H-Y-Specific T Cell Responses in Chronic GvHD

慢性 GvHD 中的 H-Y 特异性 T 细胞反应

• 批准号: 8309104
• 负责人: Edus Houston Warren
• 金额: $ 41.35万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309104
• 关键词: Acute; Allogenic; CD8B1 gene; Cell Transplantation; Cells; Chronic; Complication; Development; Effectiveness; Female; Future; H-Y Antigen; Hematological Disease; Hematopoietic; Histocompatibility Antigens; Immune response; Immunobiology; Incidence; Instruction; Intervention; Lead; Mediating; Minor; Proteins; Specificity; Survivors; T cell response; T-Lymphocyte; Testing; Transplantation; Y Chromosome; burden of illness; chronic graft versus host disease; graft vs host disease; improved; insight; male; prevent; response; sex; treatment duration

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.

移植物与宿主病（GVHD）是同种异体的最严重和常见的长期并发症 造血细胞移植，并通过识别受体小或主要的识别 供体T细胞的组织相容性抗原。 MHC匹配的造血细胞移植的男性接受者 女捐助者（F-> M HCT）提供了一个独特的机会来研究特定供体T细胞的贡献 对移植物抗宿主病（GVHD）的发展和持久性的反应。 f-¿m hct是 临床表征急性和历史上定义的慢性GVHD以及 GVHD的平均治疗持续时间要比其他任何供体 - 接收者的性别组合中所见。 在细胞水平上，F-？M移植的特征是出现供体（雌性）T细胞 对Y染色体的蛋白质产物的反应 - 称为H -yantigen-在 其他供体 - 录制组合。那是F-¿ 部分归因于针对H-Y抗原的雌性T细胞反应。该项目的研究将测试 假设供体T细胞对H-Y抗原的反应有助于第+100天的GVHD f- - MHCT之后，F- MHCT后的长期移植宿主公差将与删除相关， 失活或抑制这些反应。这些研究的结果应提供对 负责GVHD发展和持久性的机制，从而提供 未来干预措施的基本原理和方向旨在克服同种反应性和支持供体主持人 宽容。该项目的具体目的是： （1）定义CD8+和CD4+效应T细胞对男性H-Y抗原的特异性 来自MHC匹配的女供体的造血细胞移植物的接受者。 （2）确定f-€M HCT受体中H-Y特异性效应T细胞是否存在 与同种异体HCT之后的GVHD超过100天相关。 （3）确定F-f-€MHCTIS后移植物宿主公差的发展是否与 H-Y特异性T细胞的缺失，灭活或抑制。 相关性（请参阅说明）： 同种异性造血细胞移植对血液疾病治疗的有效性是 被称为移植物抗宿主病（GVHD）的并发症受到明显限制。其中描述的研究 项目将调查供体免疫反应是否专门承认接受者 与GVHD的发展有关。这些研究可能会导致改进的策略 将来防止或治疗GVHD。