![]() ![]() ( 11) showed that mice deficient in RAGE (RAGE−/−) were protected from the lethal effects of septic shock following cecal ligation, and suggested that RAGE plays a role in propagating inflammation. A role for RAGE in innate responses has been identified. However, there are other ligands for RAGE, including S100/calgranulins and HMGB1, products of cellular destruction that may be generated during inflammatory responses and released by inflammatory cells ( 10). RAGE was originally identified as the receptor for ligands for molecules whose concentrations are increased in patients with diabetes, and a role for this molecule in the development of secondary end-organ complications has been postulated. The pattern recognition receptor, receptor for advanced glycation endproducts (RAGE), 3 is a potential link between adaptive and innate responses ( 9). Clearly the progression to diabetes in animal models and in humans is primarily dependent on the adaptive responses of T cells, but the way in which the early innate responses lead to and shape adaptive immune responses is not clear. In contrast, blockade of NKG2D prevented diabetes in NOD mice ( 8). Activation of NK T cells with α-gal-cer was shown to prevent diabetes in the NOD mouse, and a biased response of invariant Vα24JαQ T cells was identified in first degree relatives of patients who progressed to diabetes when compared with nonprogressors ( 6, 7). Innate immune responses have also been shown to be involved in the control of adaptive responses. In support of this hypothesis, deficiency of IL-1 receptor and treatment with IL-1 receptor antagonist attenuates the rate of diabetes in NOD mice ( 4, 5). The link between innate and adaptive immune responses has led investigators to postulate a role of innate responses in regulating autoimmune diseases such as Type 1 diabetes ( 2, 3). ![]() Activation of innate responses may also alter the way in which Ags are presented to T and other cells of the adaptive immune response. “Danger signals,” for example, those initiated by stressed or dying cells, may stimulate pathogen-associated molecular pattern receptors, such as TLR, that lead to expression of molecules that activate the adaptive immune responses ( 1). Immune responses to foreign and autoantigens involve activation of both innate and adaptive immune responses. We conclude that activation of RAGE on T cells is involved in early events that lead to differentiation of Th1 + T cells. Indeed, by real-time PCR, we found higher levels of RAGE mRNA expression on clonal T cells activated under Th1 differentiating conditions. Furthermore, culture supernatants from cultures with anti-CD3 and anti-CD28 mAbs showed higher levels of IL-10, IL-5, and TNF-α with RAGE−/− compared with WT T cells, and WT T cells showed reduced production of IFN-γ in the presence of TTP488, suggesting that RAGE may be important in the differentiation of T cell subjects. Overall T cell proliferation following activation with anti-CD3 and anti-CD28 mAbs were similar in RAGE−/− and WT cells, but RAGE−/− T cells did not respond to costimulation with anti-CD28 mAb. This response in vivo correlated with reduced proliferative responses of RAGE−/− T cells in MLRs and in WT T cells cultured with TTP488. RAGE−/− mice with streptozotocin-induced diabetes showed delayed rejection of islet allografts compared with wild type (WT) mice ( p < 0.02). Syngeneic islet graft and islet allograft rejection was reduced in NOD and B6 mice treated with TTP488, a small molecule RAGE inhibitor ( p < 0.001). We have studied the effects of a small molecule inhibitor of RAGE and the deletion of the receptor (RAGE−/− mice) on T cell responses involved in autoimmunity and allograft rejection. ![]() The pattern recognition receptor, RAGE, has been shown to be involved in adaptive immune responses but its role on the components of these responses is not well understood.
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