INTRATHYMIC TRANSPLANTATION TOLERANCE BY MHC PEPTIDES

MHC 肽对胸腺内移植的耐受性

• 批准号: 2672270
• 负责人: Mohamed H Sayegh
• 金额: $ 11.49万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2672270
• 关键词: MHC class I antigen; MHC class II antigen; T cell receptor; T lymphocyte; anergy; binding proteins; cell transplantation; cytokine; dendritic cells; epithelium; heart transplantation; histocompatibility; histocompatibility antigens; homologous transplantation; immune tolerance /unresponsiveness; immunization; immunocytochemistry; immunosuppression; kidney transplantation; laboratory rat; macrophage; monoclonal antibody; synthetic peptide; thymectomy; thymus; tissue /cell culture

Organ transplantation is the therapy of choice for end stage organ failure. The major goal in transplantation research is the induction of tolerance to major histocompatibility complex (MHC) antigens. The thymus plays the major role in development of self tolerance, but its role in acquired tolerance to alloantigen is unknown. Several investigators have recently shown that intrathymic injection of donor cells into adult animals can induce a state of long term specific unresponsiveness to tissue and organ allografts. The availability of sequence data for the MHC genes has made it possible to synthesize polymorphic peptides and utilize them to study the mechanisms of allo-recognition. Intrathymic injection of polymorphic MHC allopeptides reproduces the same effects observed with allogeneic cells, suggesting that thymocytes recognize processed MHC molecules. The main focus of this proposal is to use synthetic MHC peptides to study the mechanisms of acquired intrathymic tolerance in the rat model of vascularized organ allografts. Specifically, the plan will be to: 1. Investigate the mechanisms of thymic recognition of MHC allopeptides. This will be accomplished by studying which thymic antigen-presenting cells, bone marrow-derived macrophages/dendritic cells or epithelial cells, bind and present MHC allopeptides to T cells. Methods will include binding studies of biotinylated MHC peptides, determining the requirement for processing, and blocking with specific anti-class I and class II MHC monoclonal antibodies. The response of T cells to specific MHC epitopes after priming by immunization with the peptides, and by an allograft, will be determined. 2. Investigate the role of thymic regulatory cells. The rat renal and cardiac transplant model will be used. The presence of regulatory mechanisms will be investigated by performing thymectomies at different time intervals after transplantation, performing adoptive transfer experiments, and studying graft infiltrating cells and cytokines by immunohistology. 3. Investigate whether thymic recognition of MHC peptides anergizes or deletes activated T cell clones. This will involve induction of immune unresponsiveness to specific MHC epitopes by injecting individual MHC peptides into the thymus, and using in vitro proliferation and precursor frequency assays to study the functional characteristics of T cells from tolerized animals. Anergy will be studied by testing for reversal of T cell unresponsiveness by cytokines. Clonal deletion will be investigated by analyzing T cell receptor Vbeta repertoire. The long term objectives are to develop novel approaches to study the mechanisms of transplantation unresponsiveness, including new strategies to induce specific transplantation tolerance.

器官移植是终末期器官衰竭的治疗选择。

项目成果

Indirect allorecognition of donor class I and II major histocompatibility complex peptides promotes the development of transplant vasculopathy.

供体 I 类和 II 类主要组织相容性复合肽的间接同种异体识别促进移植血管病变的发展。

• DOI: 10.1681/asn.v12112500
• 发表时间: 2001
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: Womer,KarlL;Stone,JamesR;Murphy,Barbara;Chandraker,Anil;Sayegh,MohamedH
• 通讯作者: Sayegh,MohamedH

A novel CD154 monoclonal antibody in acute and chronic rat vascularized cardiac allograft rejection.

一种新型 CD154 单克隆抗体，用于治疗急性和慢性大鼠血管化心脏同种异体移植排斥反应。

• DOI: 10.1097/00007890-200206150-00008
• 发表时间: 2002
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Yuan,Xueli;Dong,VictorM;Coito,AnaJ;Waaga,Ana-Maria;Salama,AlanD;Benjamin,ChristopherD;Sayegh,MohamedH;Chandraker,Anil
• 通讯作者: Chandraker,Anil

Mechanisms of indirect allorecognition: characterization of MHC class II allopeptide-specific T helper cell clones from animals undergoing acute allograft rejection.

间接同种异体识别机制：来自经历急性同种异体移植排斥的动物的 MHC II 类同种肽特异性 T 辅助细胞克隆的表征。

• DOI: 10.1097/00007890-199804150-00004
• 发表时间: 1998
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Waaga,AM;Chandraker,A;Spadafora-Ferreira,M;Iyengar,AR;Khoury,SJ;Carpenter,CB;Sayegh,MH
• 通讯作者: Sayegh,MH

Comparative strategies to induce long-term graft acceptance in fully allogeneic renal versus cardiac allograft models by CD28-B7 T cell costimulatory blockade: role of thymus and spleen.

通过 CD28-B7 T 细胞共刺激阻断在完全同种异体肾脏与心脏同种异体移植模型中诱导长期移植物接受的比较策略：胸腺和脾脏的作用。

• DOI: 10.1681/asn.v95891
• 发表时间: 1998
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: Schaub,M;Stadlbauer,TH;Chandraker,A;Vella,JP;Turka,LA;Sayegh,MH
• 通讯作者: Sayegh,MH

T-cell costimulatory blockade in experimental chronic cardiac allograft rejection: effects of cyclosporine and donor antigen.

实验性慢性心脏同种异体移植排斥中的 T 细胞共刺激阻断：环孢菌素和供体抗原的作用。

• DOI: 10.1097/00007890-199704270-00002
• 发表时间: 1997
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Chandraker,A;Russell,ME;Glysing-Jensen,T;Willett,TA;Sayegh,MH
• 通讯作者: Sayegh,MH