TOLERANCE TO VASCULARIZED ALLOGRAFTS IN MINISWINE

小型猪对血管化同种异体移植物的耐受性

• 批准号: 7922284
• 负责人: DAVID H SACHS
• 金额: $ 29.34万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922284
• 关键词: Ablation; Adoptive Transfer; Affect; Allograft Tolerance; Allografting; Animal Model; Animals; Antibodies; Antibody Formation; Antigen Presentation Pathway; Brothers; Calcineurin inhibitor; Cell physiology; Cells; Clinical; Clinical Protocols; Cyclosporine; Cyclosporins; Data; Development; Down-Regulation; Equilibrium; Excision; Generations; Grant; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Immune system; Immunity; Immunization; In Vitro; Inbreeding; Investigation; Kidney; Kidney Transplantation; Lead; Leukapheresis; Life; Maintenance; Miniature Swine; Modeling; Monitor; Nature; Organ; Organ Transplantation; Other Genetics; Peptides; Peripheral; Peripheral Blood Mononuclear Cell; Population; Pre-Clinical Model; Progress Reports; Recombinant Haplotype; Regulation; Relative (related person); Research Personnel; Role; Serum; Sister; Skin Transplantation; Skin graft; System; T-Lymphocyte; Tacrolimus; Testing; Thymectomy; Thymus Gland; Time; Transfusion; Transplantation; Treatment Protocols; base; kidney allograft; peptide I; programs; research study; second transplant

DESCRIPTION (provided by applicant): Inbred miniature swine provide a unique preclinical model for the study of transplantation immunity and tolerance. We have previously demonstrated that robust tolerance to MHC class l-mismatched renal allografts can be achieved following a short course of calcineurin inhibitors in this model. Since, unlike central tolerance, the induction of tolerance in this system does not involve T cell ablation, and since T cells are long-lived, the central hypothesis of this proposal is that this form of tolerance involves a continuing mechanism for down-regulation of T cell reactivity. During the last project period, our inbreeding program has produced a subline with >94% coefficient of inbreeding, permitting investigation of the mechanism of tolerance by adoptive transfer for the first time in a large animal model. Our data using these animals indicate that tolerance to class I mismatched renal allografts involves regulatory T cells (T-reg) that can be isolated from the long-term tolerated kidney and can also be mobilized in the periphery following DST. We have also observed that tolerance persists for at least 3-months after removal of the graft, and that during this period, immunization by donor class I peptides, but not by rejection of donor skin grafts, abrogates the tolerant state. Finally, we have found that the treatment of tolerant animals with DST and leukapheresis, required for successful adoptive transfer of their tolerance, also leads to loss of the tolerant state. Collectively, these data suggest that tolerance relies on a balance between alloreactivity and regulation, which is maintained via definable cellular interactions between the graft and the recipient's immune system. To test these hypotheses, we will 1) Determine the nature of the cell populations responsible for transfer of tolerance by adoptive transfer; 2) Study the mechanism by which the pathway of antigen presentation determines maintenance vs. loss of tolerance; and 3) Examine the balance between alloreactivity and regulation that determines the fate of a second transplant into a tolerant recipient. It is hoped that an understanding of the mechanisms by which allograft tolerance is induced and maintained in this large-animal model will permit development of appropriate clinical protocols for induction of specific tolerance to organ allografts.

描述（申请人提供）：近交小型猪为移植免疫和耐受研究提供了独特的临床前模型。我们以前已经证明，在这个模型中，短期使用钙调磷酸酶抑制剂可以实现对MHC I类不匹配的同种异体肾移植物的耐受性。由于与中枢耐受不同，该系统中耐受的诱导不涉及T细胞消融，并且由于T细胞是长寿的，因此该提议的中心假设是这种形式的耐受涉及T细胞反应性下调的持续机制。在最后一个项目期间，我们的近亲繁殖计划产生了一个近亲繁殖系数>94%的亚系，首次在大型动物模型中通过过继转移研究耐受机制。我们使用这些动物的数据表明，对I类错配肾移植物的耐受性涉及调节性T细胞（T-reg），这些T细胞可以从长期耐受的肾脏中分离出来，也可以在DST后在外周动员。我们还观察到移植物去除后耐受性持续至少3个月，并且在此期间，通过供体I类肽免疫，而不是通过供体皮肤移植物的排斥，消除了耐受状态。最后，我们已经发现，用DST和白细胞去除术治疗耐受动物，这是成功过继转移其耐受性所必需的，也会导致耐受状态的丧失。总的来说，这些数据表明，耐受性依赖于同种异体反应性和调节之间的平衡，这是通过移植物和受体免疫系统之间的可定义的细胞相互作用来维持的。为了检验这些假设，我们将1）确定负责通过过继转移转移耐受性的细胞群的性质; 2）研究抗原呈递途径决定耐受性维持与丧失的机制; 3）检查同种异体反应性和调节之间的平衡，这决定了第二次移植到耐受受体中的命运。我们希望，在这种大型动物模型中，对同种异体移植物耐受诱导和维持机制的理解，将允许开发适当的临床方案，用于诱导对器官同种异体移植物的特异性耐受。