Accommodation in Transplantation

 描述(由申请人提供)：肾移植引起强大的B细胞反应，产生针对移植供者的特异性抗体。供者特异性抗体可导致急性和慢性排斥反应，有时还会导致移植失败。然而，在缺乏任何排斥证据的受者身上，有时会检测到供者特异性抗体。在这种情况下，供者特异性抗体似乎能激发对免疫和炎症损伤的抵抗力，而不是排斥反应。使组织和器官适应免疫和炎症的途径已被广泛研究。但是，B细胞的反应如何产生适应而不是排斥尚不清楚。这项拟议的研究将解决肾移植受者的这一主要问题，这些受者在第一年接受供者特异性抗体检测并接受三次“常规”活检。作为第一个目标，肾移植捐赠者的B细胞反应将通过检测 这不仅是通过确定血液中的捐赠者特异性抗体分泌细胞的频率和类型(因为捐赠者特异性抗体基本上可以被正常的器官移植吸收)，也是通过确定血液中捐赠者特异性抗体分泌细胞的频率和同种类型。B细胞的反应将根据“常规”活检的结果进行解释，以帮助确定反应反映的是适应还是排斥。作为第二个目标，将比较免疫球蛋白可变区基因突变的频率以及供体特异性B细胞编码抗体在适应和排斥中的亲和力和特异性范围。该项目的结果将表明适应是否是肾移植的常见结果。此外，B细胞适应与排斥反应的不同方面可能指向评估风险的新方法，甚至是移植、癌症和其他疾病的生物干预的新目标。

 DESCRIPTION (provided by applicant): Kidney transplantation elicits powerful B cell responses, which generate antibodies specific for the transplant donor. Donor-specific antibodies can cause acute and chronic rejection and sometimes graft failure. However, donor-specific antibodies are sometimes detected in recipients who lack any evidence of rejection. In this setting, donor-specific antibodies appear to evoke resistance to immune and inflammatory injury instead of rejection. The pathways that enable tissues and organs to accommodate to immunity and inflammation have been studied extensively. But, how a B cell response generates accommodation instead of rejection is not known. The proposed research will address this overarching question in kidney transplant recipients who are tested for donor-specific antibodies and undergo three "protocol" biopsies during the first year. As a first objective, B cell responses specific for kidney transplant donors will be identified by testing for donor-specific antibodies in blood; but, also by determining the frequency and isotype of donor-specific antibody-secreting cells in blood (because donor-specific antibodies can be substantially absorbed by functioning organ grafts). B cell responses will be interpreted in the light of findings in "protocol" biopsies to help determine whether a response reflects accommodation or rejection. As a second objective, frequency of mutations in Ig variable region genes and the avidity and range of specificities of the encoded antibodies from donor-specific B cells in accommodation and rejection will be compared. The results of this project will indicate whether accommodation is a common outcome of kidney transplantation. Further, distinct facets of B cell responses in accommodation versus rejection could point to novel approaches to assessing risk and even new targets for biological intervention in transplantation, cancer and other conditions.