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性的研究提供了独特的临床前模型。我们之前已经证明，在该模型中经过短疗程的钙调神经磷酸酶抑制剂后，可以实现对 MHC I 类不匹配肾同种异体移植物的强大耐受性。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 细胞寿命较长，因此该提议的中心假设是，这种形式的耐受涉及下调 T 细胞的持续机制。 T 细胞反应性。在上一个项目期间，我们的近交计划产生了近交系数>94%的亚系，从而首次在大型动物模型中研究通过收养转移的耐受机制。我们使用这些动物的数据表明，对 I 类错配肾同种异体移植物的耐受涉及调节性 T 细胞 (T-reg)，这些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，在移除移植物后，耐受性持续至少3个月，并且在此期间，通过供体I类肽进行免疫，而不是通过对供体皮肤移植物的排斥，消除了耐受状态。最后，我们发现，对耐受动物进行药敏试验和白细胞去除术治疗（成功过继转移其耐受性所需）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可确定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进行耐受性转移的细胞群的性质； 2) 研究抗原呈递途径决定耐受维持与丧失的机制； 3) 检查同种异体反应性和决定第二次移植到耐受受体的命运的调节之间的平衡。希望了解在这种大型动物模型中诱导和维持同种异体移植耐受的机制将允许开发适当的临床方案以诱导对器官同种异体移植的特异性耐受。