Islet Antigen-Specific Th17 Cells Can Induce TNF- -Dependent Autoimmune Diabetes (original) (raw)
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Clinical Immunology, 2010
The effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DC), is greater when administered to young NOD mice than at peak insulitis. RelB lo DC, generated in the presence of an NF-κB inhibitor, induce T regulatory (Treg) cells and suppress inflammation in a model of rheumatoid arthritis. IL-1β is over-expressed in humans and mice at risk of T1DM, dysregulates Treg cells, and accelerates diabetes in NOD mice. We investigated the relationship between IL-1β production and the response to RelB lo DC in the prediabetic period. Methods: We injected RelB lo DC s.c. into 4 or 14 week-old NOD mice, and tracked the incidence of diabetes and effect on Treg cell function. We measured expression of proinflammatory cytokines by stimulated splenocytes and unstimulated islets from mice of different ages and strains, and proliferative and cytokine responses of T effectors to Treg in vitro. Results: Tolerising RelB lo DC significantly inhibited diabetes progression when administered to 4 week but not 14 week-old mice. IL-1β production by NOD splenocytes and mRNA expression by islets increased from 6-16 weeks of age, when MHC-restricted islet antigen presentation to autoreactive T cells occurred. IL-1 reduced the capacity of Treg cells to suppress effector cells and promoted their conversion to Th17 cells. RelB lo DC exacerbated the IL-1-dependent decline in Treg function and promoted Th17 conversion. Conclusion: IL-1β, generated by islet-autoreactive cells in MHC-susceptible mice, accelerates diabetes by differentiating Th17 at the expense of Treg. Tolerizing DC-therapies can regulate islet autoantigen priming and prevent diabetes, but progression past the IL-1β/IL-17 checkpoint signals the need for other strategies.
Renegade homeostatic cytokine responses in T1D: Drivers of regulatory/effector T cell imbalance
Clinical Immunology, 2014
Homeostatic cytokines contribute to the balance between regulatory and effector T cells (Tregs and Teffs respectively) and are necessary to maintain peripheral tolerance. These cytokines include IL-2 that supports Treg and IL-7 and IL-15 that drive Teff. In overt settings of lost tolerance (i.e. graft rejection), IL-2 Treg signatures are decreased while IL-7 and IL-15 Teff signatures are often enhanced. Similar cytokine profile imbalances also occur in some autoimmune diseases. In type 1 diabetes (T1D), there are underlying defects in the IL-2 pathway and Teff cytokine blockade can prevent and treat diabetes in NOD mice. In this review, we summarize evidence of IL-2, IL-7 and IL-15 genetic and cellular alterations in T1D patients. We then discuss how the combined effect of these cytokine profiles may together contribute to altered Treg/Teff ratios and functions in T1D. Implications for combination therapies and suggestions for integrated cytokine and Treg/Teff biomarker development are then proposed.
Dynamic Immune Phenotypes of B and T Helper Cells Mark Distinct Stages of T1D Progression
Diabetes, 2019
Multiple studies of B- and T-cell compartments and their response to stimuli demonstrate alterations in established type 1 diabetes (T1D). Yet it is not known whether these alterations reflect immune mechanisms that initiate islet autoimmunity, promote disease progression, or are secondary to disease. To address these questions, we used samples from the TrialNet Pathway to Prevention study to investigate T-cell responses to interleukin (IL)-2 and regulatory T cell–mediated suppression, the composition of the B-cell compartment, and B-cell responses to B-cell receptor and IL-21 receptor engagement. These studies revealed stage-dependent T- and B-cell functional and immune phenotypes; namely, early features that differentiate autoantibody-positive at-risk first-degree relatives (FDRs) from autoantibody-negative FDRs and persisted through clinical diagnosis; late features that arose at or near T1D diagnosis; and dynamic features that were enhanced early and blunted at later disease sta...
Immunobiology, 2013
A balance between proinflammatory (Th17 and Tc17) and anti-inflammatory (regulatory T cells) subsets of T cells is essential to maintain immunological tolerance and prevent the onset of several autoimmune diseases, including type 1 diabetes. However, the kinetics of these subsets and disease severity during the streptozotocin (STZ)-induced diabetes course has not been determined. Thus, susceptible C57BL/6 mice were administrated with multiple low doses of STZ and we evaluated the frequency/absolute number of these T cell subsets in the pancreatic lymph nodes (PLNs) and spleen and Th1, Th17, Treg cytokine production in the pancreatic tissue. At different time points of the disease progression (6, 11, 18 and 25 days after the last STZ administration), the histopathological alterations were also evaluated by H&E and immunohistochemistry staining. During the initial phase of diabetes development (day 6), we noted increased numbers of CD4 + and CD8 + T cells in spleen and PLNs. At the same time, the frequencies of Th17 and Tc17 cells in PLNs were also enhanced. In addition, the early augment of interferon gamma (IFN-␥), tumoral necrosis factor (TNF-␣), IL-6 and IL-17 levels in pancreatic tissue correlated with pancreatic islet inflammation and mild -cell damage. Notably, the absolute number of Treg cells increased in PLNs during over time when compared to control group. Interestingly, increased IL-10 levels were associated with control of the inflammatory process during the late phase of the type 1 diabetes (day 25). In agreement, mice lacking the expression of IL-17 receptor (Il17r) showed impairment in STZ-induced diabetes progression, reduced peri-insulitis and beta cells preservation when compared with wild-type mice. Our findings suggest that dynamic changes of pathogenic Th17/Tc17 and regulatory T cell subsets numbers is associated with early strong inflammation in the pancreatic islets followed by late regulatory profile during the experimental STZ-induced diabetes course.
Diabetes, 2011
The effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DCs), is greater when administered to young nonobese diabetic (NOD) mice than at peak insulitis. RelB(lo) DCs, generated in the presence of an nuclear factor-κB inhibitor, induce T-regulatory (Treg) cells and suppress inflammation in a model of rheumatoid arthritis. Interleukin (IL)-1β is overexpressed in humans and mice at risk of type 1 diabetes, dysregulates Treg cells, and accelerates diabetes in NOD mice. We investigated the relationship between IL-1β production and the response to RelB(lo) DCs in the prediabetic period. We injected RelB(lo) DCs subcutaneously into 4- or 14-week-old NOD mice and tracked the incidence of diabetes and effect on Treg cell function. We measured the expression of proinflammatory cytokines by stimulated splenocytes and unstimulated islets from mice of different ages and strains and proliferative and cytokine responses of T effectors to Treg in vitro. ...
Diabetes, 2010
OBJECTIVEThe effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DCs), is greater when administered to young nonobese diabetic (NOD) mice than at peak insulitis. RelBlo DCs, generated in the presence of an nuclear factor-κB inhibitor, induce T-regulatory (Treg) cells and suppress inflammation in a model of rheumatoid arthritis. Interleukin (IL)-1β is overexpressed in humans and mice at risk of type 1 diabetes, dysregulates Treg cells, and accelerates diabetes in NOD mice. We investigated the relationship between IL-1β production and the response to RelBlo DCs in the prediabetic period.RESEARCH DESIGN AND METHODSWe injected RelBlo DCs subcutaneously into 4- or 14-week-old NOD mice and tracked the incidence of diabetes and effect on Treg cell function. We measured the expression of proinflammatory cytokines by stimulated splenocytes and unstimulated islets from mice of different ages and strains and proliferative and cytokine responses of T...
Antigen-Specific Regulatory T Cells and Low Dose of IL-2 in Treatment of Type 1 Diabetes
Frontiers in Immunology, 2016
Regulatory T cells (Tregs) play an important role in preventing effector T-cell (Teff) targeting of self-antigens that can lead to tissue destruction in autoimmune settings, including type 1 diabetes (T1D). Autoimmunity is caused in part by an imbalance between Teff and Tregs. Early attempts to treat with immunosuppressive agents have led to serious side effects, thus requiring a more targeted approach. Low-dose IL-2 (LD IL-2) can provide immunoregulation with few side effects by preferentially acting on Tregs to drive tolerance. The concept of LD IL-2 as a therapeutic approach is supported by data in mouse models where autoimmunity is cured and further strengthened by success in human clinical studies in hepatitis C virus-induced vasculitis, chronic graft-versus-host disease, and Alopecia areata. Treatment will require identification of a safe therapeutic window, which is a difficult task given that patients are reported to have deficient or defective IL-2 production or signaling and have experienced mild activation of NK cells and eosinophils with LD IL-2 therapy. In T1D, an LD IL-2 clinical trial concluded that Tregs can be safely expanded in humans; however, the study was not designed to address efficacy. Antigen-specific therapies have also aimed at regulation of the autoimmune response but have been filled with disappointment despite an extensive list of diverse islet antigens tested in humans. This approach could be enhanced through the addition of LD IL-2 to the antigenic treatment regimen to improve the frequency and function of antigen-specific Tregs, without global immunosuppression. Here, we will discuss the use of LD IL-2 and islet antigen to enhance antigen-specific Tregs in T1D and focus on what is known about their immunological impact, their safety, and potential efficacy, and need for better methods to identify therapeutic effectiveness.
The Journal of Clinical Endocrinology & Metabolism, 1999
Type I (insulin-dependent) diabetes mellitus (IDDM) is an autoimmune disease that results from the destruction of insulin-secreting pancreatic islet -cells by autoreactive cells and their mediators. Although its exact cause is not completely understood, it is well established that IDDM is associated with dysregulated humoral and cellular immunity, exemplified by altered production of and response to macrophage-and T cell-derived cytokines and a shift in T helper (Th) cell differentiation in favor of a pathogenic Th1 pathway. Th1 cytokines, including interleukin-2 and interferon-␥, induced islet -cell destruction directly by accelerating activation-induced cell death (apoptosis) and by up-regulating the expression of select adhesion molecules, Th1 cytokines facilitated the pancreatic homing of autoreactive leukocytes, hence enhancing -cell destruction. More