Molecular Immunology of Minor Histocompatibility Antigen

描述（由申请人提供）：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-受体MHC同种异体抗原相容性和免疫抑制。尽管采取了这些预防措施，但移植物抗宿主病（GvHD）仍然存在，因此BMT的治疗潜力尚未完全实现。该项目的长期目标是阐明次要组织相容性（mH）同种异体抗原启动GvHD的机制。在上一个资助期间，我们已经取得了重要的新发现，这些发现是对mH抗原免疫的分子基础的基础：a）我们发现了难以捉摸的H4 mH同种异体抗原，其中苏氨酸到异亮氨酸的变化引起差异磷酸化和同种异体反应性; c）异常高的H60特异性CTL前体（pCTL）频率影响其相对于其它mH抗原的免疫显性;和d）CD 4 T细胞辅助对于针对显性和隐性mH抗原的初级CTL应答是必需的。从这些新的发现中出现了几个重要的问题：a）mH同种异体抗原在体内交叉呈递的细胞和生化基础是什么？和B）是什么决定了体内免疫显性pCTL频率？在这个建议中，我们将测试的中心假设，mH抗原捐赠的蛋白酶体产品（而不是作为表位本身）的受体树突状细胞的交叉介绍特定的CTL的剧目和前体频率的形状由AIRE依赖的胸腺髓质上皮细胞表达的自我变异的次要同种异体抗原。我们检验这一假设的策略是：a）确定MHC I类限制性mH抗原加工和交叉呈递的细胞和生化机制;和B）描述自身肽调节mH抗原特异性pCTL库发育的机制。由于我们在T细胞抗原加工、呈递和识别的各个方面的研究方面有着丰富的经验，我们非常适合进行拟议的研究。在完成这个项目后，我们希望阐明的机制，一类限制性的mH抗原的树突状细胞提出的特定的T细胞和mH同种异体抗原特异性pCTL库是如何产生的。对这些机制的深入了解可以用来制定针对GvHD的预防和治疗策略。此外，移植物抗白血病（GvHD的副产物）的有益作用可用作对抗癌症的疗法。

DESCRIPTION (provided by applicant): 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 compatibility and on immuno-suppression. Despite these preventive measures, graft-versus-host disease (GvHD) ensues and hence, the therapeutic potential of BMT is not fully realized. 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 and precursor 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 expect 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 utilized as a therapy against cancers.