Induction of Tolerance using T cells to Deliver Antigen

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，而不需要终生免疫抑制，这与显著的发病率和经济成本相关。辐照嵌合体的研究表明，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诱导耐受性存在许多并发症，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，以及可能使宿主免疫功能受损。我们假设，如果能够鉴定出能够诱导耐受性的造血谱系，就有可能获得自体耐受性诱导谱系，在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性，而不可能诱导GvHD或需要同种异体骨髓移植。我们的实验室使用骨髓嵌合体、分子嵌合体和过继细胞移植方法获得的数据导致了新的观察，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性。我们的中心假设是，在成熟的T细胞上递送同种异体抗原可以用来诱导对移植抗原的长期稳定耐受性，有效地重塑免疫库。因此，本建议的具体目的是：确定T细胞递送抗原可用于诱导耐受性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；并开发临床相关策略，通过在成熟T细胞上递送同种异体抗原来诱导耐受性。这些研究可能使开发新的方法来诱导移植耐受成为可能，从而消除与使用同种异体骨髓移植相关的许多问题，并消除或减少移植患者终身免疫抑制的需要。这些研究也可能对自我-非自我认知的基本规律提供见解。

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.