COSTIMULATORY BLOCKADE AND CHIMERISM TOLERANCE

CD40/CD28共刺激阻断是一种非常有效的延长 同种异体移植物存活率。然而，最终接受这种疗法的接受者 接受晚期移植排斥反应，表明协同刺激单独阻断 不会导致稳定的移植耐受。相比之下，协议 导致高水平的造血细胞嵌合体 在成年动物中形成强大的供体特异性耐受性。然而， 这些方案依赖于使用细胞毒剂来耗尽 受者的外周免疫系统和/或骨髓创造“空间” 用于移植的造血干细胞(HSC)。 我们开发了一种新的方案，在这种方案中，捐赠者的骨髓 作为骨髓基质的碎片移植到肾被膜下或 受者的皮下间隙。我们观察到这些骨头 骨髓移植(BG)包含完整的基质微环境和 外周血中植入和填充造血素 血液循环，不需要使用骨髓减少剂。我们发现，当 在小鼠体内移植了完全不匹配的MHC障碍，这种组合 CD40/CD28共刺激阻断和BG可允许植入 这些骨移植并诱导对后续供者的稳定耐受性 特定的皮肤移植。 这个项目的中心假设是协同刺激 BLOKADE/BG方案可以始终如一地植骨 移植物、稳定的造血嵌合体和稳定的移植耐受 通过选择性删除同种异体反应性T细胞。在这个项目中，我们将 严格探索骨髓移植障碍，优化 克服这些障碍的策略，并研究 通过这种方法在小鼠身上诱导耐受性。然后我们将整合这一点 对临床前恒河猴肾移植研究的几点认识 模型，目标是产生一种耐受性诱导方案， 适用于临床移植试验。

CD40/CD28 costimulation blockade is a very effective strategy to prolong allograft survival. However, recipients receiving this therapy ultimately undergo late graft rejection, suggesting that costimulation blockade alone will not induce stable transplantation tolerance. In contrast, protocols that induce high levels of hematopoietic chimerism result in the development of robust donor-specific tolerance in adult animals. However, these protocols rely on the use of cytotoxic agents to deplete the recipient's peripheral immune system and or bone marrow to create "space" for the transplanted hematopoietic stem cells (HSC's). We have developed a novel protocol in which the donor's bone marrow is grafted as fragments of bone marrow matrix under the kidney capsule or in the subcutaneous space of the recipient. We have observed that these bone marrow grafts (BG) which contain an intact microenvironment of stromal and hematopoietic elements engraft and populate the peripheral blood circulation without the need for myelo-reductive agents. We find that when transplanted across fully MHC mismatched barriers in mice, the combination of CD40/CD28 co-stimulation blockade and BG can permit engraftment of these bone grafts and induce stable tolerance to a subsequent donor specific skin graft. The central hypothesis of this project is that the costimulation blockade/BG protocol can consistently produce engraftment of the bone graft, stable hematopoietic chimerism and stable transplantation tolerance via selective deletion of alloreactive T cells. In this project we will rigorously explore barriers to bone marrow engraftment, optimize strategies to overcome these barriers, and study the mechanisms of tolerance induced by this approach in mice. We will then integrate this knowledge into our studies in the pre-clinical Rhesus renal allograft model, with the goal of producing a tolerance induction protocol that is suitable for testing in clinical transplantation.