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Type 1 diabetes is a disorder of insulin deficiency resulting from the autoimmune destruction of β-cells (1). Monoclonal antibodies directed against a variety of lymphocyte subsets or their products (e.g., [...], OBJECTIVE--Antilymphocyte serum can reverse overt type 1 diabetes in NOD mice; yet, the therapeutic parameters and immunological mechanisms underlying the ability for this agent to modulate autoimmune responses against β-cells are unclear, forming the rationale for this investigation. RESEARCH DESIGN AND METHODS--A form of antilymphocyte serum, rabbit anti-mouse thymocyte globulin (mATG), was utilized in a variety of in Vivo and in vitro settings, each for the purpose of defining the physiological, immunological, and metabolic activities of this agent, with particular focus on actions influencing development of type 1 diabetes. RESULTS--We observed that mATG attenuates type 1 diabetes development in an age-dependent fashion, only proving efficacious at disease onset or in the late pre-diabetic phase (12 weeks of age). When provided at 12 weeks of age, mATG reversed pancreatic insulitis, improved metabolic responses to glucose challenge, and rapidly increased frequency of antigen-presenting cells in spleen and pancreatic lymph nodes. Surprisingly, mATG therapy dramatically increased, in an age-dependent fashion, the frequency and the functional activity of [CD4.sup.+] [CD25.sup.+] regulatory T-cells. Adoptive transfer/cotransfer studies of type 1 diabetes also support the concept that mATG treatment induces a stable and transferable immunomodulatory repertoire in Vivo. CONCLUSIONS--These findings indicate that an induction of immunoregulation, rather than simple lymphocyte depletion, contributes to the therapeutic efficacy of antithymocyte globulin and suggest that time-dependent windows for the ability to delay or reverse type 1 diabetes exist based on the capacity to enhance the functional activity of regulatory T-cells.

Type 1 diabetes is an autoimmune disease characterized by a local inflammatory reaction in and around islets followed by selective destruction of insulin-secreting β-cells (1). The factors leading to the [...], OBJECTIVE--Type 1 diabetes is an autoimmune disease characterized by a local inflammatory reaction in and around islets followed by selective destruction of insulin-secreting p-cells. We tested the hypothesis that chemokines affect different mechanisms responsible for the development of diabetes in NOD mice. RESEARCH DESIGN AND METHODS--We examined chemokine expression in islets of NOD mice and tested their functional relevance to development of diabetes using transgenic mice expressing the mouse herpesvirus 68-encoded chemokine decoy receptor M3 (NOD-M3 mice) in insulin-secreting β-cells. RESULTS--Multiple chemokines were expressed in pancreatic islets of NOD mice before development of diabetes. Islet-specific expression of the pan-chemokine inhibitor M3 dramatically reduced leukocyte infiltration and islet destruction and completely blocked development of diabetes in NOD-M3 mice. M3 blocked diabetes by inhibiting the priming of diabetogenic cells in the pancreatic lymph nodes and their recruitment into the islets. This effect was specific to the pancreatic islets because M3 expression did not affect other ongoing autoimmune processes. CONCLUSIONS--These results demonstrate that chemokines mediate afferent and efferent immunity in type 1 diabetes and suggest that broad chemokine blockade may represent a viable strategy to prevent insulitis and islet destruction.