IMMUNE MECHANISMS OF CHRONIC ALLOGRAFT REJECTION

慢性同种异体移植排斥的免疫机制

• 批准号: 6124393
• 负责人: CHARLES B CARPENTER
• 金额: $ 35.33万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6124393
• 关键词: MHC class I antigen; MHC class II antigen; T cell receptor; antigen presenting cell; chemokine; chronic disease /disorder; clone cells; cytokine; gene expression; heart transplantation; helper T lymphocyte; homologous transplantation; immunocytochemistry; isoantibody; isoantigen; kidney transplantation; laboratory rat; leukocyte activation /transformation; monoclonal antibody; mutant; nucleic acid sequence; pathologic process; polymerase chain reaction; transplant rejection; transplantation immunology

Vascularized organ transplants frequently develop a progressive obliterative vasculopathy, interstitial fibrosis and, in the case of kidneys, glomerulosclerosis, that lead to organ failure within a few years, in spite of continuing immunosuppressive therapy. This 'chronic rejection' process is poorly understood, and although there is clear evidence that T cell recognition of alloantigen plays a key role in initiating early acute rejection, there is little direct evidence that an active alloimmune response is responsible for progression of chronic rejection. In an established rat model of kidney and heart transplants (F344 and LEW strains) in which the sequential morphological and immunohistologic features, with associated cytokine/chemokine gene activation patterns, are well defined, the MHC antigen-driven T cell and antibody responses will be studied. These strains differ only by a class II public antigen. The hypothesis is that an ongoing alloantigen-driven response initiated by T cells primed by the indirect pathway of allorecognition is responsible for mediating the chronic rejection process. The sequences of F344 will be obtained and peptides prepared which represent the difference(s) with LEW MHC class II in order to establish the presence of T cell priming to the indirect pathway during chronic rejection. Preparation of T cell clones for transfer to naive recipients of grafts, and the use of monoclonal antibodies to TCRV/Beta families to block recognition in vivo, will test the significance of priming to immunodominant epitopes in chronic rejection. Tolerance- inducing strategies using synthetic peptides after transplantation will then be applied to interrupt the ongoing process of T cell activation. The hypothesis is supported by preliminary data showing that a single injection of CTLA4Ig to block T cell costimulation via CD28-B7, in addition to preventing chronic rejection if given early, can interrupt progression of chronic rejection when given 8 weeks after transplantation. Further study using antibodies and CTLA4Ig mutants which distinguish between B7-1 and B7-2 pathways should further elucidate approaches to interrupting chronic rejection. The synthetic MHC peptide and costimulatory blockade protocols will be tested for synergistic interaction, and full MHC class I and II strain differences will be subsequently studied. The above studies should provide relevant information for development of novel strategies to prevent and possibly interrupt chronic allograft rejection in clinical transplantation.

带血管的器官移植经常出现进展性疾病