The dynamics of CD4(+) effector T cells (Teff cells) and CD4(+)Foxp3(+) regulatory T cells (Treg cells) during diabetes progression in nonobese diabetic mice was investigated to determine whether an imbalance of Treg cells and Teff cells contributes to the development of type 1 diabetes. Our results demonstrated a progressive decrease in the Treg cell:Teff cell ratio in inflamed islets but not in pancreatic lymph nodes. Intra-islet Treg cells expressed reduced amounts of CD25 and Bcl-2, suggesting that their decline was due to increased apoptosis. Additionally, administration of low-dose interleukin-2 (IL-2) promoted Treg cell survival and protected mice from developing diabetes. Together, these results suggest intra-islet Treg cell dysfunction secondary to defective IL-2 production is a root cause of the progressive breakdown of self-tolerance and the development of diabetes in nonobese diabetic mice.

Dendritic cells (DCs) are essential in T cell-mediated destruction of insulin-producing ␤ cells in the islets of Langerhans in type 1 diabetes. In this study, we investigated T cell induction of intra-islet DC maturation during the progression of the disease in both autoimmune-prone NOD and resistant C57BL/6 mice. We demonstrated steady-state capture and retention of unprocessed ␤ cellderived proteins by semimature intra-islet DCs in both mouse strains. T cell-mediated intra-islet inflammation induced an increase in CD40 and CD80 expression and processing of captured Ag by resident DCs without inducing the expression of the p40 subunit of IL-12/23. Some of the CD40 high intra-islet DCs up-regulated CCR7, and a small number of CD40 high DCs bearing unprocessed islet Ags were detected in the pancreatic lymph nodes in mice with acute intra-islet inflammation, demonstrating that T cell-mediated tissue inflammation augments migration of mature resident DCs to draining lymph nodes. Our results identify an amplification loop during the progression of autoimmune diabetes, in which initial T cell infiltration leads to rapid maturation of intra-islet DCs, their migration to lymph nodes, and expanded priming of more autoreactive T cells. Therapeutic interventions that intercept this process may be effective at halting the progression of type 1 diabetes.

Summary This study examined the effect of thymoglobulin induction therapy on leukocyte population dynamics in kidney transplant patients. Patients receiving standard immunosuppression were compared with those who received additional thymoglobulin at the time of kidney transplantation. Thymoglobulin induction led to an immediate and significant decrease of all T cells and NK cells, but not B cells or monocytes. CD8+ T cells recovered to near pretransplant level by 4 weeks post‐transplant. CD4+ T cells remained at less than 30% of pretransplant level for the entire study period of 78 weeks. Both CD4+ and CD8+ T cells showed reduced cytokine production after recovery. Deletion of CD4+FOXP3+HELIOS+ regulatory T cells (Tregs) was less profound than that of CD4+FOXP3− cells, thus the relative percentage of Tregs elevated significantly when compared with pretransplant levels in thymoglobulin‐treated patients. In contrast, the percentages of Tregs and their expression of FOXP3 in the standard immunosuppression group decreased steadily and by 12 weeks after transplant the average percentage of Tregs was 56% of the pretransplant level. Thus, thymoglobulin‐induced deletion of T cells led to significant and long‐lasting alterations of the T‐cell compartment characterized by a preservation of Tregs and long‐lasting reduction in CD4+, and potentially pathogenic, T cells.

Autoimmune pancreatitis (AIP) is a heterogeneous autoimmune disease in humans characterized by a progressive lymphocytic and plasmacytic infiltrate in the exocrine pancreas. In this study, we report that regulatory T cell-deficient NOD.CD28KO mice spontaneously develop AIP that closely resembles the human disease. NOD mouse AIP was associated with severe periductal and parenchymal inflammation of the exocrine pancreas by CD4+ T cells, CD8+ T cells, and B cells. Spleen CD4+ T cells were found to be both necessary and sufficient for the development of AIP. Autoantibodies and autoreactive T cells from affected mice recognized a ∼50-kDa protein identified as pancreatic amylase. Importantly, administration of tolerogenic amylase-coupled fixed spleen cells significantly ameliorated disease severity, suggesting that this protein functions as a key autoantigen. The establishment and characterization of this spontaneous pancreatic amylase-specific AIP in regulatory T cell-deficient NOD.CD28KO mice provides an excellent model for the study of disease pathogenesis and development of new therapies for human autoimmune pancreatitis.

Background:We have treated islet transplant recipients with thymoglobulin induction and maintenance immunosuppression consisted of sirolimus or mycophenolate along with either efalizumab to block LFA-1. Dosing of sirolimus or mycophenolate was adjusted when efalizumab was withdrawn from the market. The immunological impact of Elalizumab was compared to belatacept in this study. Methods: Peripheral blood mononuclear cells were collected and cryopreserved beginning at enrollment before transplantation. Donor spleens were banked at the time of transplant. Percentages of regulatory T cells (Tregs) were determined using fl ow cytometry. Proliferative responses of CD4, CD8, and Tregs were measured in vitro using a CFSE dilution assay. Results: All patients on efalizumab showed dramatic increase of percentage of Tregs from 5 to 10% among CD4 + T cells pre-transplant to peaks of 15 to 67% between 1 and 3 months post transplant. Treg percentages remained elevated while patients were on the regimen. T cell proliferation to donor and polyclonal stimulations was markedly reduced in patients on efalizumab and returned to pre-transplant levels 5 months after the cessation of efalizumab (Figure 1). In contrast, percentages of Tregs and T cell proliferative responses remained stable in patients on the belatacept. Efalizumab led to profound changes of patients' immunological make-up when compared to belatacept. Particularly, one of the most severely immunosuppressed efalizumab patient experienced recurrent infections that necessitated complete withdrawal of immunosuppression. Her anti-donor and polyclonal responses rebounded from non-detectable levels to her pre-transplant baseline after efalizumab withdrawal. Remarkably, she has remained insulin independent despite receiving no immunosuppression in the past 16 months.