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

描述(申请人提供)：人类移植中对外周免疫耐受的探索仍未实现，需要新的见解。到目前为止，能够在小鼠模型中诱导外周耐受的治疗策略一直无法在非人类灵长类动物(NHP)中可靠地诱导耐受。尽管如此，小鼠模型在确定重要的靶点和证明联合治疗要强大得多方面具有指导意义。事实上，抗CD154作为一种单一的药物，即使没有达到真正的耐受性，也可以在NHP中实现显著的无治疗存活。基于在最严格的小鼠移植模型中与抗CD154和其他药物的强大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和从头产生调节性T细胞(Tregs)，我们现在提议研究基于抗CD45RB的方案在NHP中诱导肾移植耐受的能力。使用抗人CD45RB作为单一药物或与雷帕霉素联合使用的初步研究结果表明，偶尔会有长期存活。然而，抗鼠抗体(MAMA)的快速发展可能会阻碍成功。基于在耐受诱导和作用机制方面的强大协同作用，我们现在建议：在目标1中，我们将确定抗CD45RB与抗CD40(通过CD40/CD154阻断正向共刺激结合通过CTLA-4增强负向共刺激信号)的疗效；在目标2中，将抗CD45RB与sCD83相结合，sCD83是一种新型而强大的DC成熟抑制因子(因为耐受性DC与抗CD45RB对Treg的从头诱导形成一个正反馈环路以产生Tregs)。额外的药物，如供体特异性输血(DST)或雷帕霉素，将在必要时添加，同样基于在小鼠和NHP模型中的强大协同作用。在目标3中，将进行机制研究，以扩大从小鼠研究中获得的洞察力，并具体讨论添加的药物对Treg的生成、无能、缺失和抑制B细胞和DC激活的影响。在目标4中，将定义诱导非调节性细胞从头转化为调节性T细胞(Treg)而不需要细胞激活的特定信号。这将为Treg免疫生物学提供新的见解，并为未来定义新的更有效和更具体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.