Induction of Tolerance using T cells to Deliver Antigen

描述(申请人提供)：在移植中，诱导供者特异性耐受的能力有可能克服排斥反应，而不需要与显著的发病率和经济成本相关的终身免疫抑制。对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者。然而，使用异基因骨髓移植来诱导耐受有许多并发症，包括需要毒性宿主条件以允许供者造血干细胞植入，移植物抗宿主病，以及使宿主免疫受损的可能性。我们推测，如果能够确定能够诱导耐受的造血系，就有可能获得自体耐受诱导系，体外修饰它们以表达供体类型的同种异体抗原，并在适当的条件下将它们重新注入患者体内以诱导耐受，而不可能诱导GvHD或需要异基因骨髓移植。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，即表达同种抗原的T细胞能够诱导对MHC I类和MHC II类不相合皮肤移植物的耐受。我们的中心假设是，将同种异体抗原输送到成熟的T细胞可用于诱导对移植抗原的长期稳定耐受，有效地重塑免疫学谱系。因此，这项建议的具体目的是：确定T细胞递送抗原在多大程度上可用于诱导耐受和防止慢性排斥反应；确定同种异体抗原在成熟T细胞上表达导致耐受的机制；以及开发临床上相关的策略，通过向成熟T细胞递送同种异体抗原来诱导耐受。这些研究可能会开发出诱导移植耐受的新方法，消除许多与使用异基因骨髓移植相关的问题，并消除或减少移植患者对终身免疫抑制的要求。这些研究还可能提供对自我-非我识别的基本调节的洞察。

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.