Modification of adverse inflammation is required to cure new-onset type 1 diabetic hosts (original) (raw)
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The Journal of Immunology, 2015
Regulatory T cells (Treg) play a crucial role in the maintenance of self-tolerance. In this study, we sought to expand Ag-specific Tregs in vivo and investigate whether the expanded Tregs can prevent or delay the development of type 1 diabetes (T1D) in the NOD mouse model. NOD mice were treated with a combination of IL-2/anti–IL-2 Ab complex, islet Ag peptide, and rapamycin. After the combined treatment, CD4+CD25+Foxp3+ Tregs were significantly expanded in vivo, they expressed classical Treg markers, exerted enhanced suppressive functions in vitro, and protected against spontaneous development of T1D in NOD mice. Moreover, treated mice were almost completely protected from the adoptively transferred, aggressive form of T1D caused by in vitro–activated cytotoxic islet Ag-specific CD8 T cells. Protection from T1D was transferrable by Tregs and could be attributed to reduced islet infiltration of immune cells as well as the skewing of the immune response toward a Th2 cytokine profile. ...
Diabetes, 2009
OBJECTIVE-The autoimmune destruction of -cells in type 1 diabetes results in a loss of insulin production and glucose homeostasis. As such, an immense interest exists for the development of therapies capable of attenuating this destructive process through restoration of proper immune recognition. Therefore, we investigated the ability of the immune-depleting agent antithymocyte globulin (ATG), as well as the mobilization agent granulocyte colony-stimulating factor (GCSF), to reverse overt hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes.
Curative and cell regenerative effects of 1-antitrypsin treatment in autoimmune diabetic NOD mice
Proceedings of the National Academy of Sciences, 2008
Invasive insulitis is a destructive T cell-dependent autoimmune process directed against insulin-producing  cells that is central to the pathogenesis of type 1 diabetes mellitus (T1DM) in humans and the clinically relevant nonobese diabetic (NOD) mouse model. Few therapies have succeeded in restoring long-term, drug-free euglycemia and immune tolerance to  cells in overtly diabetic NOD mice, and none have demonstrably enabled enlargement of the functional  cell mass. Recent studies have emphasized the impact of inflammatory cytokines on the commitment of antigen-activated T cells to various effector or regulatory T cell phenotypes and insulin resistance and defective insulin signaling. Hence, we tested the hypothesis that inflammatory mechanisms trigger insulitis, insulin resistance, faulty insulin signaling, and the loss of immune tolerance to islets. We demonstrate that treatment with ␣1-antitrypsin (AAT), an agent that dampens inflammation, does not directly inhibit T cell activation, ablates invasive insulitis, and restores euglycemia, immune tolerance to  cells, normal insulin signaling, and insulin responsiveness in NOD mice with recent-onset T1DM through favorable changes in the inflammation milieu. Indeed, the functional mass of  cells expands in AAT-treated diabetic NOD mice.
Transplantation, 2002
Background. Successful islet transplantation in type 1 diabetes requires tolerance induction of both alloand autoreactive T-cell responses. Monoclonal antibodies targeting the CD4 coreceptor on T-helper cells have been shown to be effective in this regard. In type 1 diabetes, there is some evidence to suggest that cytokines such as interleukin (IL)-1 may be involved in -cell destruction. The high glucose levels associated with type 1 diabetes are also known to be toxic to beta cells. Method. The tempo of T-cell and macrophage infiltration into syngeneic islets transplanted into diabetic nonobese diabetic (NOD) mice was examined by immunohistochemistry. We investigated the ability of a nondepleting anti-CD4 monoclonal antibody (YTS177) to induce tolerance to syngeneic islet grafts in female spontaneous diabetic NOD mice and in an adoptive transfer model of diabetes in NOD mice. The spontaneous model was used to test the effect on graft function of perioperative insulin therapy in mice treated with YTS177. The ability of soluble interleukin (sIL)-1 receptor (R) type II (sIL-1RII) to inhibit IL-1 effects in syngeneic islet transplants was also assessed. Results. Cellular infiltration of CD3 ؉ cells and macrophages into the islet graft coincided with loss of graft function in untreated mice. Self-tolerance to beta cells was restored with YTS177, allowing long-term graft survival in a proportion of animals. The use of perioperative insulin therapy increased the number of successful grafts in spontaneously diabetic NOD mice treated with YTS177. The combination of YTS177 with sIL-1RII significantly improved the rates of graft survival compared with graft survival in YTS177-treated spontaneously diabetic NOD mice. Conclusions. Nondepleting anti-CD4 antibodies restore self tolerance to syngeneic islet transplants in diabetic NOD mice. Insulin therapy improves graft survival in mice treated with YTS177. Preventing the action of IL-1 greatly improves graft survival induced with YTS177.
Clinical and Experimental Immunology, 1997
SUMMARY The effect of an IL-1 receptor antagonist on recurrence of hyperglycaemia after syngeneic pancreatic islet transplantation to spontaneously diabetic female NOD mice was investigated. The transplanted animals were treated with either the receptor antagonist (8.0 mg/kg body weight per day for 12–14 days) or PBS, delivered by subcutaneously implanted osmotic pumps. In the control animals, a transient normoglycaemia was achieved, but hyperglycaemia was generally observed 6 days after islet transplantation. Administration of IL-1 receptor antagonist had a clear protective effect against recurrence of hyperglycaemia until day 14, but after cessation of drug delivery hyperglycaemia re-appeared. The results indicate that continuous administration of the IL-1 receptor antagonist can prevent recurrence of the diabetogenic process in NOD mice. IL-1 receptor antagonist may therefore become a useful adjuvant immunomodulating therapy after human islet transplantation in insulin-dependent ...