Immunobiology of Tolerance FF Allogeneic Hematopoietic Cell Transplantation

耐受性FF同种异体造血细胞移植的免疫生物学

• 批准号: 8508157
• 负责人: John Andrew Hansen
• 金额: $ 115.5万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2015-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508157
• 关键词: Acceleration; Acute; Acute Graft Versus Host Disease; Address; Allogenic; Applications Grants; Biocompatible Materials; Blood specimen; CD8B1 gene; Cell Transplants; Cells; Chronic; Clinical; Clinical Research; Collaborations; Collection; Complication; Data; Development; Disease; Female; Frequencies; Future; Gene Expression; Goals; H-Y Antigen; Health; Hematopoietic; Histocompatibility Antigens; Immune; Immune Tolerance; Immunobiology; Immunosuppression; Incidence; Intervention; Lead; MHC binding peptide; Mediating; Methods; Minor; Monitor; Morbidity - disease rate; Normal Cell; Outcome; Pathway interactions; Patients; Phase; Process; Program Research Project Grants; Proteins; Public Health; Quality of life; Reaction; Regulatory T-Lymphocyte; Research; Research Personnel; Resource Sharing; Resources; Role; Specificity; Survivors; Syndrome; T cell response; T-Lymphocyte; Technology Assessment; Testing; Transplant Recipients; Transplantation; Universities; Work; Y Chromosome; burden of illness; chronic graft versus host disease; graft vs host disease; hematopoietic cell transplantation; human subject; illness length; improved; innovation; insight; male; mortality; programs; response; sex; treatment duration

DESCRIPTION (provided by applicant): This program project grant, titled "Immunobiology of Tolerance Following Allogeneic Hematopoietic Cell Transplantation" consists of 2 projects aimed at understanding the cellular immune components andinteractions that contribute to graft-versus-host disease (GVHD) and development of immunological tolerance after allogeneic hematopoietic cell transplants (HCT). The transplantation of immune competent hematopoietic cells from normal donors is invariably associated with the activation and expansion of donor T cells reacting to host histocompatibility antigen. This reaction results in a clinical syndrome known as GVHD. GVHD is a major complications of allo-HCT, and causes significant morbidity and mortality. Project 1 ("Role of H-Y-specific T cell responses in GVHD") will investigate the role of H-Y specific T cell responses in male patients transplanted from a female donor (F-"M). The incidence of acute and chronic GVHD and the duration of immune suppression therapy necessary for treatment of chronic GVHD (cGVHD) are significantly longer in F-"M HCT recipients compared to other donor/recipient sex combinations. Project 1 will track anti-H-Y T cells in patients, and study the frequency and activity of these cells in different phases of active and resolving cGVHD, and ask if long-term tolerance after F->M HCT is associated with the deletion, inactivation or suppression of these responses. The goal of Project 2 ("Regulatory T Cells in GVHD") is to identify changes in helper, effector and regulatory T cells that are associated with cGVHD and the development of tolerance. The studies proposed will test the hypothesis that the development of tolerance is an active process that can succeed when the activity of regulatory T cells and molecules exceeds and/or suppresses the activity of host-specific responder and effector T cells. The approach will utilize DMA array technology for the assessment of global gene expression to identify the transcriptional profiles of T lymphocytes and selected subsets from HCT patients that are associated with the active chronic GVHD and those associated with the development of tolerance. Critical clinical resources, blood samples and clinical outcome data, provided to projects 1 and 2 by the Core B shared clinical resource. Collaboration between project 1, project 2 and Core B will provide the essential opportunity and synergy necessary to broadly characterize the activation pathways, cellular components and regulatory factors that are responsible for 1) sustaining alloreactivity in patients with active cGVHD, and 2) the mechanism(s) responsible for the development of immunological tolerance. PROJECT 1: H-Y-Specific T Cell Responses in Chronic GvHD Warren, Edus Houston PROJECT 1 DESCRIPTION (provided by applicant): 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-Y antigens - which are not possible in other donor-recipient combinations. Thus, the excess GVHD burden borne by F-"M HCT 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-"M HCT, and that long-term graft-host tolerance after F-"M HCT 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-"M HCT is associated with deletion, inactivation, or suppression of H-Y-specific T cells.

描述（由申请人提供）：该计划项目赠款的标题为“同种异性造血细胞移植后耐受性的免疫生物学”由2个项目组成，旨在了解促进嫁接抗抗抗性宿主疾病（GVHD）的细胞免疫成分和相互作用，以及在同种异体学细胞术后的免疫学耐受性（GVHD）的发展（Hefter）。从正常供体中的免疫胜任造血细胞的移植与供体T细胞的激活和扩展与宿主的组织相容性抗原反应。该反应导致一种称为GVHD的临床综合征。 GVHD是Allo-HCT的主要并发症，并引起明显的发病率和死亡率。项目1（“ H-Y特异性T细胞在GVHD中的作用”将调查H-Y特异性T细胞反应在女性供体移植的男性患者中的作用。急性和慢性GVHD的发生率以及免疫抑制持续时间是对慢性GVHD（CGVHD）的治疗所必需的。组合。项目1将跟踪患者中的抗H-Y T细胞，并研究这些细胞在主动和解决CGVHD不同阶段的频率和活性，并询问F-> M HCT后的长期公差是否与这些反应的删除，灭活或抑制相关。项目2（“ GVHD中的调节性T细胞”）的目的是确定与CGVHD相关的助手，效应子和调节性T细胞的变化以及耐受性的发展。提出的研究将检验以下假设：耐受性的发展是一个主动过程，当调节T细胞和分子的活性超过和/或抑制宿主特异性响应者和效应T细胞的活性时，可以成功。该方法将利用DMA阵列技术评估全球基因表达，以确定与活性慢性GVHD有关的HCT患者的T淋巴细胞的转录特征和与HCT患者的选定子集以及与耐受性发展相关的子集。关键的临床资源，血液样本和临床结果数据，由核心B共享临床资源提供给项目1和2。项目1，项目2和核心B之间的协作将提供必要的必要机会和协同作用，以广泛表征负责1）活跃CGVHD患者的同种反应性的激活途径，细胞组件和调节因素，以及2）造成免疫学耐受性发展的机制。 项目1：慢性GVHD Warren的H-Y特异性T细胞响应，Edus Houston 项目1描述（由申请人提供）：移植物抗宿主病（GVHD）是同种异体造血细胞移植的最严重和最常见的长期并发症，并且是通过供体T细胞识别受体次要或主要的组织兼容性抗原来介导的。来自MHC匹配的女捐助者（F-> M HCT）的造血细胞移植物的男性接受者为研究特定供体T细胞对移植物抗宿主病（GVHD）的发育和持久性的贡献提供了独特的机会。 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-Y antigens - which are not在其他捐赠者 - 启用组合中可能。因此，F-“ M HCT受体可能部分归因于女性T细胞反应对H-Y抗原的反应。该项目的研究将检验以下假设：针对H-Y抗原的供体T细胞反应有助于GVHD在F- hCT和F- hCT之后的GVHD中有助于GVHD，并在F- hct和f-ost portert pors vere terress will hect will hect will te f-- hct h.这些研究的灭绝或抑制作用应深入了解造成GVHD的发展和持久性的机制，从而为未来的干预措施提供了旨在克服同种反应性的理由和方向。来自MHC匹配的雌性供体的造血细胞移植物的抗原（2）。 （3）确定F-“ M HCT后移植物宿主公差的发展与缺失，失活或抑制H-Y特异性T细胞有关。

项目成果

Genomic and proteomic analysis of allogeneic hematopoietic cell transplant outcome. Seeking greater understanding the pathogenesis of GVHD and mortality.

• DOI: 10.1016/j.bbmt.2008.12.500
• 发表时间: 2009-01-01
• 期刊: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
• 作者: Hansen, John A

Cell cycle control of apoptosis in human leukemic T cells.

• DOI: 10.4049/jimmunol.154.1.192
• 发表时间: 1995-01
• 期刊: Journal of immunology
• 影响因子: 4.4
• 作者: L. Zhu;C. Anasetti

Improving hematopoietic cell transplant outcomes in a new era of genomic research.

在基因组研究的新时代改善造血细胞移植结果。

• DOI: 10.1016/j.bbmt.2008.11.003
• 发表时间: 2009
• 期刊: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
• 作者: Chien,JasonW;Zhao,LuePing;Storer,Barry;Martin,PaulJ;Boeckh,Michael;Warren,EdusH;Hansen,JohnA
• 通讯作者: Hansen,JohnA

Serious acute or chronic graft-versus-host disease after hematopoietic cell transplantation: a comparison of myeloablative and nonmyeloablative conditioning regimens.

造血细胞移植后严重的急性或慢性移植物抗宿主病：清髓性和非清髓性预处理方案的比较。

• DOI: 10.1038/sj.bmt.1705987
• 发表时间: 2008
• 期刊: Bone marrow transplantation
• 影响因子: 4.8
• 作者: Sala-Torra,O;Martin,PJ;Storer,B;Traina,F;Sorror,ML;Storb,R;Sandmaier,BM;Flowers,MED
• 通讯作者: Flowers,MED

Oligonucleotide arrays for high-throughput SNPs detection in the MHC class I genes: HLA-B as a model system.

• DOI: 10.1101/gr.206402
• 发表时间: 2002-03
• 期刊: Genome research
• 影响因子: 7
• 作者: Zhen Guo;Mark S. Gatterman;L. Hood;J. Hansen;E. Petersdorf