Molecular Immunology of Minor Histocompatibility Antigen

描述(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。骨髓移植的成功依赖于供受者MHC同种异体抗原的相容和免疫抑制。尽管采取了这些预防措施，移植物抗宿主病(GvHD)仍随之而来，因此，骨髓移植的治疗潜力尚未完全实现。该项目的长期目标是描述次要组织相容(MH)同种异体抗原启动GvHD的机制。在上一次资助期间，我们在MH抗原免疫的分子基础上有了重大的新发现：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异导致不同的磷酸化和同种异体反应；jb)Mh同种抗原呈递的持续时间和抗原/TCR相互作用的亲和力影响免疫优势；c)H60特异的CTL前体(PCTL)频率异常高，影响其相对于其他Mh抗原的免疫优势；以及d)CD4T细胞帮助对于显性和隐性Mh抗原的初级CTL反应是必不可少的。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？以及b)是什么决定了体内免疫显性PCTL的频率？在这个提议中，我们将检验MH抗原作为蛋白酶体产物(而不是作为表位本身)捐赠给受体树突状细胞以交叉呈递到特定的CTL的中心假设，该CTL的谱系和前体频率是由次要同种异体抗原自身变体的AIRE依赖的髓质胸腺上皮表达决定的。我们检验这一假说的策略将是：a)确定MHC类L限制的Mh抗原加工和交叉递呈的细胞和生化机制；b)描述自体多肽(S)调节Mh抗原特异性PCTL谱系发展的机制。由于我们在T细胞抗原处理、呈递和识别的各个方面的研究方面拥有丰富的经验，我们非常适合进行拟议的研究。在这个项目完成后，我们希望能够阐明L限制的MH类抗原由树突状细胞递送给特定的T细胞的机制，以及MH同种异体抗原特异的PCTL谱系是如何产生的。对这些机制的洞察可以被用来制定预防和治疗GvHD的策略。此外，移植物抗白血病是GvHD的副产品，其有益效果可用于癌症治疗。

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.