Accommodation in Transplantation

 描述（由申请人提供）：肾移植激发强大的B细胞应答，产生对移植供体特异性的抗体。供体特异性抗体可引起急性和慢性排斥反应，有时甚至会导致移植失败。然而，供体特异性抗体有时在缺乏任何排斥证据的受体中检测到。在这种情况下，供体特异性抗体似乎引起对免疫和炎症损伤的抵抗，而不是排斥。使组织和器官能够适应免疫和炎症的途径已被广泛研究。但是，尚不清楚B细胞反应如何产生调节而不是排斥。这项拟议中的研究将解决肾移植受者的这一首要问题，这些受者在第一年接受供体特异性抗体检测并接受三次“协议”活检。作为第一个目标，将通过检测以下指标来鉴定肾移植供体特异性的B细胞应答： 血液中的供体特异性抗体;而且，还通过确定血液中供体特异性抗体分泌细胞的频率和同种型（因为供体特异性抗体可以被功能器官移植物充分吸收）。B细胞反应将根据“方案”活检中的发现来解释，以帮助确定反应是反映适应还是排斥。作为第二个目的，将比较IG可变区基因中突变的频率和来自供体特异性B细胞的编码抗体在适应和排斥中的亲合力和特异性范围。该项目的结果将表明调节是否是肾移植的常见结果。此外，B细胞在适应与排斥反应中的不同方面可能指向评估风险的新方法，甚至是移植、癌症和其他疾病中生物干预的新靶点。

 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.