The novel role of beta3 integrin in regulating alloimmunity

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Abstract Heart transplantation is the optimal therapy for patients with irreversible, end-stage heart disease. However, a several challenges remain to improve allograft and recipient survival. Immunosuppressive agents used to prevent rejection have improved, but they still cannot consistently eliminate acute and chronic rejection, and they are implicated in the pathogenesis of organ failure. New insights into how innate and adaptive immunity contribute to rejection, identification of new therapeutic targets, and novel approaches to promote immune tolerance are major unmet needs in transplantation. Early innate inflammatory responses in the organs (e.g., due to ischemia-reperfusion injuries) enhance acute and chronic heart allograft rejection. Integrins are heterodimeric cell surface receptors involved in immune cell trafficking and signaling; therefore, they are attractive targets to inhibit inflammation, including transplant rejection. The main goal of this project is to elucidate the novel role of β3 integrin in regulating alloimmune responses via control of platelet- and T cell- mediated immunity. Our ultimate objective is to develop new anti-β3 integrin-based strategies to promote engraftment. Our data indicate that β3 integrin-/- mice (β3-/-) show significantly prolonged heart allograft survival in comparison to wild-type (WT) mice, a finding that is associated with reduced CD8+ T cell infiltration into the grafts. We also show that β3 is expressed by activated CD8+ T cells, and that the trafficking of T cells from β3-/- mice is impaired. Notably, targeting β3 integrin also substantially reduces lesions typical of chronic rejection. The β3 subunit is shared by the two integrin molecules, αVβ3 and αIIbβ3, which are expressed by T cells and platelets, respectively. Based on extensive preliminary data, our specific hypothesis is that β3 on both cell types contributes to rejection. In this proposal, we aim to define the relative roles of β3 integrins expressed on platelets (in early promotion of inflammatory responses) and T cells (in enhancement of alloimmunity) in mediating allograft rejection. Furthermore, our targeted delivery method of therapeutics usingnanoparticles (NPs) has emerged as a promising method that increases efficacy and reduces side effects. Here, we have developed first- in-class NPs for targeted delivery of cyclic RGD tripeptides (cRGD) to suppress β3 integrin- mediated recruitment of platelets and T cells for early reduction of chronic rejection, using a murine model of heart transplantation. In this proposal, we present three main aims to determine the roles of αIIbβ3 on platelets (Aim 1) and T cell- expressed β3 (Aim 2) in regulating alloimmunity. In Aim 3, we will perfuse organs prior to transplantation with NPs carrying cRGD to promote graft acceptance.