Tolerance to allografts through gene therapy

通过基因治疗对同种异体移植物产生耐受

• 批准号: 7225621
• 负责人: John J Iacomini
• 金额: $ 30.63万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7225621
• 关键词: Acute; Allogenic; Allografting; Antigen Presentation Pathway; Autologous; B-Lymphocytes; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chimera organism; Chimerism; Chronic; Class; Development; Discrimination; Engineering; Engraftment; Failure; Funding; Genetic Engineering; Hematopoietic; Histocompatibility; Histocompatibility Antigens; Histocompatibility Antigens Class I; IL2RA gene; Immunosuppression; Lead; Life; MHC Class I Genes; MHC Class II Genes; Memory; Molecular; Mus; Numbers; Organ Transplantation; Protocols documentation; Rate; Research Personnel; Retroviral Vector; Retroviridae; Severities; Shapes; Skin; Surface; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic immunosuppression; Transplantation; Transplantation Tolerance; Treatment Protocols; base; clinically relevant; conditioning; gene therapy; graft vs host disease; heart allograft; histocompatibility gene; novel; prevent; programs; reconstitution; response; retroviral transduction; skin allograft

DESCRIPTION (provided by applicant): Induction of hematopoietic cellular chimerism through bone marrow transplantation can lead to life-long transplantation tolerance without the need for chronic immunosuppression. However, bone marrow transplantation across major histocompatibility (MHC) barriers is severely limited by problems associated with the severity of the host preparative regimen required to achieve engraftment, the potential for lethal graft-versus-host disease (GVHD), and a high rate of engraftment failure. These problems could potentially be avoided by using a gene therapy approach to introduce allogeneic MHC genes into autologous bone marrow resulting in a state of molecular rather than cellular chimerism. In the last funding period, we examined whether such a gene therapy based approach could be used to induce tolerance to an allogeneic major histocompatibility (MHC) class I antigen. Reconstitution of lethally irradiated B10.AKM mice (H-2Kk, Ik, Dq) with syngeneic bone marrow infected with retroviruses carrying the allogeneic MHC class I gene H-2Kb, resulted in life-long expression of Kb on the surface of bone marrow cells, and specific tolerance to Kb. Mice reconstituted with H-2Kb transduced bone marrow accepted K b disparate skin allografts long-term without the need for any additional immunosuppression. Thus, genetic engineering of bone marrow using retroviral transduction to establish molecular chimerism can be used to induce long-term stable tolerance to transplantation antigens, effectively re-shaping the immunological repertoire. The specific aims of this proposal are: 1) To determine the mechanism by which CD4 T cell tolerance induced by gene therapy is maintained in molecular chimeras; 2) Develop clinically relevant non-myeloablative protocols to induce tolerance by genetic engineering of bone marrow; and 3) Test the hypothesis that induction of molecular chimerism can be used to induce tolerance to MHC class I and class II disparate grafts and prevent acute as well as chronic allograft rejection. These studies should expand the use of gene therapy to induce immunological tolerance, provide practical information important for the field of transplantation on mechanisms of tolerance, and may also advance our understanding of self-nonself discrimination with respect to MHC antigens. Ultimately, these studied may provide a novel means of inducing acceptance of allogeneic organ transplants without the need for life-long immunosuppression.

描述（由申请人提供）： 通过骨髓移植诱导造血细胞嵌合，可以导致终身移植耐受性，而无需慢性免疫抑制。然而，跨主要组织相容性（MHC）障碍的骨髓移植受到与宿主制剂的严重程度相关的问题的严重限制，需要实现植入的宿主制备方案，致命的疗法 - 抗抗菌病（GVHD）的潜力，以及急性失败的速率。通过使用基因疗法方法将同种异体MHC基因引入自体骨髓，从而可能避免这些问题，从而导致分子而非细胞嵌合。在最后一个资金期间，我们检查了这种基于基因疗法的方法是否可以用来诱导同种异体主要组织相容性（MHC）I类抗原的耐受性。对致命辐照的B10.AKM小鼠（H-2KK，IK，DQ）的重建，该小鼠用载同性同种异体MHC I类H-2KB感染了逆转录病毒的同性骨髓，从而导致骨骨髓细胞表面KB表达终身表达，并具有对Kb的特异性耐受性。用H-2KB转导的骨髓重构的小鼠长期接受K B的皮肤同种异体移植物，而无需任何其他免疫抑制。因此，可以使用逆转录病毒转导的骨髓基因工程来建立分子嵌合，可用于诱导长期稳定的对移植抗原的稳定耐受性，从而有效地重塑免疫学库。该提案的具体目的是：1）确定基因治疗诱导的CD4 T细胞耐受性在分子嵌合体中保持的机制； 2）开发临床上相关的非毛囊方案，以通过骨髓的基因工程诱导耐受性； 3）检验以下假设：诱导分子嵌合物可用于诱导对MHC I类和II类不同的移植物的耐受性，并防止急性以及慢性同种异体移植排斥。这些研究应扩大基因疗法来诱导免疫耐受性，为耐受机制移植领域重要的实用信息，并可能提高我们对MHC抗原自我歧视的理解。最终，这些所研究的可能提供了一种新颖的手段，可以诱导同种异体器官移植，而无需终身免疫抑制。