Role of macrophages in pancreatic islet graft rejection

描述（由候选人提供）：胰岛移植已成为治疗1型糖尿病（T1D）的一种有前景的治疗方法。在胰岛移植后的最初5 - 7年，完全和持续的胰岛素独立已经实现。然而，移植胰岛的长期接受和存活目前受到限制，主要是由于免疫介导的排斥反应和/或自身免疫的复发。广泛的研究工作致力于了解适应性免疫系统效应细胞对胰岛移植排斥反应的分子机制。新出现的证据也表明先天免疫系统在这一过程中起着突出的作用，要么直接作用，要么通过与适应性免疫系统细胞的相互作用。这些证据表明，先天免疫和适应性免疫之间的交叉对话部分是通过髓细胞产生的可溶性因子（如细胞因子、趋化因子）介导的，这些因子促进了效应淋巴细胞向移植组织的募集。然而，对于移植物中这两个免疫系统臂之间可能发生的细胞-细胞接触知之甚少。在这个应用中，我们的目标是建立移植物浸润巨噬细胞和效应T淋巴细胞之间的细胞-细胞接触在胰岛排斥反应中的作用。我们的初步结果显示，在同种和异体受体小鼠的胰岛移植后不久，巨噬细胞浸润，但随着急性排斥反应的进展，同种异体移植中浸润的巨噬细胞数量显著增加。结果还表明，巨噬细胞的消耗在同种异体移植受体延迟排斥反应。这些结果表明巨噬细胞参与了同种异体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巨噬细胞在胰岛异体移植排斥反应中具有效应细胞功能。为了验证这一假设，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 et al., 2011）。我们将通过追求以下三个具体目标来实现该应用的目标：(1)巨噬细胞是有效的胰岛异体移植排斥反应所必需的~(2)浸润性巨噬细胞在急性排斥反应中获得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积极作用的一种新的细胞机制。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/防止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.