Targeting Inflammation and Alloimmunity in Heart Transplant Recipients with Tocilizumab

项目摘要/摘要 心脏移植是治疗不可逆的终末期心脏病的最佳方法。然而， 长期结果受限于早期发生的广泛的炎症和免疫反应。 在移植后。这些包括缺血再灌注损伤，先天免疫激活，急性细胞 排斥反应和抗体介导的排斥反应，所有这些都导致晚期同种异体心脏移植血管病变和 纤维化(慢性排斥反应)。这些有效反应的多因素性质解释了为什么目前的临床 免疫抑制策略，专门针对抗供体T细胞反应和急性细胞 排斥反应，在预防慢性排斥反应和实现可接受的长期生存方面都不成功。 白介素6是一种独特的多效性细胞因子，因其增强和连接的能力而日益得到认可 适应性反应、先天反应和炎症反应。IL-6独特而关键的参与了每一种免疫- 上述炎症途径使其成为一种特别有吸引力的靶向细胞因子。Tocilizumab (Actemra®)是一种针对IL-6受体(IL-6R)的一流人源化单抗。它是 FDA批准用于治疗难治性炎症性疾病。在实验模型中，tocilizumab(TCZ) 已被证明倾斜Th17/Treg平衡，有利于调节细胞的承诺，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(初级 和召回)。在人体试验中，TCZ已被证明在治疗抗体介导的自身免疫性疾病方面非常有效。 联合调查员S.Jordan最近报道了TCZ在人类移植受者中的首次使用。不仅 它在降低高度致敏的肾移植受者的同种异体抗体水平方面是否安全有效，但 能够改善患有最严重慢性抗体形式的肾移植受者的移植物和患者的存活率- 中介性排斥。考虑到通过阻断IL-6/IL-6R途径实现的免疫调节的广度，我们 假设移植后早期在常规免疫抑制的基础上加用TCZ将 减少促炎、适应性和先天免疫反应，同时加强调节机制。这 会对宿主的免疫系统产生长期影响的保护性/消炎性环境 同种异体移植可提高移植物的长期存活率和患者的存活率。为了验证这一假设，我们将进行一项 随机临床试验：1)确定早期曲克西平治疗对心脏移植结果的影响。 至少一年，2)研究TCZ治疗对小鼠炎症和同种异体免疫反应的影响 心脏移植受者，以及3)将几个非侵入性生物标记物的效用定义为风险评估， 预测心脏移植受者预后的诊断性和预测性检测策略。我们的 全面和综合的机制研究将使我们能够阐明治疗成功或失败的原因。 因此，无论结果如何，这些研究都将通过指导未来的试验设计而使心脏受者受益。

PROJECT SUMMARY / ABSTRACT Heart transplantation is the optimal therapy for patients with irreversible, end-stage heart disease. However, long-term outcomes are limited by a broad range of inflammatory and immune responses that occur early following transplantation. These include ischemia reperfusion injury, innate immune activation, acute cellular rejection, and antibody-mediated rejection, all of which contribute to late cardiac allograft vasculopathy and fibrosis (chronic rejection). The multifactorial nature of these potent responses explains why current clinical immunosuppressive strategies, designed specifically to target anti-donor T cell responses and acute cellular rejection, are unsuccessful in preventing chronic rejection and achieving acceptable long term survival. Interleukin (IL)-6 is a uniquely pleiotropic cytokine increasingly recognized for its ability to augment and link adaptive, innate, and inflammatory responses. The unique and critical involvement of IL-6 in each of the immune- inflammatory pathways described above makes it an especially attractive cytokine to target. Tocilizumab (Actemra®) 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, tocilizumab (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 proven highly effective in treating antibody-mediated autoimmune disorders. The first use of TCZ in human transplant recipients was recently reported by co-investigator S. Jordan. Not only was it safe and effective in reducing alloantibody levels in highly sensitized kidney allograft recipients, but it was able to improve graft and patient survival in kidney recipients with the most severe form of chronic antibody- mediated rejection. Given the breadth of immune modulation achieved by blocking the IL-6/IL-6R pathway, we hypothesize that the addition of TCZ to conventional immunosuppression in the early post-transplant period will diminish proinflammatory, adaptive and innate immune responses while enhancing regulatory mechanisms. This will initiate a protective/anti-inflammatory milieu that will have long-lasting effects on the host's immune system and allograft resulting in improved long term graft and patient survival. To test this hypothesis, we will conduct a randomized clinical trial to, 1) determine the effect of early TCZ treatment on heart transplant outcomes at a minimum of one year, 2) investigate the effects of TCZ therapy on inflammatory and alloimmune responses in heart transplant recipients, and 3) define the utility of several noninvasive biomarkers as risk assessment, diagnostic, and predictive testing strategies for anticipating outcomes in heart transplant recipients. Our comprehensive and integrated mechanistic studies will allow us to elucidate why therapy succeeded, or failed. Thus, regardless of outcomes, these studies will benefit heart recipients by guiding future trial design.