrate that Treg cell migration requires the activation of glycolysis by the enzyme glucokinase induced via a Treg cell-selective PI3K-mTORC2 pathway.
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- 2017
190. Incidence of immune-mediated inflammatory diseases following COVID-19: a matched cohort study in UK primary care.
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Syed U, Subramanian A, Wraith DC, Lord JM, McGee K, Ghokale K, Nirantharakumar K, and Haroon S
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- Adult, Humans, SARS-CoV-2, Post-Acute COVID-19 Syndrome, Incidence, Cohort Studies, Immunomodulating Agents, Primary Health Care, United Kingdom epidemiology, COVID-19 epidemiology, Diabetes Mellitus, Type 1
- Abstract
Background: Some patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) go on to experience post-COVID-19 condition or long COVID. Preliminary findings have given rise to the theory that long COVID may be due in part to a deranged immune response. In this study, we assess whether there is an association between SARS-CoV-2 infection and the incidence of immune-mediated inflammatory diseases (IMIDs)., Methods: Matched cohort study using primary care electronic health record data from the Clinical Practice Research Datalink Aurum database. The exposed cohort included 458,147 adults aged 18 years and older with a confirmed SARS-CoV-2 infection and no prior diagnosis of IMIDs. They were matched on age, sex, and general practice to 1,818,929 adults with no diagnosis of confirmed or suspected SARS-CoV-2 infection. The primary outcome was a composite of any of the following IMIDs: autoimmune thyroiditis, coeliac disease, inflammatory bowel disease (IBD), myasthenia gravis, pernicious anaemia, psoriasis, rheumatoid arthritis (RA), Sjogren's syndrome, systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1DM), and vitiligo. The secondary outcomes were each of these conditions separately. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for the primary and secondary outcomes, adjusting for age, sex, ethnic group, smoking status, body mass index, relevant infections, and medications., Results: Six hundred and nighty six (0.15%) and 2230 (0.12%) patients in the exposed and unexposed cohort developed an IMID during the follow-up period over 0.29 person-years, giving a crude incidence rate of 4.59 and 3.65 per 1000 person-years, respectively. Patients in the exposed cohort had a 22% increased risk of developing an IMID, compared to the unexposed cohort (aHR 1.22, 95% CI 1.12 to 1.33). The incidence of three IMIDs was significantly associated with SARS-CoV-2 infection. These were T1DM (aHR 1.56, 1.09 to 2.23), IBD (aHR 1.36, 1.18 to 1.56), and psoriasis (1.23, 1.05 to 1.42)., Conclusions: SARS-CoV-2 was associated with an increased incidence of IMIDs including T1DM, IBD and psoriasis. However, these findings could be potentially due to ascertainment bias. Further research is needed to replicate these findings in other populations and to measure autoantibody profiles in cohorts of individuals with COVID-19., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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191. Symptoms and risk factors for long COVID in non-hospitalized adults.
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Subramanian A, Nirantharakumar K, Hughes S, Myles P, Williams T, Gokhale KM, Taverner T, Chandan JS, Brown K, Simms-Williams N, Shah AD, Singh M, Kidy F, Okoth K, Hotham R, Bashir N, Cockburn N, Lee SI, Turner GM, Gkoutos GV, Aiyegbusi OL, McMullan C, Denniston AK, Sapey E, Lord JM, Wraith DC, Leggett E, Iles C, Marshall T, Price MJ, Marwaha S, Davies EH, Jackson LJ, Matthews KL, Camaradou J, Calvert M, and Haroon S
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- Adult, Cohort Studies, Ethnicity, Female, Humans, Male, Minority Groups, Retrospective Studies, Risk Factors, SARS-CoV-2, Post-Acute COVID-19 Syndrome, COVID-19 complications, COVID-19 epidemiology
- Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with a range of persistent symptoms impacting everyday functioning, known as post-COVID-19 condition or long COVID. We undertook a retrospective matched cohort study using a UK-based primary care database, Clinical Practice Research Datalink Aurum, to determine symptoms that are associated with confirmed SARS-CoV-2 infection beyond 12 weeks in non-hospitalized adults and the risk factors associated with developing persistent symptoms. We selected 486,149 adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection. Outcomes included 115 individual symptoms, as well as long COVID, defined as a composite outcome of 33 symptoms by the World Health Organization clinical case definition. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for the outcomes. A total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. The largest aHRs were for anosmia (aHR 6.49, 95% CI 5.02-8.39), hair loss (3.99, 3.63-4.39), sneezing (2.77, 1.40-5.50), ejaculation difficulty (2.63, 1.61-4.28) and reduced libido (2.36, 1.61-3.47). Among the cohort of patients infected with SARS-CoV-2, risk factors for long COVID included female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, obesity and a wide range of comorbidities. The risk of developing long COVID was also found to be increased along a gradient of decreasing age. SARS-CoV-2 infection is associated with a plethora of symptoms that are associated with a range of sociodemographic and clinical risk factors., (© 2022. The Author(s).)
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- 2022
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192. SARS-CoV-2 Spike- and Nucleoprotein-Specific Antibodies Induced After Vaccination or Infection Promote Classical Complement Activation.
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Lamerton RE, Marcial-Juarez E, Faustini SE, Perez-Toledo M, Goodall M, Jossi SE, Newby ML, Chapple I, Dietrich T, Veenith T, Shields AM, Harper L, Henderson IR, Rayes J, Wraith DC, Watson SP, Crispin M, Drayson MT, Richter AG, and Cunningham AF
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- Antibodies, Viral, Complement Activation, Complement C1q, Humans, Immunoglobulin G, Nucleoproteins, Spike Glycoprotein, Coronavirus, Vaccination, COVID-19, SARS-CoV-2
- Abstract
Antibodies specific for the spike glycoprotein (S) and nucleocapsid (N) SARS-CoV-2 proteins are typically present during severe COVID-19, and induced to S after vaccination. The binding of viral antigens by antibody can initiate the classical complement pathway. Since complement could play pathological or protective roles at distinct times during SARS-CoV-2 infection we determined levels of antibody-dependent complement activation along the complement cascade. Here, we used an ELISA assay to assess complement protein binding (C1q) and the deposition of C4b, C3b, and C5b to S and N antigens in the presence of antibodies to SARS-CoV-2 from different test groups: non-infected, single and double vaccinees, non-hospitalised convalescent (NHC) COVID-19 patients and convalescent hospitalised (ITU-CONV) COVID-19 patients. C1q binding correlates strongly with antibody responses, especially IgG1 levels. However, detection of downstream complement components, C4b, C3b and C5b shows some variability associated with the subject group from whom the sera were obtained. In the ITU-CONV, detection of C3b-C5b to S was observed consistently, but this was not the case in the NHC group. This is in contrast to responses to N, where median levels of complement deposition did not differ between the NHC and ITU-CONV groups. Moreover, for S but not N, downstream complement components were only detected in sera with higher IgG1 levels. Therefore, the classical pathway is activated by antibodies to multiple SARS-CoV-2 antigens, but the downstream effects of this activation may differ depending the disease status of the subject and on the specific antigen targeted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lamerton, Marcial-Juarez, Faustini, Perez-Toledo, Goodall, Jossi, Newby, Chapple, Dietrich, Veenith, Shields, Harper, Henderson, Rayes, Wraith, Watson, Crispin, Drayson, Richter and Cunningham.)
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- 2022
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193. Therapies for Long COVID in non-hospitalised individuals: from symptoms, patient-reported outcomes and immunology to targeted therapies (The TLC Study).
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Haroon S, Nirantharakumar K, Hughes SE, Subramanian A, Aiyegbusi OL, Davies EH, Myles P, Williams T, Turner G, Chandan JS, McMullan C, Lord J, Wraith DC, McGee K, Denniston AK, Taverner T, Jackson LJ, Sapey E, Gkoutos G, Gokhale K, Leggett E, Iles C, Frost C, McNamara G, Bamford A, Marshall T, Zemedikun DT, Price G, Marwaha S, Simms-Williams N, Brown K, Walker A, Jones K, Matthews K, Camaradou J, Saint-Cricq M, Kumar S, Alder Y, Stanton DE, Agyen L, Baber M, Blaize H, and Calvert M
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- COVID-19 Testing, Humans, Patient Reported Outcome Measures, Quality of Life, Syndrome, Post-Acute COVID-19 Syndrome, COVID-19 complications, COVID-19 therapy
- Abstract
Introduction: Individuals with COVID-19 frequently experience symptoms and impaired quality of life beyond 4-12 weeks, commonly referred to as Long COVID. Whether Long COVID is one or several distinct syndromes is unknown. Establishing the evidence base for appropriate therapies is needed. We aim to evaluate the symptom burden and underlying pathophysiology of Long COVID syndromes in non-hospitalised individuals and evaluate potential therapies., Methods and Analysis: A cohort of 4000 non-hospitalised individuals with a past COVID-19 diagnosis and 1000 matched controls will be selected from anonymised primary care records from the Clinical Practice Research Datalink, and invited by their general practitioners to participate on a digital platform (Atom5). Individuals will report symptoms, quality of life, work capability and patient-reported outcome measures. Data will be collected monthly for 1 year.Statistical clustering methods will be used to identify distinct Long COVID-19 symptom clusters. Individuals from the four most prevalent clusters and two control groups will be invited to participate in the BioWear substudy which will further phenotype Long COVID symptom clusters by measurement of immunological parameters and actigraphy.We will review existing evidence on interventions for postviral syndromes and Long COVID to map and prioritise interventions for each newly characterised Long COVID syndrome. Recommendations will be made using the cumulative evidence in an expert consensus workshop. A virtual supportive intervention will be coproduced with patients and health service providers for future evaluation.Individuals with lived experience of Long COVID will be involved throughout this programme through a patient and public involvement group., Ethics and Dissemination: Ethical approval was obtained from the Solihull Research Ethics Committee, West Midlands (21/WM/0203). Research findings will be presented at international conferences, in peer-reviewed journals, to Long COVID patient support groups and to policymakers., Trial Registration Number: 1567490., Competing Interests: Competing interests: MC is Director of the Birmingham Health Partners Centre for Regulatory Science and Innovation, Director of the Centre for the Centre for Patient Reported Outcomes Research and is a National Institute for Health Research (NIHR) Senior Investigator. MC receives funding from the NIHR Birmingham Biomedical Research Centre (BRC), the NIHR Surgical Reconstruction and Microbiology Research Centre and NIHR ARC West Midlands at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Health Data Research UK, Innovate UK (part of UK Research and Innovation), Macmillan Cancer Support, UCB Pharma, Janssen, GlaxoSmithKline (GSK) and Gilead. MC has received personal fees from Astellas, Aparito, CIS Oncology, Takeda, Merck, Daiichi Sankyo, Glaukos, GSK and the Patient-Centered Outcomes Research Institute (PCORI) outside the submitted work. SEH is supported by the NIHR Applied Research Centre (ARC), West Midlands at the University of Birmingham. SEH has received personal fees from Cochlear and Aparito outside the submitted work. OLA receives funding from the NIHR Birmingham BRC, NIHR ARC, West Midlands at the University of Birmingham and University Hospitals Birmingham NHS Foundation, Innovate UK (part of UK Research and Innovation), Gilead Sciences and Janssen Pharmaceuticals. OLA declares personal fees from Gilead Sciences, GSK and Merck outside the submitted work. CM receives funding from the NIHR Surgical Reconstruction and Microbiology Research Centre, Innovate UK, and has received personal fees from Aparito outside the submitted work. PM, TW, CI and EL are employees of Clinical Practice Research Datalink (CPRD), the data custodians for CPRD Aurum. CPRD is jointly sponsored by the UK government’s Medicines and Healthcare Products Regulatory Agency and the NIHR. As a not-for-profit UK government body, CPRD seeks to recoup the cost of delivering its research services to academic, industry and government researchers through research user license fees. JC is a lay member on the UK NICE COVID expert panel, a citizen partner to the COVID END Evidence Synthesis Network, PPI lead on the NIHR CICADA ME Study, patient representative at the EAN European Neurology Autonomic Nervous Systems Disorders Working Group, a member of the MRC/UKRI Advanced Pain Discovery Platform and external board member of Plymouth Institute of Health. She also reports contracts with GSK and Medable., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
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- 2022
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194. Antigen-specific immunotherapy with apitopes suppresses generation of FVIII inhibitor antibodies in HLA-transgenic mice.
- Author
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Pletinckx K, Nicolson KS, Streeter HB, Sanderson WJ, Schurgers E, Jansson L, and Wraith DC
- Subjects
- Animals, Humans, Immune Tolerance, Immunologic Factors, Immunotherapy, Mice, Mice, Transgenic, Hemophilia A genetics
- Abstract
Hemophilia A (HA) is a blood clotting disorder that is caused by various genetic deficiencies in the factor VIII (FVIII)-encoding F8 gene. Patients receiving FVIII-replacement therapy are at risk for developing neutralizing antibodies (FVIII inhibitors), rendering the FVIII-replacement therapy ineffective. Immunological tolerance toward FVIII can be achieved through immune tolerance induction protocols in some patients, but this is a lengthy and costly desensitization program. Long-term eradication of inhibitors in patients with HA could be achieved by antigen-specific immunotherapy targeting CD4+ T-cells, because formation of FVIII inhibitors is T-cell dependent. Here, we report a peptide-based antigen-specific immunotherapy that is designed to specifically reestablish immune tolerance to FVIII through the development of antigen-processing-independent epitopes (apitopes). We identified 2 FVIII immunodominant peptides in immunized HLA-DRA*0101/DRB1*1501 transgenic (HLA-DR2tg) mice that were optimized for tolerogenicity. These modified peptide analogs were initially screened for recognition using FVIII-specific T-cell hybridoma clones from FVIII-immunized HLA-DR2tg mice. The FVIII apitopes were promiscuous and bound common human HLA-DRB1* allelic variants. The combination of these 2 FVIII apitopes (ATX-F8-117), administered according to a dose-escalation protocol, promoted T-cell tolerance toward FVIII in HLA-DR2tg mice. Furthermore, treatment with ATX-F8-117 significantly reduced FVIII inhibitor formation. ATX-F8-117 regulates anti-FVIII T-cell and B-cell responses, specifically the generation of FVIII inhibitors, revealing peptide-based antigen-specific immunotherapy as a promising approach to suppress and treat inhibitor formation in susceptible patients with HA., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2022
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195. Adaptive T cell tuning in immune regulation and immunotherapy of autoimmune diseases ✰ .
- Author
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Wraith DC
- Subjects
- Humans, Immune Tolerance, Immunologic Factors, Immunotherapy, Receptors, Antigen, T-Cell, Autoimmune Diseases therapy, T-Lymphocytes
- Abstract
Lymphocyte receptors confer antigen specificity on the adaptive immune response. Increasing evidence points to the role of adaptive tuning particularly amongst CD4
+ T cell responses. This review summarises how T cell tuning impacts on critically important aspects of immune regulation including thymic selection, the immune response to chronic antigen exposure and antigen-specific immunotherapy of autoimmune conditions. Recent work has revealed a novel mechanism for T cell anergy and regulatory type 1 T cell differentiation through a limitation of T cell receptor mediated signalling combined with epigenetic priming of tolerance associated genes., (Copyright © 2022 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)- Published
- 2022
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196. Preclinical models of arthritis for studying immunotherapy and immune tolerance.
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Meehan GR, Thomas R, Al Khabouri S, Wehr P, Hilkens CM, Wraith DC, Sieghart D, Bonelli M, Nagy G, Garside P, Tough DF, Lewis HD, and Brewer JM
- Subjects
- Animals, Anti-Citrullinated Protein Antibodies immunology, Arthritis, Experimental prevention & control, Arthritis, Experimental therapy, Arthritis, Rheumatoid prevention & control, Arthritis, Rheumatoid therapy, Asymptomatic Diseases, Desensitization, Immunologic, Disease Models, Animal, Disease Progression, Immune Tolerance immunology, Mice, Rats, Rheumatoid Factor immunology, Arthritis, Experimental immunology, Arthritis, Rheumatoid immunology, Autoantibodies immunology, Autoimmunity immunology, Immunotherapy, Self Tolerance immunology
- Abstract
Increasingly earlier identification of individuals at high risk of rheumatoid arthritis (RA) (eg, with autoantibodies and mild symptoms) improves the feasibility of preventing or curing disease. The use of antigen-specific immunotherapies to reinstate immunological self-tolerance represent a highly attractive strategy due to their potential to induce disease resolution, in contrast to existing approaches that require long-term treatment of underlying symptoms.Preclinical animal models have been used to understand disease mechanisms and to evaluate novel immunotherapeutic approaches. However, models are required to understand critical processes supporting disease development such as the breach of self-tolerance that triggers autoimmunity and the progression from asymptomatic autoimmunity to joint pain and bone loss. These models would also be useful in evaluating the response to treatment in the pre-RA period.This review proposes that focusing on immune processes contributing to initial disease induction rather than end-stage pathological consequences is essential to allow development and evaluation of novel immunotherapies for early intervention. We will describe and critique existing models in arthritis and the broader field of autoimmunity that may fulfil these criteria. We will also identify key gaps in our ability to study these processes in animal models, to highlight where further research should be targeted., Competing Interests: Competing interests: GM, RT, CMUH, DCW, DS, MB, PG and JMB all received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777357. DCW is the founder and serves as a consultant to Apitope International NV. RT reports additional grants from Arthritis Queensland, and an NHMRC senior research fellowship during the conduct of the study; grants from NHMRC grants 1083192 and 1071822, past funding from Janssen Biotech Inc to Uniquest outside the submitted work; In addition, RT has patent 9,017,697 B2: 2006 issued, a grant from JDRF Australia and US The Leona M. and Harry B. Helmsley Charitable Trust for antigen-specific immunotherapy in type 1 diabetes, and investment from CSL to UniQuest to develop and commercialise antigen-specific immunotherapy in Sjogren's syndrome. DS and MB report grants from Medical University of Vienna during the conduct of the study. HDL and DFT are both employees and shareholders of GSK (Pharma partner in RTCure Consortium)., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)
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- 2021
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197. Induction of Tolerance to Therapeutic Proteins With Antigen-Processing Independent T Cell Epitopes: Controlling Immune Responses to Biologics.
- Author
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Schurgers E and Wraith DC
- Subjects
- Humans, Immunotherapy adverse effects, Antigen Presentation immunology, Biological Products immunology, Epitopes, T-Lymphocyte immunology, Immune Tolerance immunology
- Abstract
The immune response to exogenous proteins can overcome the therapeutic benefits of immunotherapies and hamper the treatment of protein replacement therapies. One clear example of this is haemophilia A resulting from deleterious mutations in the FVIII gene. Replacement with serum derived or recombinant FVIII protein can cause anti-drug antibodies in 20-50% of individuals treated. The resulting inhibitor antibodies override the benefit of treatment and, at best, make life unpredictable for those treated. The only way to overcome the inhibitor issue is to reinstate immunological tolerance to the administered protein. Here we compare the various approaches that have been tested and focus on the use of antigen-processing independent T cell epitopes (apitopes) for tolerance induction. Apitopes are readily designed from any protein whether this is derived from a clotting factor, enzyme replacement therapy, gene therapy or therapeutic antibody., Competing Interests: DW is CSO and Founder of Apitope International NV. ES is an employee of Apitope International NV., (Copyright © 2021 Schurgers and Wraith.)
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- 2021
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198. Serological responses to SARS-CoV-2 following non-hospitalised infection: clinical and ethnodemographic features associated with the magnitude of the antibody response.
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Shields AM, Faustini SE, Perez-Toledo M, Jossi S, Allen JD, Al-Taei S, Backhouse C, Dunbar LA, Ebanks D, Emmanuel B, Faniyi AA, Garvey M, Grinbergs A, McGinnell G, O'Neill J, Watanabe Y, Crispin M, Wraith DC, Cunningham AF, Drayson MT, and Richter AG
- Subjects
- Adult, Female, Health Personnel, Humans, Immunoglobulin A blood, Immunoglobulin G blood, Immunoglobulin M blood, Male, Middle Aged, Retrospective Studies, Seroepidemiologic Studies, United Kingdom, Antibodies, Viral blood, Antibody Formation, COVID-19 immunology
- Abstract
Objective: To determine clinical and ethnodemographic correlates of serological responses against the SARS-CoV-2 spike glycoprotein following mild-to-moderate COVID-19., Design: A retrospective cohort study of healthcare workers who had self-isolated due to COVID-19., Setting: University Hospitals Birmingham NHS Foundation Trust, UK (UHBFT)., Participants: 956 healthcare workers were recruited by open invitation via UHBFT trust email and social media between 27 April 2020 and the 8 June 2020., Intervention: Participants volunteered a venous blood sample that was tested for the presence of anti-SARS-CoV-2 spike glycoprotein antibodies. Results were interpreted in the context of the symptoms of their original illness and ethnodemographic variables., Results: Using an assay that simultaneously measures the combined IgG, IgA and IgM response against the spike glycoprotein (IgGAM), the overall seroprevalence within this cohort was 46.2% (n=442/956). The seroprevalence of immunoglobulin isotypes was 36.3%, 18.7% and 8.1% for IgG, IgA and IgM, respectively. IgGAM identified serological responses in 40.6% (n=52/128) of symptomatic individuals who reported a negative SARS-CoV-2 PCR test. Increasing age, non-white ethnicity and obesity were independently associated with greater IgG antibody response against the spike glycoprotein. Self-reported fever and fatigue were associated with greater IgG and IgA responses against the spike glycoprotein. The combination of fever and/or cough and/or anosmia had a positive predictive value of 92.3% for seropositivity in self-isolating individuals a time when Wuhan strain SARS-CoV-2 was predominant., Conclusions and Relevance: Assays employing combined antibody detection demonstrate enhanced seroepidemiological sensitivity and can detect prior viral exposure even when PCR swabs have been negative. We demonstrate an association between known ethnodemographic risk factors associated with mortality from COVID-19 and the magnitude of serological responses in mild-to-moderate disease., Competing Interests: Competing interests: MTD reports personal fees from Abingdon Health, outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)
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- 2021
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199. Manipulating antigen presentation for antigen-specific immunotherapy of autoimmune diseases.
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Streeter HB and Wraith DC
- Subjects
- Animals, Antigen-Presenting Cells immunology, Humans, Antigen Presentation immunology, Autoimmune Diseases immunology
- Abstract
Current treatments for autoimmune diseases do not address the immune pathology underlying their initiation and progression and too often rely on non-specific immunosuppressive drugs for control of symptoms. Antigen-specific immunotherapy aims to induce tolerance selectively among the cells causing the disease while leaving the rest of the adaptive immune system capable of protecting against infectious diseases and cancers. Here we describe how novel approaches for antigen-specific immunotherapy are designed to manipulate antigen presentation and promote tolerance to specific self-antigens. This analysis points to liver antigen presenting cells, targeted by carrier particles, and steady-state dendritic cells, to which antigen-processing independent T-cell epitopes (apitopes) bind directly, as the principal targets for antigen-specific immunotherapy. Delivery of antigens to these cells holds great promise for effective control of this rapidly expanding group of diseases., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2021
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200. Peptide allergen-specific immunotherapy for allergic airway diseases-State of the art.
- Author
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Wraith DC and Krishna MT
- Subjects
- Asthma immunology, Asthma therapy, CD4-Positive T-Lymphocytes, Conjunctivitis, Allergic immunology, Conjunctivitis, Allergic therapy, Humans, Peptides immunology, Respiratory Hypersensitivity immunology, Rhinitis, Allergic immunology, Rhinitis, Allergic therapy, Allergens immunology, Desensitization, Immunologic methods, Epitopes immunology, Peptides therapeutic use, Respiratory Hypersensitivity therapy
- Abstract
Allergen-specific immunotherapy (AIT) is the only means of altering the natural immunological course of allergic diseases and achieving long-term remission. Pharmacological measures are able to suppress the immune response and/or ameliorate the symptoms but there is a risk of relapse soon after these measures are withdrawn. Current AIT approaches depend on the administration of intact allergens, often comprising crude extracts of the allergen. We propose that the challenges arising from current approaches, including the risk of serious side-effects, burdensome duration of treatment, poor compliance and high cost, are overcome by application of peptides based on CD4
+ T cell epitopes rather than whole allergens. Here we describe evolving approaches, summarize clinical trials involving peptide AIT in allergic rhinitis and asthma, discuss the putative mechanisms involved in their action, address gaps in evidence and propose future directions for research and clinical development., (© 2021 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)- Published
- 2021
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