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Thrombospondin-1 (TSP-1) is a key mediator of renal ischemia-reperfusion injury (IRI), a major cause of kidney dysfunction under various disease conditions and a risk factor of renal allograft rejection. In this study, we developed a nanotechnology-based therapy targeting TSP-1 to prevent renal IRI. A biocompatible nanoparticle (NP) capable of specific binding to TSP-1 was prepared by conjugating NPs with TSP-1-binding (LSKL) peptides. LSKL/NPs not only effectively adsorbed recombinant TSP-1 proteins in vitro, but also efficiently neutralized TSP-1 in mice undergoing renal IRI. IRI-induced elevation of TSP-1 in the kidney was significantly inhibited by post-IR treatment with LSKL/NPs, but not free LSKL or NPs. Furthermore, TSP-1 proteins adsorbed on LSKL/NPs were functionally inactive and unable to induce apoptosis in renal tubular epithelial cells. Importantly, LSKL/NPs induced strong protection against renal IRI, as shown by markedly diminished serum creatinine levels and improved histological lesions of the kidney. Thus, LSKL/NPs provide a useful means of depleting and inactivating TSP-1 and a potential therapy for renal IRI., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Alloantigen-specific regulatory T cell (Treg) therapy is a promising approach for suppressing alloimmune responses and minimizing immunosuppression after solid organ transplantation. Chimeric antigen receptor (CAR) targeting donor alloantigens can confer donor reactivity to Tregs. However, CAR Treg therapy has not been evaluated in vascularized transplant or multi-MHC mismatched models. Here, we evaluated the ability of CAR Tregs targeting HLA-A2 (A2-CAR) to prolong the survival of heterotopic heart transplants in mice. After verifying the in vitro activation, proliferation, and enhanced suppressive function of A2-CAR Tregs in the presence of A2-antigen, we analyzed the in vivo function of Tregs in C57BL/6 (B6) mice receiving A2-expressing heart allografts. A2-CAR Treg infusion increased the median survival of grafts from B6.HLA-A2 transgenic donors from 23 to 99 days, whereas median survival with polyclonal Treg infusion was 35 days. In a more stringent model of haplo-mismatched hearts from BALB/cxB6.HLA-A2 F1 donors, A2-CAR Tregs slightly increased median graft survival from 11 to 14 days, which was further extended to >100 days when combined with a 9-day course of rapamycin treatment. These findings demonstrate the efficacy of CAR Tregs, alone or in combination with immunosuppressive agents, toward protecting vascularized grafts in fully immunocompetent recipients., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Human infection with Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne pathogen in the family Nairoviridae , can result in a spectrum of outcomes, ranging from asymptomatic infection through mild clinical signs to severe or fatal disease. Studies of CCHFV immunobiology have investigated the relationship between innate and adaptive immune responses with disease severity, attempting to elucidate factors associated with differential outcomes. In this article, we begin by highlighting unanswered questions, then review current efforts to answer them. We discuss in detail current clinical studies and research in laboratory animals on CCHF, including immune targets of infection and adaptive and innate immune responses. We summarize data about the role of the immune response in natural infections of animals and humans and experimental studies in vitro and in vivo and from evaluating immune-based therapies and vaccines, and present recommendations for future research. • Humans are uniquely susceptible to severe disease upon infection with Crimean-Congo hemorrhagic fever virus (CCHFV). • CCHFV pathogenesis appears to be a contribution of virus-induced pathology and dysregulated inflammatory immune responses. • Both innate and adaptive immunity likely contribute to control of CCHFV infection. • Recent advances in animal modeling of infection will further studies of host and viral determinants of immunity and disease. • A better understanding of CCHFV immunobiology is needed to direct vaccine and antiviral advancement. [ABSTRACT FROM AUTHOR]

Abstract: A recently discovered population of lymphocytes, called T regulatory cells (Tregs), is characterized by expression of transcription factor Forkhead box P3 (FoxP3). These cells have been successfully used as therapeutic treatments and prophylaxis for graft-versus-host disease (GVHD) and diabetes and might become an attractive alternative to traditional immunotherapy. Here we evaluated how the type of culture medium and the type of serum can influence yield and quality of Tregs after in vitro expansion. We compared Treg fold of expansion and their phenotypical characteristics including expression of FoxP3, CD25, CD127, CD62L and CD45RA in three commercially available culture media (RPMI 1640 (Cellgro; Manassas VA, USA), SCGM (Cellgenix; Freiburg, Germany), and X-VIVO 20 (Lonza; Walkersville, MD, USA)) with addition of human serum (HS, 10%) or fetal bovine serum (FBS, 10%). Among the tested media, X-VIVO 20 supplemented with HS produced the highest yield after 17days of in vitro expansion (a median of 86-fold expansion, range 30–1365) and highest level of FoxP3 expression (a median of 66.8% of positive cells, range 56–84.8%) in CD4+ CD25hiCD127lo/neg FACS sorted polyclonal Tregs. There was no difference in Tregs yield whether HS or FBS serum was used. In conclusion, the yield of the ex vivo expanded Tregs is related to the type of media applied. Supplementation of the culture with FBS or human serum is equally beneficial. [Copyright &y& Elsevier]

The idiotypic network theory (INT) was conceived by the Danish immunologist Niels Kaj Jerne in 1973/1974. It proposes an overall view of the immune system as a network of lymphocytes and antibodies. The paper tries to offer a reconstruction of the genesis of the theory, now generally discarded and of mostly historical interest, first of all, by taking into account the context in which Jerne's theoretical proposal was advanced. It is argued the theory challenged, in a sense, the supremacy of the clonal selection theory (CST), this being regarded as the predominant paradigm in the immunological scenario. As CST found shortcomings in explaining certain phenomena, anomalies, one could view INT as a competing paradigm claiming to be able to make sense of such phenomena in its own conceptual framework. After a summary outline of the historical background and some relevant terminological elucidations, a narrative of the various phases of elaboration of the theory is proposed, up to its official public presentation. [ABSTRACT FROM AUTHOR]

Owing to the major limitations of current antiviral therapies in HBV (hepatitis B virus) infection, there is a strong need for novel therapeutic approaches to this major health burden. Stimulation of the host's innate and adaptive immune responses in a way that results in the resolution of viral infection is a promising approach. A better understanding of the virus-host interaction in acute and chronic HBV infection revealed several possible novel targets for antiviral immunotherapy. In the present review, we will discuss the current state of the art in HBV immunology and illustrate how control of infection could be achieved by immunotherapeutic interventions. [ABSTRACT FROM AUTHOR]

Ischemia reperfusion injury (IRI) that occurs with solid organ transplantation activates the innate immune system to induce inflammation. This leads to enhanced acute allograft rejection, impaired transplant tolerance and accelerated progression of chronic rejection. In this review, we discuss the innate immune signaling pathways that have been shown to play a role in organ transplantation. In particular, we focus on Toll-like receptor signaling pathways and how they have influenced outcomes after organ transplantation both experimentally and from clinical studies. Furthermore, we describe the substances that trigger the innate immune system after transplantation and several of the key cellular mediators of inflammation. We specifically point out unique aspects of activation of the innate immune system after lung transplantation. Finally, we discuss the areas that should be investigated in the future to more clearly understand the influence of the innate immune system after organ transplantation. [ABSTRACT FROM AUTHOR]

Diminishing homeostatic proliferation of memory T cells is essential for improving the efficacy of lymphoablation in transplant recipients. Our previous studies in a mouse heart transplantation model established that B lymphocytes secreting proinflammatory cytokines are critical for T cell recovery after lymphoablation. The goal of the current study was to identify mediators of B cell activation following lymphoablation in allograft recipients. Transcriptome analysis revealed that macrophage-inducible C-type lectin (Mincle, Clec4e) expression is up-regulated in B cells from heart allograft recipients treated with murine anti-thymocyte globulin (mATG). Recipient Mincle deficiency diminishes B cell production of pro-inflammatory cytokines and impairs T lymphocyte reconstitution. Mixed bone marrow chimeras lacking Mincle only in B lymphocytes have similar defects in T cell recovery. Conversely, treatment with a synthetic Mincle ligand enhances T cell reconstitution after lymphoablation in non-transplanted mice. Treatment with agonistic CD40 mAb facilitates T cell reconstitution in CD4 T cell-depleted, but not in Mincle-deficient, recipients indicating that CD40 signaling induces T cell proliferation via a Mincle-dependent pathway. These findings are the first to identify an important function of B cell Mincle as a sensor of damage-associated molecular patterns released by the graft and demonstrate its role in clinically relevant settings of organ transplantation., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Restoration of lymphatic drainage across the bronchial anastomosis after lung transplantation requires several weeks. As donor antigen and antigen presenting cell trafficking via lymphatics into graft-draining lymph nodes is an important component of the alloresponse, alternative pathways must exist that account for rapid rejection after pulmonary transplantation. Here, we describe a novel allorecognition pathway mediated through donor extracellular vesicle (EV) trafficking to mediastinal lymph nodes via the pleural space. Pleural fluid collected early after lung transplantation in rats and humans contains donor-specific EVs. In a fully MHC mismatched rat model of lung transplantation, we demonstrate EVs carrying donor antigen preferentially accumulate in mediastinal lymph nodes and colocalize with MHC II expressing cells within 4 h of engraftment. Injection of allogeneic EVs into pleural space of syngeneic lung transplant recipients confirmed their selective trafficking to mediastinal lymph nodes and resulted in activation of T cells in mediastinal, but not peripheral lymph nodes. Thus, we have uncovered an alternative pathway of donor antigen trafficking where pulmonary EVs released into the pleural space traffic to locoregional lymph nodes via pleural lymphatics. This pathway obviates the need for restoration of lymphatics across the bronchial anastomosis for trafficking of donor antigen to draining lymph nodes., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

CCR5 KO kidney transplant (KTx) recipients are extraordinarily high alloantibody producers and develop pathology that mimics human antibody-mediated rejection (AMR). C57BL/6 and CCR5 KO mice (H-2 b ) were transplanted with A/J kidneys (H-2 a ); select cohorts received adoptive cell therapy (ACT) with alloprimed CXCR5 + CD8 + T cells (or control cells) on day 5 after KTx. ACT efficacy was evaluated by measuring posttransplant alloantibody, pathology, and allograft survival. Recipients were assessed for the quantity of CXCR5 + CD8 + T cells and CD8-mediated cytotoxicity to alloprimed IgG + B cells. Alloantibody titer in CCR5 KO recipients was four-fold higher than in C57BL/6 recipients. The proportion of alloprimed CXCR5 + CD8 + T cells 7 days after KTx in peripheral blood, lymph node, and spleen was substantially lower in CCR5 KO compared to C57BL/6 recipients. In vivo cytotoxicity towards alloprimed IgG + B cells was also reduced six-fold in CCR5 KO recipients. ACT with alloprimed CXCR5 + CD8 + T cells (but not alloprimed CXCR5 - CD8 + or third-party primed CXCR5 + CD8 + T cells) substantially reduced alloantibody titer, ameliorated AMR pathology, and prolonged allograft survival. These results indicate that a deficiency in quantity and function of alloprimed CXCR5 + CD8 + T cells contributes to high alloantibody and AMR in CCR5 KO recipient mice, which can be rescued with ACT., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Skin sensitization remains a major environmental and occupational health hazard. Animal models have been used as the gold standard method of choice for estimating chemical sensitization potential. However, a growing international drive and consensus for minimizing animal usage have prompted the development of in vitro methods to assess chemical sensitivity. In this paper, we examine existing approaches including in silico models, cell and tissue based assays for distinguishing between sensitizers and irritants. The in silico approaches that have been discussed include Quantitative Structure Activity Relationships (QSAR) and QSAR based expert models that correlate chemical molecular structure with biological activity and mechanism based read-across models that incorporate compound electrophilicity. The cell and tissue based assays rely on an assortment of mono and co-culture cell systems in conjunction with 3D skin models. Given the complexity of allergen induced immune responses, and the limited ability of existing systems to capture the entire gamut of cellular and molecular events associated with these responses, we also introduce a microfabricated platform that can capture all the key steps involved in allergic contact sensitivity. Finally, we describe the development of an integrated testing strategy comprised of two or three tier systems for evaluating sensitization potential of chemicals. [ABSTRACT FROM AUTHOR]

Background: Studies have shown that caffeine might be capable to prevent colon cancer development. This activity is linked in part to its anti-inflammatory properties mediated through modulation of immune responses. It was the aim of the study to evaluate the role of caffeine in the immune balance between peripheral blood mononuclear cells (PBMC) and those of HT-29 and RKO human colon cancer lines. Methods: Cytokine production was evaluated following incubation of the two types of cancer cells without and with three concentrations of caffeine. Results: A concentration-dependent inhibition of TNFα and IFNγ secretion by PBMC was observed only after their stimulation by cancer cells. Reduction of the anti-inflammatory IL-1ra and IL-10 production was observed using higher caffeine concentrations only. Conclusion: We presume that by changing the equilibrium between pro- and anti-inflammatory cytokines in favor of anti-inflammation, caffeine may reduce the inflammatory process with a consequent suppression of colorectal cancer progress. [ABSTRACT FROM AUTHOR]

Invariant NKT cells (NKT) cells become activated after stimulation with antigen-presenting cells (APCs) loaded with the NKT cell ligand, alpha-galactosylceramide (alpha-GalCer). In this study, we investigated whether human APCs loaded with alpha-GalCer have the ability to activate NKT cells in mice. We found that human dendritic cells (DCs) loaded with alpha-GalCer (hDC/Gal) and injected into C57BL/6 mice stimulated the secretion of IFN-gamma by activated murine NKT cells. Furthermore, the number of transferred hDC/Gal correlated with the number of recovered IFN-gamma-producing spleen cells, indicating that the capacity of APCs to load alpha-GalCer can be measured by IFN-gamma release in an ELISPOT assay. Finally, alpha-GalCer-loaded human leukemic cell lines and primary leukemic cells injected into C57BL/6 mice also had the capacity to stimulate murine NKT cells in vivo. These results indicate that in vivo murine NKT cell responses can be used to quantitate the alpha-GalCer-loading capacity of human APCs. This method could be utilized to develop future immunotherapies in which NKT cells are targeted for activation. [ABSTRACT FROM AUTHOR]

Corneal transplantation, first reported a century ago, is the oldest and most frequent form of solid tissue transplantation. Although keratoplasty is also considered as the most successful transplant procedure, several studies indicate that the long term survival of corneal grafts is even lower than that of transplanted parenchymatous organs. Despite the immune privilege enjoyed by the cornea and anterior segment of the eye, immunologic graft rejection is a major limitation to corneal transplantation. This review gives an update on corneal immunobiology and the mechanisms of corneal graft rejection, focusing on antigen presentation, as well as on the molecular and cellular mediators of this particular immune response. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSC) are multipotent cells that differentiate into osteoblasts, myocytes, chondrocytes and adipocytes as well as insulin-producing cells. The mechanism underlying their in vivo differentiation is not clear and is thought to be caused by spontaneous cell fusion or factors present in the microenvironment. However, their ease of isolation, high 'ex-vivo' expansion potential and ability to differentiate into multiple lineages make them attractive tools for potential use in cell therapy. MSC have been isolated from several tissues, including bone/bone marrow, fat, Wharton's jelly, umbilical cord blood, placenta and pancreas. The 'immunosuppressive' property of human MSC makes them an important candidate for cellular therapy in allogeneic settings. Use of allogeneic MSC for repair of large defects may be an alternative to autologous and allogeneic tissue-grafting procedures. An allogeneic approach would enable MSC to be isolated from any donor, expanded and cryopreserved, providing a readily available source of progenitors for cell replacement therapy. Their immunomodulatory properties have raised the possibility of establishing allogeneic MSC banks for tissue regeneration. These facts are strongly reflected in the current exponential growth in stem cell research in the pharmaceutical and biotechnology communities. Current knowledge regarding the immunobiology and clinical application of MSC needs to be strengthened further to establish MSC as a safe and effective therapeutic tool in regenerative medicine. This paper discusses human MSC with particular reference to the expression of their surface markers, their role as immunomodulators and their multilineage differentiation potential and possible use in tissue regeneration and repair. [ABSTRACT FROM AUTHOR]

Chlamydia disease expression is the result of complex molecular and cellular interactions between the host and a pathogen which appears to have been sculpted by evolutionary forces. Recent genomic, immunologic, and epidemiologic findings are reviewed. A synthesis is offered which suggests that Chlamydia disease expression results from persistent infection and host immune responses. [ABSTRACT FROM AUTHOR]

The problem of statistical recognition is considered, as it arises in immunobiology, namely, the discrimination of foreign antigens against a background of the body’s own molecules. The precise mechanism of this foreign-self-distinction, though one of the major tasks of the immune system, continues to be a fundamental puzzle. Recent progress has been made by van den Berg, Rand, and Burroughs (J. Theor. Biol. 209:465–486, ), who modelled the probabilistic nature of the interaction between the relevant cell types, namely, T-cells and antigen-presenting cells (APCs). Here, the stochasticity is due to the random sample of antigens present on the surface of every APC, and to the random receptor type that characterises individual T-cells. It has been shown previously (van den Berg et al. in J. Theor. Biol. 209:465–486, ; Zint et al. in J. Math. Biol. 57:841–861, ) that this model, though highly idealised, is capable of reproducing important aspects of the recognition phenomenon, and of explaining them on the basis of stochastic rare events. These results were obtained with the help of a refined large deviation theorem and were thus asymptotic in nature. Simulations have, so far, been restricted to the straightforward simple sampling approach, which does not allow for sample sizes large enough to address more detailed questions. Building on the available large deviation results, we develop an importance sampling technique that allows for a convenient exploration of the relevant tail events by means of simulation. With its help, we investigate the mechanism of statistical recognition in some depth. In particular, we illustrate how a foreign antigen can stand out against the self background if it is present in sufficiently many copies, although no a priori difference between self and nonself is built into the model. [ABSTRACT FROM AUTHOR]

Thyroid disease has been associated with lymphohematopoietic cancer (LHC). No previous study using clinical, sonographic and laboratory data has explored whether thyroid disease and specifically autoimmune thyroid disease (ATD) is associated with multiple myeloma (MM) risk. 73 patients with incident primary MM and 73 hospital controls admitted for non-neoplastic and non-infectious conditions, matched on gender and age were studied between 2001 and 2007. Blood samples were collected. All subjects were submitted to clinical, ultrasound and laboratory thyroid evaluation. The prevalence of clinical thyroid disease in MM patients was significantly higher than in controls (p = 0.002). ATD was associated with increased risk of MM, adjusting for age, gender, body mass index and familial history of LHC [OR = 5.68, 95% confidence interval (CI): 1.69-19.13]. Controlling for the above variables, an individual suffering from any thyroid disease more than 10 years has about 2.41 times more likely the risk to develop MM than an individual without any thyroid disease (OR = 2.41, 95% CI: 1.35-4.29). Also, adjusting for age, gender, BMI and family history of LHC, a familial history of thyroid disease is associated with increased risk of MM (OR = 3.23, 95% CI: 1.25-8.31). Further studies are needed to explore underlying mechanisms associating thyroid autoimmunity with plasma cell transformation. [ABSTRACT FROM AUTHOR]

Artificial T cell receptor (TCR) ligands can be used to direct virus-specific cytotoxic T lymphocytes (CTL) towards tumor cells. Because of their size, these constructs may differ from cognate peptides in their ability to induce T cell activation. We here analysed signalling outcomes upon synapse formation between human cytomegalovirus (CMV)-specific CTL and chronic lymphocytic leukemia (CLL) cells through targeted complexes (TC) containing anti-CD20 single-chain variable fragment and biotinylated major histocompatibility complex class I molecules presenting peptides from CMVpp65. TC coated CLL cells were effectively lysed by CMVpp65-specific CTL but induced less interferon gamma (IFN-γ) production than peptide loaded targets. Confocal microscopy revealed that TC induced a redistribution of TCR/CD3 but not CD2 towards the immunological synapse. Furthermore, morphological examination of immunological synapses showed smaller and 'patchy' interactions between TC coated B cells and CTL as compared with peptide coated targets. Finally, pre-incubation of CTL with CD2 antibodies led to an Fc-dependent redistribution of CD2 into TC-induced synapses and restored IFN-γ production by CMV-specific CTL. Thus, redistribution of CD2 towards the immunological synapse appears to be essential for full T cell activation. However, CD2 triggering is not required for efficient lysis of tumor cells, demonstrating that CTL require only minimal stimulation to release their cytotoxic content. [ABSTRACT FROM AUTHOR]

Embryonic stem cells (ESCs) offer an attractive potential in cell replacement therapy and regenerative medicine because of their inherent plasticity and ability to self-renew. However, the immunological response against transplanted ESC-derived allografts requires further evaluation. In this study, we showed that ESCs expressing the major histocompatibility complex class I molecule H2Kb escape immune recognition by H2Kb-reactive CD8+ T cells, irrespective of H2Kb expression levels. In the face of more robust immunological challenge, however, evidence of ESC allograft rejection becomes apparent. We further assessed the adaptive immune response against terminally differentiated insulinproducing tissue derived from an ESC source to examine the potential future applicability of this tissue as a β-cell replacement therapy for type 1 diabetes mellitus. The functional ESC-derived insulin-producing tissue was infiltrated by alloreactive T cells and rejected in immunocompetent hosts. Hence, although ESCs and their terminally differentiated derivatives may possess a fragile immune privilege, they still represent novel targets of attack by elements of the immune system and are rejected. These findings provide insight into the mechanisms of adaptive immunity toward ESCs and their derivatives. [ABSTRACT FROM AUTHOR]

The emergence of rituximab has changed the clinical outcome of patients with B-cell lymphoma, which necessitates reassessment of previously determined prognostic factors. Thus, we evaluated the prognostic significance of serum soluble interleukin-2 receptor (sIL2R) levels in patients with diffuse large B cell lymphoma (DLBCL), treated with CHOP (n = 108) or RCHOP (n = 94). Serum sIL2R level ranged from 316 to 23 800 U/mL (median 1064 U/mL) and levels were generally higher in higher IPI risk group. Multivariate analyses revealed that sIL2R ≥1000 U/mL was associated with shorter progression free survival [hazard ratio (HR) = 2.52, p = 0.011] and overall survival (HR = 2.34, p = 0.037) independent of IPI risk group or rituximab use. Further subgroup analyses revealed that the impact of sIL2R was most apparent in patients with IPI low risk, both in CHOP alone and RCHOP group. Our study confirmed the prognostic value of sIL2R in patients with DLBCL with low International Prognostic Index (IPI) risk, also in the era of rituximab. [ABSTRACT FROM AUTHOR]

A transgenic mouse model of autochthonous mammary carcinoma was chosen to study the impact of tumor progression on the immune system over an extended period. We found: i) that splenocyte numbers, particularly myeloid cells, increased concurrently with tumor burden; ii) the percentage of tumor-infiltrating Treg cells was similar to that in human breast cancer; iii) suppressed T cell proliferation and cytokine production and; iv) significantly elevated MCP-1 and TNF-α in the sera of tumor-bearing mice. The modified immune status in these tumor-bearing hosts is consistent with a "syndrome" that likely impacts the efficacy of cancer immunosurveillance and response to therapy. [ABSTRACT FROM AUTHOR]

Follicular dendritic cells (FDCs) support the survival of follicular lymphoma (FL). Tumor necrosis factor alpha (TNFα) is overexpressed by FL cells and is critical in the development and maintenance of FDCs. We hypothesised that TNFα might be an ideal therapeutic target. We treated seven patients with relapsed/refractory FL with 8 weeks of etanercept, 25 mg SC on day 1 and 4 of each week. Patients without progression received 16 additional weeks of etanercept. All patients completed at least 8 weeks of etanercept and two patients completed 24 weeks. At the 8 week evaluation five patients had SD. Of the five with SD, two progressed at 9 and 12 weeks on therapy and the remaining three progressed between 12 and 24 weeks after initiating therapy. Minimal toxicity was observed. FDG-PET imaging demonstrated decreases in standardized uptake value (SUV) following treatment with etanercept in five patients. Further studies in FL targeting the microenvironment in conjunction with standard cytotoxic therapy are warranted. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) cells rapidly undergo apoptosis when cultured in vitro, which contrasts with their prolonged survival in vivo. Multiple cytokines and cytokine receptors are believed to work together to regulate the survival of CLL cells. The aim of the current study was to measure the endogenous expression and secretion of cytokines and cytokine receptors in CLL cells when exogenous cytokines are minimized. We demonstrated that the intracellular and secreted levels of 174 cytokines and cytokine receptors of purified CLL B-cells were not significantly different from those of normal B-cells except for the secreted levels of IL-6 and eotaxin. IL-6 was 3.0 times lower (p = 0.038) whereas eotaxin was 2.2 times higher (p = 0.027) in CLL conditioned medium than in normal B-cell conditioned medium. Our results suggest that, except for IL-6 and eotaxin, CLL B-cells and their normal counterparts produce and secrete similar amounts of cytokines and cytokine receptors in vitro. [ABSTRACT FROM AUTHOR]

The cancer-testis antigen SPAN-XB has been recently identified in multiple myeloma (MM). In the present study, we identified and characterized for the first time a cytotoxic cellular immune response against SPAN-XB in healthy donors and patients with MM. Using two independent computer algorithms, two SPAN-XB-derived peptides (peptides 624 and 626) with predicted binding to HLA-A2 were identified. To further improve the immunogenicity of peptide 626 we designed a heteroclitic peptide (peptide 627) by modifying one amino acid on the HLA binding position 2 of peptide 626. Using an IFN-γ Elispot assay we could demonstrate the presence and functional activity of CD8 peptide specific T cells with all tested peptides. By analysis of peripheral blood of 13 healthy donors and five patients with MM peptide specific T-cell precursors specifically recognizing at least one of the tested peptides could be detected and expanded in 9 of 13 of tested donors and 3 of 5 tested patients. Importantly, in two donors specific peptides could be generated against the heteroclitic peptide 627 but not against the native peptide 626. We conclude that SPAN-XB-derived peptides can elicit a consistent CD8 T cell response in healthy donors and patients with MM. [ABSTRACT FROM AUTHOR]

MSCs are nonhematopoietic stromal cells that are capable of differentiating into, and contribute to the regeneration of, mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, and adipose. MSCs are rare in bone marrow, representing ∼1 in 10,000 nucleated cells. Although not immortal, they have the ability to expand manyfold in culture while retaining their growth and multilineage potential. MSCs are identified by the expression of many molecules including CD105 (SH2) and CD73 (SH3/4) and are negative for the hematopoietic markers CD34, CD45, and CD14. The properties of MSCs make these cells potentially ideal candidates for tissue engineering. It has been shown that MSCs, when transplanted systemically, are able to migrate to sites of injury in animals, suggesting that MSCs possess migratory capacity. However, the mechanisms underlying the migration of these cells remain unclear. Chemokine receptors and their ligands and adhesion molecules play an important role in tissue-specific homing of leukocytes and have also been implicated in trafficking of hematopoietic precursors into and through tissue. Several studies have reported the functional expression of various chemokine receptors and adhesion molecules on human MSCs. Harnessing the migratory potential of MSCs by modulating their chemokine-chemokine receptor interactions may be a powerful way to increase their ability to correct inherited disorders of mesenchymal tissues or facilitate tissue repair in vivo. The current review describes what is known about MSCs and their capacity to home to tissues together with the associated molecular mechanisms involving chemokine receptors and adhesion molecules. [ABSTRACT FROM AUTHOR]

The BIOMED-2 PCR-based immunoglobulin gene rearrangement assays have quickly become the most commonly used laboratory method for detection of B-cell clonality. Therefore, the reliability of these assays under various conditions has become increasingly important. When studying paired cases of follicular lymphoma (FL) from individual patients, we used these assays to assess clonality in 40 formalin-fixed paraffin-embedded (FFPE) specimens from 19 patients diagnosed with FL. The assays of IGH rearrangement failed to give a clonal result in 26/40 (65%) specimens, while the IGK assays failed in only 3/40 (8%) specimens. The high failure rate of the IGH assays for this set of FFPE lymphomas cannot be explained by systematic problems with DNA extraction or amplification because the same IGH assays resulted in a low failure rate (3/32, 9%) for FFPE small lymphocytic lymphoma/chronic lymphocytic leukemia specimens and for fresh frozen FL specimens (1/6, 17%). Furthermore, in a second validation set of 13 FFPE follicular lymphoma the failure rate was 9/13 (69%). Therefore, the BIOMED-2 IGH assay did not perform well on FFPE follicular lymphoma specimens, and the IGK assay may be superior for assessing clonality when no fresh/frozen tissue is available. [ABSTRACT FROM AUTHOR]

Owing to the importance of dendritic cells (DC) in the induction and control of immunity, an understanding of their biology is central to the development of potent immunotherapies for cancer, chronic infections, autoimmune disease, and induction of transplantation tolerance. This review surveys the heterogeneity of DC with regards to their phenotype and developmental origin, and how they initiate, modify and regulate the immune response, with emphasis on their maturation, migration, antigen-presentation and interaction with T cells and other immune cells. Much of this knowledge is obtained through research on murine DC. Research on human DC has been hampered by limitations associated with in vitro assays and limited access to human tissues. New approaches on human DC research are required in order to develop novel strategies for the treatment of microbial infections, the control of graft rejection, and the improvement of DC-based immunotherapeutic protocols for autoimmunity, allergy, and cancer. [ABSTRACT FROM AUTHOR]

The author reflects on an article published in human experimental medicine of bronchoscopic installation of either purified protein derivative (PPD) or bacillus Calmette-Guerin (BCG). It mentions BCG is the only licensed vaccine against tuberculosis (TB) and highly variable efficacy against pulmonary disease. It also mentions vaccination strategy will be required to achieve the ambitious targets described in Sustainable Development Goals and the Stop TB Partnership's Global Plan to End TB.

Organ transplantation represents the only definitive therapy for many causes of end-organ failure. However, the universal success of this therapy is limited by chronic allograft rejection, the side effects of chronic immunosuppressive therapy, and a severe shortage of donor organs. Presently, the success of solid-organ transplantation depends on the continuous administration of toxic and nonspecific immunosuppressive agents, therapies that present risks for opportunistic infection, malignancy, and a variety of agent-specific side effects. To promote the use of transplantation with limited risk of long-term sequelae, three dominant research challenges emerge: (i) elimination of the need for exogenous immunosuppression by immunological tolerance induction; (ii) prevention of chronic rejection/graft dysfunction; and (iii) expansion of available organs for transplantation. Gene therapy may provide significant advances and solutions in each of these areas. Rejection of the graft in the immediate post-transplant period has been attacked through the transfer of immunomodulatory molecules in addition to tolerance inducing approaches. Chronic graft rejection may be similarly addressed through permanent tolerance induction or alternatively through the introduction of molecules to resist chronic graft damage. Genetic manipulation of stem cells may ultimately produce transgenic animals to serve as tissue donors to overcome the limited donor organ supply. This review will highlight ongoing developments in the translation of gene therapy approaches to the challenges inherent in transplantation. [ABSTRACT FROM AUTHOR]