![]() ( 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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