H-Y-Specific T Cell Responses in Chronic GvHD

移植物抗宿主病(GVHD)是异基因移植最严重和最常见的长期并发症。 造血细胞移植，通过识别受体的次要或主要 供者T细胞的组织相容性抗原。MHC相合的男性造血细胞移植受者 女性捐献者(F&GT；M Hct)为研究特定捐赠者T细胞的贡献提供了一个独特的机会 对移植物抗宿主病(GVHD)发展和持续的反应。F-M Hct为 临床特点是急性和历史上定义的慢性移植物抗宿主病的发病率较高，以及 GVHD的平均治疗时间比任何其他供受者性别组合都要长。 在细胞水平上，F-M移植的特点是出现供者(女性)T细胞 对Y染色体蛋白产物的反应--称为H-Y抗原--这在 其他捐赠者和受赠者的组合。因此，F-MHCT受者承担的额外GVHD负担可能在 部分原因是女性T细胞对H-Y抗原的反应。该项目中的研究将测试 供者T细胞对H-Y抗原的应答与存活100天以上的GVHD有关的假说 在F-MHCT之后，F-MHCT后长期的移植物-宿主耐受将与缺失相关， 使这些反应失活或抑制。这些研究的结果应该会让我们深入了解 负责全球艾滋病毒/艾滋病的发展和持续的机制，从而将提供 旨在克服同种异体反应和促进捐赠者-宿主的未来干预措施的理由和方向 宽容。该项目的具体目标是： (1)明确男性CD8+和CD4+效应性T细胞对H-Y抗原反应的特异性 接受MHC相合的女性捐献者的造血细胞移植。 (2)确定F-M血细胞移植受者体内是否存在H-Y特异性效应T细胞 与异基因HCT后+100天以上移植物抗宿主病的存在相关。 (3)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细胞的删除、失活或抑制。 相关性(请参阅说明)： 异基因造血细胞移植治疗血液病的疗效 严重受限于一种称为移植物抗宿主病(GVHD)的并发症。在这篇文章中描述的研究 该项目将调查特定识别受者的捐赠者免疫反应是否 与移植物抗宿主病的发展有关。这些研究可能会导致改进战略，以 未来预防或治疗移植物抗宿主病。

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.