Molecular Immunology of Minor Histocompatibility Antigen

次要组织相容性抗原的分子免疫学

• 批准号: 7331511
• 负责人: SEBASTIAN JOYCE
• 金额: $ 37.26万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7331511
• 关键词: Alloantigen; Allografting; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Avidity; Biochemical; Blood Cells; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; Cells; Cellular Immunity; Class; Cross Presentation; Dendritic Cells; Development; Disease; Epithelial; Epithelium; Epitopes; Frequencies; Funding; Genetic Variation; Goals; Histocompatibility; Immune response; Immunity; Immunologic Deficiency Syndromes; Immunosuppression; Isoleucine; Knowledge; Malignant Neoplasms; Measures; Mediator of activation protein; Minor; Minor Histocompatibility Antigens; Modeling; Molecular; Molecular Immunology; Mouse Strains; Pattern; Peptides; Peripheral; Phosphorylation; Preventive; Process; Property; Proteins; Research; Shapes; Staging; T-Lymphocyte; TCR Activation; Testing; Therapeutic; Therapeutic immunosuppression; Threonine; Thymus Gland; Tumor Immunity; Vaccine Design; Variant; antigen processing; base; experience; graft vs host disease; in vivo; insight; leukemia; novel; response; success; tumor

Bone marrow transplantation (BMT) has emerged as a major therapeutic for end-stage blood cell diseases. The success of BMT depends on donor-recipient Mhc alloantigen comptibility and on immuno-suppression. Despite these preventive measures, graft-verus-host disease (GvHD) ensues and hence, the therapeutic potential of BMT is not fully realised. The long-term goal of this project is to delineate the mechanisms by which minor histocompatibility (mH) alloantigens initiate GvHD. We have made significant new discoveries underlying the molecular basis of immunity to mH antigens during the last funding period: a) we discovered the elusive H4 mH alloantigen in which a threonine to isoleucine variation causes differential phosphorylation and alloreactivity; Jb) the duration of mH alloantigen presentation and the avidity of antigen/Tcr interaction impacts immunodominance; c) an unusually high H60-specific CTL precursor (pCTL) frequency impacts its immunodominance over the other mH antigens; and d) CD4 T cell help is essential for primary CTL response to both dominant and recessive mH antigens. From these novel findings several important questions emerge: a) what are the cellular and biochemical bases of mH alloantigen cross-presentation in vivo? and b) what determines immunodominant pCTL frequencies in vivo? In this proposal, we will test the central hypothesis that mH antigens are donated as proteasomal products (but not as the epitope itself) to acceptor dendritic cells for cross-presentation to specific CTL whose repertoire andprecursor frequency are shaped by AIRE-dependent medullary thymic epithelial expression of self variants of the minor alloantigens. Our strategy to test this hypothesis will be to: a) determine the cellular and biochemical mechanisms of Mhc class l-restricted mH antigen processing and cross-presentation; and b) delineate the mechanisms by which self peptide(s) regulate the development of the mH antigen-specific pCTL repertoire. Because of our extensive experience with studies of various aspects of T cell antigen processing, presentation and recognition, we are well situated to undertake the proposed research. Upon completion of this project, we expecf to elucidate the mechanisms by which class l-restricted mH antigens are presented by dendritic cells to specific T cells and how mH alloantigen-specific pCTL repertoires are generated. Insights into these mechanisms can be harnessed to develop preventive and therapeutic strategies against GvHD. Additionally, the beneficial effects of graft-versus-leukemia, a by-product of GvHD, can be utilised as a therapy against cancers.

骨髓移植（BMT）已成为终末期血细胞疾病的主要治疗方法。 BMT的成功取决于供体与受体Mhc同种抗原的相容性和免疫抑制。 尽管采取了这些预防措施，移植物抗宿主病（GvHD）仍然存在，因此， BMT的潜力还没有完全发挥出来。该项目的长期目标是通过以下方式来描述这些机制： 其中次要组织相容性（mH）同种异体抗原引发GvHD。我们有了重大的新发现 在上一个资助期间，我们发现了对mH抗原免疫的分子基础：a）我们发现 一种难以捉摸的H4 mH同种异体抗原，其中苏氨酸到异亮氨酸的变异引起差异磷酸化 Jb）mH同种抗原呈递的持续时间和抗原/Tcr相互作用的亲合力 c）异常高的H60特异性CTL前体（pCTL）频率影响其免疫优势; 相对于其他mH抗原的免疫优势;以及d）CD 4 T细胞辅助对于初级CTL是必需的 对显性和隐性mH抗原的反应。从这些新发现中， 问题出现了：a）mH同种异体抗原交叉呈递的细胞和生化基础是什么？ 体内？和B）是什么决定了体内免疫显性pCTL频率？在本提案中，我们将测试 mH抗原作为蛋白酶体产物（而不是表位本身）被捐赠给 受体树突状细胞交叉呈递特异性CTL，其库和前体频率是 由次要同种异体抗原自身变体的AIRE依赖性胸腺髓质上皮表达形成。 我们检验这一假设的策略是：a）确定Mhc的细胞和生化机制 I类限制性mH抗原加工和交叉呈递;和B）描述了 自身肽调节mH抗原特异性pCTL库的发育。因为我们的 在T细胞抗原加工、呈递和免疫应答的各个方面的研究方面具有丰富的经验。 认识到这一点，我们完全有能力开展拟议的研究。在这个项目完成后，我们 期望阐明树突状细胞呈递l类限制性mH抗原的机制 特异性T细胞以及mH同种异体抗原特异性pCTL库是如何产生的。洞察这些 可以利用这些机制来开发针对GvHD的预防和治疗策略。此外，本发明还 GvHD的副产物移植物抗白血病的有益作用可用作治疗 癌的