Induction of Tolerance using T cells to Deliver Antigen

使用 T 细胞传递抗原诱导耐受

• 批准号: 7369678
• 负责人: John J Iacomini
• 金额: $ 38.64万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-15 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7369678
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Alloantigen; Allogeneic Bone Marrow Transplantation; Allogenic; Allografting; Antigens; Autologous; Back; Bone Marrow; Bone Marrow Transplantation; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Cardiac; Cell Lineage; Cells; Chimera organism; Chronic; Clinic; Data; Economics; Engraftment; Goals; Graft Rejection; Harvest; Hematopoietic; Hematopoietic stem cells; Histocompatibility Antigens; Immunocompromised Host; Immunosuppression; Inbred BALB C Mice; Informal Social Control; Laboratories; Left; Life; Link; MHC Class I Genes; MHC Class II Genes; Mature T-Lymphocyte; Minor; Molecular; Morbidity - disease rate; Mus; Pathway interactions; Patients; Purpose; Shapes; Skin graft; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic immunosuppression; Thymus Gland; Transgenic Mice; Transplant Recipients; Transplantation; Transplantation Tolerance; Treatment Protocols; clinical application; clinically relevant; conditioning; cost; graft vs host disease; insight; irradiation; novel; novel strategies; prevent

DESCRIPTION (provided by applicant): In transplantation, the ability to induce donor specific tolerance has the potential to overcome rejection without the need for life-long immunosuppression that is associated with significant morbidity and economic cost. Studies in irradiation chimeras have shown that bone marrow derived hematopoietic cells are potent inducers of transplantation tolerance. However, the use of allogeneic bone marrow transplantation to induce tolerance suffers from many complications that include the need for toxic host conditioning to allow donor hematopoietic stem cell engraftment, graft versus host disease, and the possibility of leaving the host immunocompromised. We hypothesized that if hematopoietic lineages could be identified that are capable of inducing tolerance, it may be possible to harvest autologous tolerance inducing lineages, modify them ex vivo to express donor type alloantigens and re-infuse them back into the patient following appropriate conditioning to induce tolerance without the possibility of inducing GvHD or the need for an allogeneic bone marrow transplant. Data from our laboratory obtained using bone marrow chimeras, molecular chimeras, and adoptive cell transfer approaches have led to the novel observation that alloantigen expressing T cells are capable of inducing tolerance to MHC class I and MHC class II mismatched skin grafts. Our central hypothesis is that delivery of alloantigen on mature T cells 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 therefore to: Determine the extent to which delivery of antigen by T cells can be used to induce tolerance and prevent chronic rejection; Determine the mechanisms by which expression of alloantigen on mature T cells leads to tolerance; and Develop clinically relevant strategies to induce tolerance by delivery of alloantigen on mature T cells. These studies may make it possible to develop novel approaches to inducing transplantation tolerance that eliminate many of the problems associated with using allogeneic bone marrow transplantation for this purpose, as well as eliminate or reduce the requirement for life-long immunosuppression in transplant patients. These studies may also provide insight into fundamental regulation of self-nonself recognition.

描述（由申请人提供）：在移植中，诱导供体特异性耐受的能力有可能克服排斥反应，而不需要终身免疫抑制，终身免疫抑制与显著的发病率和经济成本相关。辐射嵌合体的研究表明，骨髓来源的造血细胞是移植耐受的有效诱导剂。然而，使用同种异体骨髓移植来诱导耐受遭受许多并发症，包括需要毒性宿主调节以允许供体造血干细胞植入、移植物抗宿主病以及使宿主免疫功能低下的可能性。我们假设，如果可以鉴定出能够诱导耐受的造血谱系，则可以收获自体耐受诱导谱系，离体修饰它们以表达供体类型同种抗原，并在适当的调节后将它们重新输注回患者体内以诱导耐受，而不可能诱导GvHD或需要同种异体骨髓移植。我们实验室使用骨髓嵌合体、分子嵌合体和过继细胞转移方法获得的数据导致了新的观察结果，即表达同种异体抗原的T细胞能够诱导对MHC I类和MHC II类错配皮肤移植物的耐受。我们的中心假设是，在成熟T细胞上递送同种异体抗原可用于诱导对移植抗原的长期稳定耐受，有效地重塑免疫库。因此，本提案的具体目的是：确定T细胞递送抗原可用于诱导耐受和预防慢性排斥的程度;确定同种异体抗原在成熟T细胞上的表达导致耐受的机制;以及开发临床相关策略，通过在成熟T细胞上递送同种异体抗原诱导耐受。这些研究有可能开发新的方法来诱导移植耐受，消除许多与使用同种异体骨髓移植相关的问题，以及消除或减少移植患者终身免疫抑制的需要。这些研究也可能提供洞察自我-非自我识别的基本调节。