Role of macrophages in pancreatic islet graft rejection

巨噬细胞在胰岛移植排斥中的作用

• 批准号: 8707446
• 负责人: Midhat H Abdulreda
• 金额: $ 13.83万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707446
• 关键词: Acute; Adverse effects; Allogenic; Allografting; Antibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Beta Cell; Blocking Antibodies; CD3 Antigens; CD8B1 gene; Cell physiology; Cells; Chronic; Data; Effector Cell; Elements; Eye; Goals; Graft Rejection; Image; Immune; Immune response; Immune system; Immunosuppression; In Situ; Infiltration; Inflammation; Inflammatory Response; Insulin; Insulin-Dependent Diabetes Mellitus; Interferon Gamma Receptor Complex; Interferon Type II; Intervention; Islets of Langerhans; Islets of Langerhans Transplantation; Knowledge; Label; Lymphoid Cell; Macrophage Activation; Malignant Neoplasms; Mediating; Molecular; Monitor; Movement; Mus; Myeloid Cells; Natural Immunity; Phenotype; Process; Recurrence; Research; Resolution; Role; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transplantation; Transplanted tissue; Validation; Work; Wound Healing; adaptive immunity; allograft rejection; anterior chamber; arm; base; chemokine; cytokine; improved; in vivo; in vivo Model; in vivo imaging; islet; islet allograft; knowledge base; macrophage; non-invasive imaging; novel; prevent; public health relevance; reconstitution; response

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.

描述（由候选人提供）：胰岛移植已成为治疗 1 型糖尿病 (T1D) 的一种有前途的疗法。在胰岛移植后的前五到七年内，已经实现了完全且持久的胰岛素独立。然而，移植胰岛的长期接受和存活目前主要由于免疫介导的排斥和/或自身免疫的复发而受到限制。广泛的研究工作致力于了解适应性免疫系统的效应细胞排斥胰岛移植物的分子机制。新出现的证据还表明，先天免疫系统在这一过程中发挥着重要作用，无论是直接作用还是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串扰部分是通过骨髓细胞产生的可溶性因子（例如细胞因子、趋化因子）介导的，这些因子促进效应淋巴细胞向移植组织的募集。然而，人们对移植物内免疫系统的这两个臂之间可能发生的细胞与细胞接触知之甚少。在此应用中，我们的目标是确定移植物浸润巨噬细胞和效应 T 淋巴细胞之间的细胞接触在胰岛排斥反应中的作用。我们的初步结果表明，同基因和同种异体受体小鼠移植后不久，巨噬细胞浸润胰岛移植物，但在急性排斥反应过程中，同种异体移植物中浸润巨噬细胞的数量显着增加。结果还表明，同种异体移植受者中巨噬细胞的消耗延迟了排斥反应。这些结果表明巨噬细胞参与同基因和同种异体移植物中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过程中发挥积极作用。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-细胞接触促进了通常参与伤口愈合和组织重塑的浸润M2巨噬细胞转化为M1巨噬细胞，从而在胰岛同种异体移植排斥中促进效应细胞功能。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，2011）。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）巨噬细胞对于有效的胰岛同种异体移植排斥是必需的~（2）浸润巨噬细胞在急性排斥期间获得M1表型~以及（3）巨噬细胞M2/M1转换是通过局部细胞与 T 淋巴细胞的接触介导。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中的积极作用的新型细胞机制。重要的是，这一新概念将使局部干预措施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。这些发现将对一般移植疗法以及癌症和自身免疫性疾病产生影响。