Acute Humoral Rejection of Renal Allografts

同种异体肾移植物的急性体液排斥

• 批准号: 7458986
• 负责人: Robert L Fairchild
• 金额: $ 37.34万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7458986
• 关键词: Acute; Allografting; Animal Model; Animals; Antibodies; Antibody Formation; Attenuated; B-Lymphocytes; Binding; Blood capillaries; CCR5 gene; Cells; Cellular Infiltration; Characteristics; Chemotactic Factors; Clinical; Complement 3d; Deposition; Development; Donor person; Edema; Endothelium; Event; Fibrin; Goals; Graft Rejection; Histopathology; Immunosuppression; Immunosuppressive Agents; Incidence; Infiltration; Inflammation; Inflammatory; Injury; Investigation; Kidney; Kidney Transplantation; Life; Mediating; Modeling; Myocardium; Neutrophil Infiltration; Outcome; Pathway interactions; Population; Production; Role; Serum; Study models; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Tissue Grafts; Tissues; Transplant Recipients; Transplantation; Treatment Protocols; base; capillary; cytokine; day; experience; graft failure; heart allograft; inhibiting antibody; insight; interstitial; kidney allograft; macrophage; neutrophil; novel; prevent; research study; response

DESCRIPTION (provided by applicant): Current immunosuppressive strategies have decreased the incidence of acute cellular rejection of renal and cardiac allografts. The incidence of acute humoral rejection (AHR) in renal transplant patients is increasing and is particularly difficult to treat. The occurrence of AHR is associated with donor-specific antibody binding to the graft endothelium followed by neutrophil and macrophage infiltration into the graft with subsequent interstitial fibrin deposition. Antibody mediated mechanisms leading to graft injury and loss remain poorly understood. Investigation into these mechanisms is hampered by the lack of good animal models to study the development of allograft injury as the donor-specific antibody response is initiated and increases and to develop strategy is to inhibit this antibody-mediated injury. For the most part, models studying acute humoral rejection use either transfer of graft-reactive antibodies or sensitization of recipients with donor cells which also primes donor-reactive T cell populations. During studies investigating the role of CCR5 in acute cellular rejection of cardiac allografts, we recently observed that the titers of donor-specific antibody in CCR5-deficient recipients were almost 20-fold higher than in wild-type recipients and the rejection of the allografts in the CCR5-deficient recipients was characteristic of acute humoral rejection. We have now extended these studies to the rejection of MHC-mismatched renal allografts. In wild-type C57BL/6 recipients, A/J renal allografts experience tubulitis with infiltration of CDS T cells but this resolves and the allograft is able to support the life of the recipient. In CCR5-deficient animals, the renal allografts are rejected between days 10 and 20 with heavy deposition of C3d, peritubular edema and neutrophil infiltration. At the time of rejection, the titers of donor-specific antibody in the CCR5-deficient recipients are more than 25-fold higher than those observed in wild-type recipients. These results have led us to propose the hypothesis that renal allografts experience acute humoral rejection in CCR5-deficient recipients. This hypothesis will be tested in three specific aims. In Specific Aim 1 we will directly test the role of antibody in mediating rejection of the renal allografts. In Specific Aim 2 we will test the induction of proinflammatory cytokines and their roles in mediating the rejection. In the final specific aim we will use a B cell depletion strategy to test the effect of limiting donor-specific antibody interaction with the renal allograft on immediate and long term graft injury.

描述（由申请人提供）：当前的免疫抑制策略降低了肾脏和心脏同种异体移植的急性细胞排斥反应的发生率。肾移植患者中急性体液排斥（AHR）的发生率正在增加，尤其难以治疗。 AHR的发生与供体特异性抗体结合与移植物内皮结合，然后中性粒细胞和巨噬细胞浸润到移植物中，随后发生间质纤维蛋白沉积。导致移植损伤和损失的抗体介导的机制知之甚少。由于缺乏良好的动物模型来研究同种异体移植损伤的发展，因此对这些机制进行了调查，因为供体特异性抗体反应的发展并增加并制定策略是抑制这种抗体介导的损伤。在大多数情况下，研究急性体液排斥的模型使用移植反应性抗体的转移或对供体细胞的受体敏化，这也是供体供体反应性T细胞种群的转移。在研究CCR5在心脏同种异体移植急性细胞排斥中的作用的研究中，我们最近观察到，供体特异性抗体在CCR5缺陷型受体中的滴度比野生型受体几乎高20倍，并且在CCR5缺乏受体中对同种异体的拒绝是CCR5缺乏症的抑制。现在，我们将这些研究扩展为拒绝MHC不匹配的肾脏同种异体移植物。在野生型C57BL/6受体中，A/J肾脏同种异体移植物经历了肾小球炎，随着CDS T细胞的浸润，但这种消退和同种异体移植能够支持受体的生活。在缺乏CCR5的动物中，肾脏同种异体移植物在第10至20天之间被拒绝，C3D沉积，周围浮肿和中性粒细胞浸润。在排斥反应时，CCR5缺陷受体中供体特异性抗体的滴度比野生型受体中观察到的受体高25倍以上。这些结果使我们提出了以下假设：肾脏同种异体移植物在CCR5缺乏的受体中经历急性体液排斥。该假设将以三个特定目的进行检验。在特定目标1中，我们将直接测试抗体在介导肾脏同种异体移植排斥反应中的作用。在特定目标2中，我们将测试促炎细胞因子及其在介导排斥中的作用。在最终的具体目的中，我们将使用B细胞耗竭策略来测试限制供体特异性抗体与肾脏同种异体移植对立即和长期移植损伤的影响。