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3. Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes

Author

Robertson, Catherine C, Inshaw, Jamie RJ, Onengut-Gumuscu, Suna, Chen, Wei-Min, Santa Cruz, David Flores, Yang, Hanzhi, Cutler, Antony J, Crouch, Daniel JM, Farber, Emily, Bridges, S Louis, Edberg, Jeffrey C, Kimberly, Robert P, Buckner, Jane H, Deloukas, Panos, Divers, Jasmin, Dabelea, Dana, Lawrence, Jean M, Marcovina, Santica, Shah, Amy S, Greenbaum, Carla J, Atkinson, Mark A, Gregersen, Peter K, Oksenberg, Jorge R, Pociot, Flemming, Rewers, Marian J, Steck, Andrea K, Dunger, David B, Wicker, Linda S, Concannon, Patrick, Todd, John A, and Rich, Stephen S

Subjects
Pediatric, Biotechnology, Human Genome, Diabetes, Genetics, Autoimmune Disease, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Alleles, Autoimmunity, CD4-Positive T-Lymphocytes, Chromosome Mapping, Diabetes Mellitus, Type 1, Drug Discovery, Gene Expression, Genetic Predisposition to Disease, Genetic Variation, Genomics, Humans, Molecular Targeted Therapy, Protein Interaction Mapping, Type 1 Diabetes Genetics Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P

Published
2021

5. Hiding in Plain Sight: Thymic CD8+FOXP3+Tregs sequester CD25 and are enriched in human tissues

Author

Jarvis, Lorna B, primary, Howlett, Sarah K, additional, Coppard, Valerie B, additional, Rainbow, Daniel B, additional, Alkwai, Sarah B, additional, Ellis, Lou B, additional, Georgieva, Zoya B, additional, Suchanek, Ondrej B, additional, Mousa, Hani S, additional, Mahbubani, Krishnaa T, additional, Saeb-Parsy, Kourosh B, additional, Wicker, Linda S, additional, and Jones, Joanne L, additional

Published
2023
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6. Therapeutically expanded human regulatory T-cells are super-suppressive due to HIF1A induced expression of CD73

Author

Jarvis, Lorna B., Rainbow, Daniel B., Coppard, Valerie, Howlett, Sarah K., Georgieva, Zoya, Davies, Jessica L., Mullay, Harpreet Kaur, Hester, Joanna, Ashmore, Tom, Van Den Bosch, Aletta, Grist, James T., Coles, Alasdair J., Mousa, Hani S., Pluchino, Stefano, Mahbubani, Krishnaa T., Griffin, Julian L., Saeb-Parsy, Kourosh, Issa, Fadi, Peruzzotti-Jametti, Luca, Wicker, Linda S., and Jones, Joanne L.

Published
2021
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8. IL2RA genetic heterogeneity in multiple sclerosis and type 1 diabetes susceptibility and soluble interleukin-2 receptor production.

Author

Maier, Lisa M, Lowe, Christopher E, Cooper, Jason, Downes, Kate, Anderson, David E, Severson, Christopher, Clark, Pamela M, Healy, Brian, Walker, Neil, Aubin, Cristin, Oksenberg, Jorge R, Hauser, Stephen L, Compston, Alistair, Sawcer, Stephen, International Multiple Sclerosis Genetics Consortium, De Jager, Philip L, Wicker, Linda S, Todd, John A, and Hafler, David A

Subjects
International Multiple Sclerosis Genetics Consortium, Humans, Multiple Sclerosis, Diabetes Mellitus, Type 1, Disease Susceptibility, Genetic Predisposition to Disease, Case-Control Studies, Genotype, Genetic Heterogeneity, Alleles, Solubility, Adult, Interleukin-2 Receptor alpha Subunit, Diabetes Mellitus, Type 1, Genetics, Developmental Biology
Abstract

Multiple sclerosis (MS) and type 1 diabetes (T1D) are organ-specific autoimmune disorders with significant heritability, part of which is conferred by shared alleles. For decades, the Human Leukocyte Antigen (HLA) complex was the only known susceptibility locus for both T1D and MS, but loci outside the HLA complex harboring risk alleles have been discovered and fully replicated. A genome-wide association scan for MS risk genes and candidate gene association studies have previously described the IL2RA gene region as a shared autoimmune locus. In order to investigate whether autoimmunity risk at IL2RA was due to distinct or shared alleles, we performed a genetic association study of three IL2RA variants in a DNA collection of up to 9,407 healthy controls, 2,420 MS, and 6,425 T1D subjects as well as 1,303 MS parent/child trios. Here, we report "allelic heterogeneity" at the IL2RA region between MS and T1D. We observe an allele associated with susceptibility to one disease and risk to the other, an allele that confers susceptibility to both diseases, and an allele that may only confer susceptibility to T1D. In addition, we tested the levels of soluble interleukin-2 receptor (sIL-2RA) in the serum from up to 69 healthy control subjects, 285 MS, and 1,317 T1D subjects. We demonstrate that multiple variants independently correlate with sIL-2RA levels.

Published
2009

10. NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis

Author

Irie, Junichiro, Wu, Yuehong, Wicker, Linda S, Rainbow, Daniel, Nalesnik, Michael A, Hirsch, Raphael, Peterson, Laurence B, Leung, Patrick SC, Cheng, Chunmei, Mackay, Ian R, Gershwin, M Eric, and Ridgway, William M

Subjects
Biomedical and Clinical Sciences, Immunology, Biotechnology, Chronic Liver Disease and Cirrhosis, Rare Diseases, Autoimmune Disease, Digestive Diseases, Liver Disease, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Adoptive Transfer, Animals, Autoantibodies, Autoimmune Diseases, CD3 Complex, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cholangitis, Chromosome Mapping, Dihydrolipoyllysine-Residue Acetyltransferase, Disease Models, Animal, Granuloma, Humans, Inflammation, Liver Cirrhosis, Biliary, Liver Cirrhosis, Experimental, Mice, Mice, Congenic, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Mitochondrial Proteins, Protein Structure, Tertiary, Quantitative Trait Loci, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

Primary biliary cirrhosis (PBC) is an autoimmune disease with a strong genetic component characterized by biliary ductular inflammation with eventual liver cirrhosis. The serologic hallmark of PBC is antimitochondrial antibodies that react with the pyruvate dehydrogenase complex, targeting the inner lipoyl domain of the E2 subunit (anti-PDC-E2). Herein we demonstrate that NOD.c3c4 mice congenically derived from the nonobese diabetic strain develop an autoimmune biliary disease (ABD) that models human PBC. NOD.c3c4 (at 9-10 wk, before significant biliary pathology) develop antibodies to PDC-E2 that are specific for the inner lipoyl domain. Affected areas of biliary epithelium are infiltrated with CD3+, CD4+, and CD8+ T cells, and treatment of NOD.c3c4 mice with monoclonal antibody to CD3 protects from ABD. Furthermore, NOD.c3c4-scid mice develop disease after adoptive transfer of splenocytes or CD4+ T cells, demonstrating a central role for T cells in pathogenesis. Histological analysis reveals destructive cholangitis, granuloma formation, and eosinophilic infiltration as seen in PBC, although, unlike PBC, the extrahepatic biliary ducts are also affected. Using a congenic mapping approach, we define the first ABD (Abd) locus, Abd1. These results identify the NOD.c3c4 mouse as the first spontaneous mouse model of PBC.

Published
2006

15. HLA-DQβ57, anti-insulin T cells and insulin mimicry in autoimmune diabetes

Author

García, Arcadio Rubio, primary, Paterou, Athina, additional, Doherty, Rebecca D. Powell, additional, Landry, Laurie G., additional, Lee, Mercede, additional, Anderson, Amanda M., additional, Slawinski, Hubert, additional, Ferreira, Ricardo C., additional, Trzupek, Dominik, additional, Szypowska, Agnieszka, additional, Wicker, Linda S., additional, Teyton, Luc, additional, Ternette, Nicola, additional, Nakayama, Maki, additional, Todd, John A., additional, and Pekalski, Marcin L., additional

Published
2022
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17. Circulating C-Peptide Levels in Living Children and Young People and Pancreatic β-Cell Loss in Pancreas Donors Across Type 1 Diabetes Disease Duration

Author

Carr, Alice L.J., primary, Inshaw, Jamie R.J., additional, Flaxman, Christine S., additional, Leete, Pia, additional, Wyatt, Rebecca C., additional, Russell, Lydia A., additional, Palmer, Matthew, additional, Prasolov, Dmytro, additional, Worthington, Thomas, additional, Hull, Bethany, additional, Wicker, Linda S., additional, Dunger, David B., additional, Oram, Richard A., additional, Morgan, Noel G., additional, Todd, John A., additional, Richardson, Sarah J., additional, and Besser, Rachel E.J., additional

Published
2022
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18. Circulating C-Peptide Levels in Living Children and Young People and Pancreatic Beta Cell Loss in Pancreas Donors Across Type 1 Diabetes Disease Duration

Author

Carr, Alice L.J., primary, Inshaw, Jamie R.J., primary, Flaxman, Christine S., primary, Leete, Pia, primary, Wyatt, Rebecca C., primary, Russell, Lydia A., primary, Palmer, Matthew, primary, Prasolov, Dmytro, primary, Worthington, Thomas, primary, Hull, Bethany, primary, Wicker, Linda S., primary, Dunger, David B., primary, Oram, Richard A., primary, Morgan, Noel G., primary, Todd, John A., primary, Richardson, Sarah J., primary, and Besser, Rachel E.J., primary

Published
2022
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19. Low-dose IL-2 reduces IL-21+T cells and induces a long-lived anti-inflammatory gene expression signature inversely modulated in COVID-19 patients

Author

Zhang, Jia-Yuan, primary, Hamey, Fiona, additional, Trzupek, Dominik, additional, Mickunas, Marius, additional, Lee, Mercede, additional, Godfrey, Leila, additional, Yang, Jennie H.M., additional, Pekalski, Marcin L, additional, Kennet, Jane, additional, Waldron-Lynch, Frank, additional, Evans, Mark L., additional, Tree, Timothy I. M., additional, Wicker, Linda S., additional, Todd, John A., additional, and Ferreira, Ricardo C., additional

Published
2022
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22. Development of an integrated genome informatics, data management and workflow infrastructure: A toolbox for the study of complex disease genetics

Author

Burren Oliver S, Healy Barry C, Lam Alex C, Schuilenburg Helen, Dolman Geoffrey E, Everett Vincent H, Laneri Davide, Nutland Sarah, Rance Helen E, Payne Felicity, Smyth Deborah, Lowe Chris, Barratt Bryan J, Twells Rebecca CJ, Rainbow Daniel B, Wicker Linda S, Todd John A, Walker Neil M, and Smink Luc J

Subjects
type 1 diabetes, complex disease, genome informatics, data management, genetics, Medicine, Genetics, QH426-470
Abstract

Abstract The genetic dissection of complex disease remains a significant challenge. Sample-tracking and the recording, processing and storage of high-throughput laboratory data with public domain data, require integration of databases, genome informatics and genetic analyses in an easily updated and scaleable format. To find genes involved in multifactorial diseases such as type 1 diabetes (T1D), chromosome regions are defined based on functional candidate gene content, linkage information from humans and animal model mapping information. For each region, genomic information is extracted from Ensembl, converted and loaded into ACeDB for manual gene annotation. Homology information is examined using ACeDB tools and the gene structure verified. Manually curated genes are extracted from ACeDB and read into the feature database, which holds relevant local genomic feature data and an audit trail of laboratory investigations. Public domain information, manually curated genes, polymorphisms, primers, linkage and association analyses, with links to our genotyping database, are shown in Gbrowse. This system scales to include genetic, statistical, quality control (QC) and biological data such as expression analyses of RNA or protein, all linked from a genomics integrative display. Our system is applicable to any genetic study of complex disease, of either large or small scale.

Published
2004
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23. HLA class II mediates type 1 diabetes risk by anti-insulin repertoire selection

Author

Rubio Garcia, Arcadio, primary, Paterou, Athina, additional, Lee, Mercede, additional, Slawinski, Hubert, additional, Ferreira, Ricardo, additional, Landry, Laurie G, additional, Trzupek, Dominik, additional, Teyton, Luc, additional, Szypowska, Agnieszka, additional, Wicker, Linda S, additional, Nakayama, Maki, additional, Todd, John A, additional, and Pekalski, Marcin L, additional

Published
2021
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29. A Type I Interferon Transcriptional Signature Precedes Autoimmunity in Children Genetically at Risk for Type 1 Diabetes

Author

Ferreira, Ricardo C., Guo, Hui, Coulson, Richard M.R., Smyth, Deborah J., Pekalski, Marcin L., Burren, Oliver S., Cutler, Antony J., Doecke, James D., Flint, Shaun, McKinney, Eoin F., Lyons, Paul A., Smith, Kenneth G.C., Achenbach, Peter, Beyerlein, Andreas, Dunger, David B., Clayton, David G., Wicker, Linda S., Todd, John A., Bonifacio, Ezio, Wallace, Chris, and Ziegler, Anette-G.

Published
2014
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31. Genetic and functional data identifying Cd101 as a type 1 diabetes (T1D) susceptibility gene in nonobese diabetic (NOD) mice

Author

Mattner, Jochen, Mohammed, Javid P., Fusakio, Michael E., Giessler, Claudia, Hackstein, Carl-Philipp, Opoka, Robert, Wrage, Marius, Schey, Regina, Clark, Jan, Fraser, Heather I., Rainbow, Daniel B., and Wicker, Linda S.

Subjects
CD4-Positive T-Lymphocytes, Endocrine Disorders, Physiology, Neutrophils, Immune Cells, Immunology, Bone Marrow Cells, CD8-Positive T-Lymphocytes, QH426-470, Research and Analysis Methods, T-Lymphocytes, Regulatory, Lymphatic System, White Blood Cells, Mice, Endocrinology, Animal Cells, Antigens, CD, Mice, Inbred NOD, Medizinische Fakultät, Immune Physiology, Medicine and Health Sciences, Diabetes Mellitus, Genetics, Animals, Antigens, Ly, Humans, Genetic Predisposition to Disease, Myeloid Cells, ddc:610, Molecular Biology Techniques, Molecular Biology, Pancreas, Mice, Knockout, Blood Cells, T Cells, Biology and Life Sciences, Cell Biology, Regulatory T cells, Diabetes Mellitus, Type 1, Gene Expression Regulation, Haplotypes, Metabolic Disorders, Lymph Nodes, Cellular Types, Anatomy, Spleen, Research Article, Cloning
Abstract

Type 1 diabetes (T1D) is a chronic multi-factorial disorder characterized by the immune-mediated destruction of insulin-producing pancreatic beta cells. Variations at a large number of genes influence susceptibility to spontaneous autoimmune T1D in non-obese diabetic (NOD) mice, one of the most frequently studied animal models for human disease. The genetic analysis of these mice allowed the identification of many insulin-dependent diabetes (Idd) loci and candidate genes, one of them being Cd101. CD101 is a heavily glycosylated transmembrane molecule which exhibits negative-costimulatory functions and promotes regulatory T (Treg) function. It is abundantly expressed on subsets of lymphoid and myeloid cells, particularly within the gastrointestinal tract. We have recently reported that the genotype-dependent expression of CD101 correlates with a decreased susceptibility to T1D in NOD.B6 Idd10 congenic mice compared to parental NOD controls. Here we show that the knockout of CD101 within the introgressed B6-derived Idd10 region increased T1D frequency to that of the NOD strain. This loss of protection from T1D was paralleled by decreased Gr1-expressing myeloid cells and FoxP3+ Tregs and an enhanced accumulation of CD4-positive over CD8-positive T lymphocytes in pancreatic tissues. As compared to CD101+/+ NOD.B6 Idd10 donors, adoptive T cell transfers from CD101−/− NOD.B6 Idd10 mice increased T1D frequency in lymphopenic NOD scid and NOD.B6 Idd10 scid recipients. Increased T1D frequency correlated with a more rapid expansion of the transferred CD101−/− T cells and a lower proportion of recipient Gr1-expressing myeloid cells in the pancreatic lymph nodes. Fewer of the Gr1+ cells in the recipients receiving CD101−/− T cells expressed CD101 and the cells had lower levels of IL-10 and TGF-β mRNA. Thus, our results connect the Cd101 haplotype-dependent protection from T1D to an anti-diabetogenic function of CD101-expressing Tregs and Gr1-positive myeloid cells and confirm the identity of Cd101 as Idd10., Author summary The complex interplay of environmental factors and genetic traits determines the susceptibility of an individual to autoimmune disease such as type 1 diabetes (T1D). Despite T1D being one of the most common and most studied polygenic autoimmune disorders, the mechanisms underlying the immune-mediated destruction of the insulin-producing pancreatic beta cells are still largely unknown. Genetic association studies identified many DNA sequence variants that confer risk to or protect from autoimmune disease. In this regard, we have identified a single gene, Cd101, as a T1D susceptibility locus. In accordance with our previous studies in which we reported an association of allelic Cd101 variants on T1D prevalence, we observed here that deletion of Cd101 perpetuated the expansion of pathogenic, pancreas-infiltrating immune cells and subsequently enhanced T1D incidence. The mechanisms by which Cd101 variants interfere with autoimmune responses will allow us to understand the regulation of molecules in autoimmunity in general as diabetes susceptibility loci have been associated with other autoimmune diseases. Consequently, our work will help to identify therapeutic approaches that can be used to guide the development of effective therapies for T1D, but also allows the identification of common targets in autoimmune disease for clinical intervention in the future.

Published
2020
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32. Additional file 3 of Discovery of CD80 and CD86 as recent activation markers on regulatory T cells by protein-RNA single-cell analysis

Author

Trzupek, Dominik, Dunstan, Melanie, Cutler, Antony J., Lee, Mercede, Godfrey, Leila, Jarvis, Lorna, Rainbow, Daniel B., Aschenbrenner, Dominik, Jones, Joanne L., Uhlig, Holm H., Wicker, Linda S., Todd, John A., and Ferreira, Ricardo C.

Abstract

Additional file 3: Figure S1. Protein expression displays much larger dynamic range of expression. Figure S2. Targeted scRNA-seq provides increased sensitivity to detect lowly expressed transcripts. Figure S3. Effects of different data normalisation methods on cell clustering. Figure S4. Differential expression in the identified resting and in vitro stimulated primary CD4+ T-cell subsets. Figure S5. In vitro stimulation reinforces the trajectories of CD4+ T cell differentiation. Figure S6. Interplay between the BACH2 and BLIMP-1 transcriptional programmes regulates CD4+ Treg differentiation in humans. Figure S7. Characterising the expression of the B7 molecules CD80 and CD86 on CD4+ T cells. Figure S8. Integration of data from resting and in vitro stimulated CD4+ T cells. Figure S9. Single-cell mRNA and protein quantification identifies distinct functional populations of human circulating CD3+ T cells. Figure S10. Targeted multi-omics approach reveals trajectories of B-cell differentiation and class switching in blood and tissue.

Published
2020
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34. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease

Author

Ueda, Hironori, Howson, Joanna M. M., Esposito, Laura, Heward, Joanne, Snook, Chamberlain, Giselle, Rainbow, Daniel B., Hunter, Kara M. D., Smith, Annabel N., Di Genova, Gianfranco, Herr, Mathias H., Dahlman, Ingrid, Payne, Felicity, Smyth, Deborah, Lowe, Christopher, Twells, Rebecca C. J., Howlett, Sarah, Healy, Barry, Nutland, Sarah, Rance, Helen E., Everett, Vin, Smink, Luc J., Lam, Alex C., Cordell, Heather J., Walker, Neil M., Bordin, Cristina, Hulme, John, Motzo, Costantino, Cucca, Francesco, Hess, J. Fred, Metzker, Michael L., Rogers, Jane, Gregory, Simon, Allahabadia, Amit, Nithiyananthan, Ratnasingam, Tuomilehto-Wolf, Eva, Tuomilehto, Jaakko, Bingley, Polly, Gillespie, Kathleen M., Undlien, Dag E., Rønningen, Kjersti S., Guja, Cristian, Ionescu-Tîrgovişte, Constantin, Savage, David A., Maxwell, A. Peter, Carson, Dennis J., Patterson, Chris C., Franklyn, Jayne A., Clayton, David G., Peterson, Laurence B., Wicker, Linda S., Todd, John A., and Gough, Stephen C. L.

Published
2003
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36. Natural Genetic Variants Influencing Type 1 Diabetes in Humans and in the NOD Mouse

Author

Wicker, Linda S., primary, Moule, Carolyn L., additional, Fraser, Heather, additional, Penha-Goncalves, Carlos, additional, Rainbow, Dan, additional, Garner, Valerie E. S., additional, Chamberlain, Giselle, additional, Hunter, Kara, additional, Howlett, Sarah, additional, Clark, Jan, additional, Gonzalez-Munoz, Andrea, additional, Marie Cumiskey, Anne, additional, Tiffen, Paul, additional, Howson, Joanna, additional, Healy, Barry, additional, Smink, Luc J., additional, Kingsnorth, Amanda, additional, Lyons, Paul A., additional, Gregory, Simon, additional, Rogers, Jane, additional, Todd, John A., additional, and Peterson, Laurence B., additional

Published
2008
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43. Idd9.1 locus controls the suppressive activity of [FoxP3.sup.+] [CD4.sup.+] [CD25.sup.+] regulatory T-cells

Author

Yamanouchi, Jun, Puertas, Maria-Carmen, Verdaguer, Joan, Lyons, Paul A., Rainbow, Daniel B., Chamberlain, Giselle, Hunter, Kara M., Peterson, Laurence B., Wicker, Linda S., and Santamaria, Pere

Subjects
T cells -- Physiological aspects, Dextrose -- Genetic aspects, Type 1 diabetes -- Risk factors -- Genetic aspects, Glucose -- Genetic aspects, Health
Abstract

OBJECTIVE--The ~45-cM insulin-dependent diabetes 9 (Idd9) region on mouse chromosome 4 harbors several different type 1 diabetes-associated loci. Nonobese diabetic (NOD) mice congenic for the Idd9 region of C57BL/10 (B10) mice, carrying antidiabetogenic alleles in three different Idd9 subregions (Idd9.1, Idd9.2, and Iddg.3), are strongly resistant to type 1 diabetes. However, the mechanisms remain unclear. This study aimed to define mechanisms underlying the type 1 diabetes resistance afforded by B10 Idd9.1, Idd9.2, and/or Idd9.3. RESEARCH DESIGN AND METHODS--We used a reductionist approach that involves comparing the fate of a type 1 diabetes-relevant autoreactive [CD8.sup.+] T-cell population, specific for residues 206-214 of islet-specific glucose 6 phosphatase catalytic subunit-related protein ([IGRP.sub.206-214]), in noncongenic versus B10 Idd9-congenic (Idd9.1 + Idd9.2 + Idd9.3, Idd9.2 + Idd9.3, Idd9.1, Iddg.2, and Idd9.3) T-cell receptor (TCR)-transgenic (8.3) NOD mice. RESULTS--Most of the protective effect of Idd9 against 8.3-[CD8.sup.+] T-cell-enhanced type 1 diabetes was mediated by Idd9.1. Although Idd9.2 and Idd9.3 afforded some protection, the effects were small and did not enhance the greater protective effect of Idd9.1. B10 Idd9.1 afforded type 1 diabetes resistance without impairing the developmental biology or intrinsic diabetogenic potential of autoreactive [CD8.sup.+] T-cells. Studies in T- and B-cell-deficient 8.3-NOD.B10 Idd9.1 mice revealed that this antidiabetogenic effect was mediated by endogenous, nontransgenic T-cells in a B-cell-independent manner. Consistent with this, B10 Idd9.1 increased the suppressive function and antidiabetogenic activity of the [FoxP3.sup.+] [CD4.sup.+] [CD25.sup.+] T-cell subset in both TCR-transgenic and nontransgenic mice. CONCLUSIONS--A gene(s) within Idd9.1 regulates the development and function of [FoxP3.sup.+] [CD4.sup.+] [CD25.sup.+] regulatory T-cells and, in turn, the activation of [CD8.sup.+] effector T-cells in the pancreatic draining lymph nodes, without affecting their development or intrinsic diabetogenic potential., Type 1 diabetes in both humans and nonobese diabetic (NOD) mice is the result of a complex T-cell-mediated autoimmune process against the pancreatic β-cells. Putative poorly defined environmental triggers conspire [...]

Published
2010
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47. Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

Author

Todd, John A., Evangelou, Marina, Cutler, Antony J., Pekalski, Marcin L., Walker, Neil M., Stevens, Helen E., Porter, Linsey, Smyth, Deborah J., Rainbow, Daniel B., Ferreira, Ricardo C., Esposito, Laura, Hunter, Kara M. D., Loudon, Kevin, Irons, Kathryn, Yang, Jennie H., Bell, Charles J. M., Schuilenburg, Helen, Heywood, James, Challis, Ben, Neupane, Sankalpa, Clarke, Pamela, Coleman, Gillian, Dawson, Sarah, Goymer, Donna, Anselmiova, Katerina, Kennet, Jane, Brown, Judy, Caddy, Sarah L., Lu, Jia, Greatorex, Jane, Goodfellow, Ian, Wallace, Chris, Tree, Tim I., Evans, Mark, Mander, Adrian P., Bond, Simon, Wicker, Linda S., and Waldron-Lynch, Frank

Subjects
Immunotherapy -- Analysis -- Health aspects -- Research, Interleukin-2 -- Physiological aspects -- Genetic aspects -- Research, Type 1 diabetes -- Analysis -- Health aspects -- Genetic aspects -- Care and treatment -- Research, T cells -- Analysis -- Health aspects -- Physiological aspects -- Genetic aspects -- Research, Biological sciences
Abstract

Background Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4.sup.+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4.sup.+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. Methods and Findings To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3.sup.+ CD4.sup.+ CD25.sup.high CD127.sup.low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 x 10.sup.6 to 1.5 x 10.sup.6 IU/m.sup.2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 x 10.sup.6 IU/m.sup.2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 x 10.sup.6 IU/m.sup.2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 x 10.sup.6 and 0.045 x 10.sup.6 IU/m.sup.2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the [beta] chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. Conclusions The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. Trial Registration ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735, Author(s): John A. Todd 1,*, Marina Evangelou 2, Antony J. Cutler 1, Marcin L. Pekalski 1, Neil M. Walker 1, Helen E. Stevens 1, Linsey Porter 1, Deborah J. Smyth [...]

Published
2016
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49. T1DBase: integration and presentation of complex data for type 1 diabetes research

Author

Hulbert, Erin M., Smink, Luc J., Adlem, Ellen C., Allen, James E., Burdick, David B., Burren, Oliver S., Cavnor, Christopher C., Dolman, Geoffrey E., Flamez, Daisy, Friery, Karen F., Healy, Barry C., Killcoyne, Sarah A., Kutlu, Burak, Schuilenburg, Helen, Walker, Neil M., Mychaleckyj, Josyf, Eizirik, Decio L., Wicker, Linda S., Todd, John A., and Goodman, Nathan

Published
2007

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