Targeting Inflammation and Alloimmunity in Heart Transplant Recipients with Tocilizumab

 描述(申请人提供)：心脏移植是不可逆转的终末期心脏病患者的最佳治疗方法。然而，心脏移植后的长期结果受到心脏移植血管病变(CAV)形式的慢性排斥反应的限制。由于其发病机制复杂、多因素，CAV一直难以预防和/或治疗。研究人员在这方面的研究和其他研究表明，CAV不仅由适应性免疫系统的组成部分(B细胞和T细胞)引起，还由与天然免疫(NK细胞)和炎症级联反应(缺血再灌注损伤(IRI))相关的细胞和细胞因子引起。因此，目前针对抗供体T细胞反应的临床免疫抑制策略在预防CAV方面不成功也就不足为奇了。白介素6是一种独特的多效性细胞因子，越来越多地被 因其增强和连接适应性、先天和炎症反应的能力而被公认。IL-6在CAV的每一条免疫炎症途径中都发挥着重要作用，使其成为预防CAV的靶向细胞因子。Tocilizumab(TCZ，Actemra(R))是一种针对IL-6受体(IL-6R)的一流人源化单抗。FDA批准它用于治疗难治性炎症性疾病。在实验模型中，TCZ已被证明扭曲Th17/Treg平衡，有利于调节性细胞承诺，从而扩大Treg数量，减少同种异体移植排斥反应，减少记忆B细胞数量和抗体形成(原发和召回)。在人体试验中，TCZ不仅被证明在治疗抗体介导的自身免疫性疾病方面非常有效，而且联合研究员S.Jordan最近发表的一篇文章报告了TCZ在人类移植受者中的首次使用，表明它在促进难以脱敏的同种异体肾移植受者降低同种抗体水平方面是安全和有效的。通过阻断IL-6/IL-6R途径实现的免疫调节的广度增加了TCZ在改善IRI诱导的炎症、减轻同种和自身免疫以及预防CAV方面有效的可能性。这一建议的核心假设是，在心脏移植后早期，在常规免疫抑制的基础上加用IL-6信号阻断，将减少心脏移植后的促炎、适应性和先天免疫反应，并将增强受体的调节机制，从而减少IRI、急性排斥反应(AR)和CAV，从而改善移植物和患者的存活。当前R34应用程序的目标是生成一个 临床试验方案将通过1)确定TCZ I改善心脏移植受者预后的有效性以及2)研究TCZ对炎症和同种异体免疫反应的影响来检验我们的核心假设。

 DESCRIPTION (provided by applicant): Heart transplantation is the optimal therapy for patients with irreversible, end-stage heart disease. However, long term outcomes following heart transplantation are limited by chronic rejection in the form of cardiac allograft vasculopath (CAV). CAV has been difficult to prevent and/or treat because its pathogenesis is complex and multifactorial. Work by investigators on this application and others have shown that CAV is not only caused by components of the adaptive immune system (B cell and T cells) but also by cells and cytokines associated with innate immunity (NK cells) and the inflammatory cascade (ischemia reperfusion injury (IRI)). Thus, it is not surprising that current clinical immunosuppressive strategies designed to target anti-donor T cell responses are unsuccessful in preventing CAV. Interleukin (IL)-6 is a uniquely pleiotropic cytokine that has increasingly been recognized for its ability to augment and link adaptive, innate, and inflammatory responses. The critical involvement of IL-6 in each of the immuno-inflammatory pathways of CAV, makes it an especially attractive cytokine to target to prevent CAV. Tocilizumab (TCZ, Actemra(r)) is a first-in-class, humanized, monoclonal antibody directed against the IL-6 receptor (IL-6R). It is FDA approved for the treatment of refractory inflammatory diseases. In experimental models TCZ has been shown to skew the Th17/Treg balance in favor of regulatory cell commitment thereby expanding Treg numbers, reducing allograft rejection, and diminishing memory B cell numbers and antibody formation (primary and recall). In human trials TCZ has not only proven highly effective in treating antibody-mediated autoimmune disorders but a recent publication by co-investigator S. Jordan reporting the first use of TCZ in human transplant recipients, showed it to be safe and effective in facilitating a reduction of alloantibody levels in difficult to desensitiz kidney allograft recipients. The breadth of immune modulation achieved by blocking the IL-6/IL-6R pathway enhances the likelihood that TCZ will be effective in ameliorating IRI-induced inflammation, mitigating allo- and autoimmunity and preventing CAV. The core hypothesis underlying this proposal is that the addition of IL-6 signaling blockade to conventional immunosuppression in the early post-transplant period will diminish proinflammatory, adaptive and innate immune responses following heart transplantation, and will enhance regulatory mechanisms in the recipients, together resulting in decreased IRI, acute rejection (AR) and CAV with improved graft and patient survival. The goal of this current R34 application is to generate a clinical trial protocol that would test our core hypothesis by 1) determining the efficacy of TCZ i improving outcomes in heart transplant recipients and 2) investigating the effects of TCZ on inflammatory and alloimmune responses.