Role of macrophages in pancreatic islet graft rejection

描述（由候选人提供）：胰岛移植已成为1型糖尿病（T1 D）的一种有前途的治疗方法。在胰岛移植后的前五到七年内，已经实现了完全和持久的胰岛素依赖性。然而，移植的胰岛的长期接受和存活目前是有限的，主要是由于免疫介导的排斥反应和/或自身免疫的复发。广泛的研究努力致力于了解适应性免疫系统的效应细胞对胰岛移植物排斥的分子机制。新出现的证据也表明先天免疫系统在这一过程中的重要作用，无论是直接还是通过与适应性免疫系统细胞的交叉作用。这些证据表明，先天免疫和适应性免疫之间的相互作用部分是通过可溶性因子介导的（例如，细胞因子、趋化因子），其促进效应淋巴细胞向移植组织的募集。然而，对于移植物内免疫系统的这两个臂之间可能发生的细胞-细胞接触知之甚少。在这个应用中，我们的目的是建立细胞间的作用，移植物浸润的巨噬细胞和效应T淋巴细胞在胰岛排斥反应。我们的初步结果表明，巨噬细胞浸润胰岛移植后不久，在同基因和异基因受体小鼠，但浸润的巨噬细胞的数量显着增加，在急性排斥反应的进展过程中，在同种异体移植物。结果还表明，同种异体移植受体中巨噬细胞的耗尽会延迟排斥反应。这些结果表明巨噬细胞参与同系和同种异体胰岛移植后的初始炎症反应，并在随后的同种异体移植物急性排斥反应中发挥积极作用。因此，我们假设巨噬细胞和效应T淋巴细胞之间的局部细胞-细胞接触促进了浸润的M2巨噬细胞（通常参与伤口愈合和组织重塑）向M1巨噬细胞的转化，M1巨噬细胞在胰岛同种异体移植排斥反应中发挥效应细胞的功能。为了检验这一假设，我们将使用我们独特的技术平台对移植后胰岛内的免疫细胞进行纵向、非侵入性体内成像（Abdulreda等人，2011年）。我们将通过追求以下三个具体目标来实现本申请的目的：（1）巨噬细胞是有效的胰岛移植排斥反应所必需的;（2）在急性排斥反应期间，浸润性巨噬细胞获得M1表型;（3）巨噬细胞M2/M1转化是通过与T淋巴细胞的局部细胞-细胞接触介导的。这些目标的预期结果将在靶组织内建立局部细胞-细胞接触，作为巨噬细胞在胰岛排斥反应中发挥积极作用的新细胞机制。重要的是，这一新概念将使局部干预能够提高移植胰岛的接受度，并将最大限度地减少/预防与慢性免疫抑制相关的破坏性全身副作用。这些发现将对移植治疗以及癌症和自身免疫性疾病产生影响。

DESCRIPTION (provided by candidate): Pancreatic islet transplantation has emerged as a promising therapy for type 1 diabetes mellitus (T1D). Complete and persistent insulin independence has been accomplished during the first five to seven years after islet transplantation. However, long-term acceptance and survival of transplanted islets is currently limited mainly due to immune-mediated rejection and/or recurrence of autoimmunity. Extensive research efforts have been dedicated to understanding the molecular mechanisms underlying rejection of islet grafts by effector cells of the adaptive immune system. Emerging evidence also suggest a prominent role of the innate immune system in this process, either directly or through cross-talk with the adaptive immune system cells. Such evidence indicate that cross-talk between innate and adaptive immunity is mediated in part via soluble factors (e.g., cytokines, chemokines) produced by myeloid cells that promote recruitment of effector lymphoid cells to transplanted tissues. However, little is known about the cell-cell contacts that may take place between these two arms of the immune system within the grafts. In this application, we aim to establish the role of cell-cell contacts between graft-infiltrating macrophages and effector T lymphocytes in islet rejection. Our preliminary results showed that macrophages infiltrated islet grafts shortly after transplantation in both syngeneic and allogeneic recipient mice, but the number of infiltrating macrophages increased significantly in the allografts during progression of acute rejection. The results also showed that depletion of macrophages in allograft recipients delayed rejection. These results point to macrophage involvement in the initial inflammatory response after islet transplantation in both syngeneic and allogeneic grafts and to an active role during ensuing acute rejection of the allografts. We therefore hypothesized that local cell-cell contacts between macrophages and effector T lymphocytes promote conversion of infiltrating M2 macrophages, typically involved in wound healing and tissue remodeling, to M1 macrophages which subserve effector cell function in islet allograft rejection. To test this hypothesis, we will use our unique technological platform to perform longitudinal, non- invasive in vivo imaging of the immune cells within pancreatic islets after transplantation (Abdulreda et al., 2011). We will accomplish the objective of this application by pursuing the following three specific aims: (1) Macrophages are necessary for efficient islet allograft rejection~ (2) Infiltratng macrophages acquire M1 phenotype during acute rejection~ and (3) Macrophage M2/M1 conversion is mediated through local cell-cell contacts with T lymphocytes. The expected results from these aims will establish local cell-cell contacts within target tissues as a novel cellular mechanism underlying the active role of macrophages in pancreatic islet rejection. Importantly, this new concept will enable localized interventions to improve acceptance of transplanted islets and will minimize/prevent devastating systemic side effects associated with chronic immunosuppression. These findings will have implications in transplantation therapies in general, as well as in cancer and autoimmune conditions.