H-Y-Specific T Cell Responses in Chronic GvHD

移植物抗宿主病（GVHD）是同种异体移植最严重和最常见的长期并发症， 造血细胞移植，并通过识别受体次要或主要介导 组织相容性抗原通过供体T细胞。来自MHC匹配的造血细胞移植的男性受者 女性供体（F->M HCT）提供了研究特异性供体T细胞的贡献的独特机会。 对移植物抗宿主病（GVHD）的发展和持续的反应。F-M HCT是 临床特征为急性和历史定义的慢性GVHD的发生率较高，以及 GVHD治疗的平均持续时间长于任何其他供体-受体性别组合。 在细胞水平上，F-M移植的特征是供体（女性）T细胞的出现， 对Y染色体蛋白产物的反应-称为H-Y抗原-这是不可能的， 其他捐赠者-接受者组合。因此，F-MHCT接受者承担的额外GVHD负担可能会增加， 部分归因于女性T细胞对H-Y抗原的应答。该项目的研究将测试 供体T细胞对H-Y抗原应答导致+100天存活者中GVHD的假设 在F-<$MHCT之后，并且在F-<$MHCT之后的长期移植物-宿主耐受性将与缺失相关， 抑制或抑制这些反应。这些研究的结果应该提供深入了解 负责GVHD的发展和持续的机制，从而将提供 未来旨在克服同种异体反应性和促进供体-宿主 宽容该项目的具体目标是： (1)目的探讨男性外周血CD 8+和CD 4+效应T细胞对H-Y抗原反应的特异性。 来自MHC匹配的女性供体的造血细胞移植物的接受者。 (2)为了确定是否存在H-Y-特异性效应T细胞在受体F-<$M HCT 与同种异体HCT后+100天后GVHD的存在相关。 (3)为了确定F-<$MHCT后移植物-宿主耐受性的发展是否与 H-Y特异性T细胞的缺失、失活或抑制。 相关性（参见说明）： 异基因造血细胞移植治疗血液病的有效性是 严重受限于移植物抗宿主病（GVHD）的并发症。本文中描述的研究 该项目将调查是否捐赠者免疫反应，特别是识别受体， 与GVHD的发展有关。这些研究可能会导致改善的战略， 预防或治疗GVHD。

Graft-versus-host disease (GVHD) is the most serious and common long-term complication of allogeneic hematopoietic cell transplantation, and is mediated by recognition of recipient minor or major histocompatibility antigens by donor T cells. Male recipients of hematopoietic cell grafts from MHC-matched female donors (F->M HCT) provide a unique opportunity to study the contribution of specific donor T cell responses to the development and persistence of graft-versus-host disease (GVHD). F-¿M HCT is characterized clinically by a higher incidence of both acute and historically defined chronic GVHD, as well as a longer mean duration of treatment for GVHD, than that seen in any other donor-recipient sex combination. At the cellular level, F-¿M transplants are characterized by the occurrence of donor (female) T cell responses against protein products of the Y chromosome - termed H-Yantigens - which are not possible in other donor-recipient combinations. Thus, the excess GVHD burden borne by F-¿MHCT recipients may in part be attributable to female T cell responses against H-Y antigens. The studies in this project will test the hypothesis that donor T cell responses against H-Y antigens contribute to GVHD among day +100 survivors after F-¿MHCT, and that long-term graft-host tolerance after F-¿MHCT will be associated with deletion, inactivation, or suppression of these responses. The results of these studies should provide insight into the mechanisms responsible for the development and persistence of GVHD, and will thereby provide the rationale and direction for future interventions aimed at overcoming alloreactivity and facilitating donor-host tolerance. The specific aims of this project are: (1) To define the specificity of the CD8+ and CD4+ effector T cell response to H-Y antigens in male recipients of hematopoietic cell grafts from MHC-matched female donors. (2) To determine whether the presence of H-Y-specific effector T cells in recipients of F-¿M HCT correlates with the presence of GVHD beyond day +100 after allogeneic HCT. (3) To determine whether the development of graft-host tolerance after F-¿MHCTis associated with deletion, inactivation, or suppression of H-Y-specific T cells. RELEVANCE (See instructions): The effectiveness of allogeneic hematopoietic cell transplantation for the treatment of blood diseases is significantly limited by a complication called graft-versus-host disease (GVHD). The studies described in this Project will investigate whether donor immune responses specifically recognizing the recipient are associated with the development of GVHD. These studies could potentially lead to improved strategies for preventing or treating GVHD in the future.