Induction of Renal Allograft Tolerance in Monkeys with Anti-CD45RB Based Therapy

描述（由申请人提供）：人类移植对外周耐受性的探索尚未完成，需要新的见解。迄今为止，能够在小鼠模型中诱导外周耐受性的治疗策略无法可靠地诱导非人灵长类动物（NHP）的耐受性。尽管如此，小鼠模型在确定重要靶点和证明联合治疗更有效方面具有指导意义。事实上，即使没有达到真正的耐受性，抗cd154即使作为单一药物也能在NHP中获得显著的无治疗生存期。基于在最严格的小鼠移植模型中与抗cd154和其他药物的有效协同作用以及独特的作用机制，包括诱导内源性抑制性共刺激分子CTLA-4和调节性T细胞（Tregs）的重新生成，我们现在建议研究基于抗cd45rb的方案诱导NHP患者肾异体移植耐受的能力。初步研究结果显示，使用抗人CD45RB作为单一药物或与雷帕霉素联合使用，偶尔会有长期生存。然而，成功可能受到抗鼠抗体（MAMA）快速发展的阻碍。基于耐受性诱导和作用机制方面的强大协同作用，我们现在提出：在Aim 1中，我们将确定抗cd45rb加抗CD40的功效（通过CD40/CD154阻断正共刺激，并通过CTLA-4增强负共刺激信号）；在Aim 2中，将抗cd45rb与sCD83结合，sCD83是一种新型且强大的DC成熟抑制剂（因为耐受性DC与抗cd45rb从头诱导Treg结合形成了一个生成Treg的正反馈回路）。如有必要，将添加其他药物，如供体特异性输血（DST）或雷帕霉素，这也是基于小鼠和NHP模型的有效协同作用。在Aim 3中，将进行机制研究，以扩展从小鼠研究中获得的见解，并特别解决添加剂对Treg生成、能量、缺失和抑制B细胞和DC激活的影响。在Aim 4中，将定义在不需要细胞激活的情况下诱导非调节性细胞重新转化为调节性T细胞（Tregs）的特定信号。这将为Treg免疫生物学提供新的见解，并为未来确定新的更有效和特异性的治疗靶点提供机会。

DESCRIPTION (provided by applicant): The quest for peripheral tolerance in human transplantation remains unfulfilled and new insight is required. Therapeutic strategies able to induce peripheral tolerance in murine models have thus far been unable to reliably induce tolerance in non-human primates (NHP). Nonetheless, murine models have been instructive in defining important targets and demonstrating that combination therapy is much more robust. Indeed, anti-CD154, even as a single agent allowed significant treatment-free survival in NHP, even if true tolerance was not achieved. Based on potent synergy with anti-CD154 and other agents in the most stringent murine transplant models and a unique mechanisms of action that include induction of the endogenous inhibitory costimulatory molecule, CTLA-4 and de novo generation of regulatory T cells (Tregs), we now propose to study the ability of anti-CD45RB-based regimens to induce renal allograft tolerance in NHP. Preliminary findings using an anti-human CD45RB as a single agent or with Rapamycin demonstrate occasional long-term survival. However, success may be hampered by rapid development of anti-murine Abs (MAMA). Based on potent synergy both in terms of tolerance induction and in terms of mechanisms of action, we now propose: In Aim 1, we will determine the efficacy of anti-CD45RB plus anti-CD40 (blockade of positive costimulation through CD40/CD154 combined with augmentation of negative costimulatory signaling through CTLA-4); In Aim 2, combining anti-CD45RB with sCD83, a novel and powerful inhibitor of DC maturation (since tolerogenic DC combined with de novo induction of Treg by anti-CD45RB forms a positive feedback loop for generating Tregs). Additional agents such as donor-specific transfusion (DST) or Rapamycin will be added if necessary, again based on potent synergy in both murine and NHP models. In Aim 3, mechanistic studies will be performed to extend insight gained from murine studies, and specifically address the effects of the added agents on Treg generation, anergy, deletion, and inhibition of B cell and DC activation. In Aim 4, specific signals that induce de novo conversion of non-regulatory cells into regulatory T cells (Tregs) without requiring cell activation will be defined. This will provide new insight into Treg immunobiology and an opportunity to define new more potent and specific therapeutic targets future.