Targeting Inflammation and Alloimmunity in Heart Transplant Recipients with Tocilizumab

使用托珠单抗治疗心脏移植受者的炎症和同种免疫

• 批准号: 9143892
• 负责人: Joren C Madsen
• 金额: $ 29.3万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9143892
• 关键词: Acute; Adrenal Cortex Hormones; Allografting; Antibodies; Antibody Formation; Arterial Fatty Streak; Assessment tool; Autoimmune Diseases; Autoimmunity; B cell differentiation; B-Lymphocytes; Biological Markers; Blinded; Blood Circulation; Cell Count; Cells; Cessation of life; Chronic; Chronic Childhood Arthritis; Clinical; Clinical trial protocol document; Complement; Complex; Controlled Clinical Trials; Development; Diagnosis; Disease; Enzyme-Linked Immunosorbent Assay; Equilibrium; Experimental Models; FDA approved; Fibrosis; Flow Cytometry; Frequencies; Functional disorder; Gene Expression; Gene Expression Profiling; Generations; Goals; Heart Diseases; Heart Transplantation; Human; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; Incidence; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Institutional Review Boards; Interleukin 6 Receptor; Interleukin-6; Interleukins; Isoantibodies; Jordan; Left Ventricular Ejection Fraction; Ligands; Link; Maintenance; Mediating; Mediator of activation protein; Memory B-Lymphocyte; Natural Immunity; Natural Killer Cells; Outcome; Pathogenesis; Pathway interactions; Patients; Placebos; Plasmablast; Production; Protocols documentation; Publications; Randomized; Recruitment Activity; Refractory; Regulatory T-Lymphocyte; Reperfusion Injury; Reporting; Research Personnel; Rheumatoid Arthritis; Risk Assessment; Signal Transduction; Staging; T cell response; T-Lymphocyte; Tacrolimus; Testing; Time; Transplant Recipients; Transplantation; Ultrasonography; Vascular Diseases; Work; allograft rejection; arm; cytokine; design; efficacy testing; enzyme linked immunospot assay; experience; heart allograft; hemodynamics; humanized monoclonal antibodies; immunoregulation; improved; improved outcome; isoimmunity; kidney allograft; operation; prevent; prospective; public health relevance; response

 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.

 描述（由申请人提供）：心脏移植是不可逆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物血管通路（CAV）形式的慢性排斥反应的限制。CAV的发病机制复杂且涉及多个因素，难以预防和/或治疗。研究人员在该应用和其他方面的工作表明，CAV不仅由适应性免疫系统的组分（B细胞和T细胞）引起，而且由与先天免疫（NK细胞）和炎症级联（缺血再灌注损伤（IRI））相关的细胞和细胞因子引起。因此，目前设计用于靶向抗供体T细胞应答的临床免疫抑制策略在预防CAV方面不成功并不令人惊讶。白细胞介素（IL）-6是一种独特的多效性细胞因子， 它被认为具有增强和连接适应性、先天性和炎症反应的能力。IL-6在CAV的每个免疫炎症途径中的关键参与，使其成为靶向预防CAV的特别有吸引力的细胞因子。Tocilizumab（TCZ，Actemra（r））是一种针对IL-6受体（IL-6 R）的一流的人源化单克隆抗体。它是FDA批准用于治疗难治性炎症性疾病。在实验模型中，TCZ已经显示出使Th 17/Treg平衡偏向于调节性细胞定型，从而扩大Treg数量，减少同种异体移植排斥，并减少记忆B细胞数量和抗体形成（初次和回忆）。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，而且联合研究者S. Jordan报告了TCZ在人类移植受者中的首次使用，表明其在促进难以脱敏的肾移植受者的同种抗体水平降低方面是安全有效的。通过阻断IL-6/IL-6 R途径实现的免疫调节范围增加了TCZ有效改善IR诱导的炎症、减轻同种免疫和自身免疫以及预防CAV的可能性。该提议的核心假设是，在移植后早期将IL-6信号传导阻断添加到常规免疫抑制中将减少心脏移植后的促炎性、适应性和先天性免疫应答，并将增强受体中的调节机制，从而降低IRI、急性排斥（AR）和CAV，改善移植物和患者存活。当前R34应用程序的目标是生成一个 临床试验方案，其将通过1）确定TCZ改善心脏移植受者的结果的功效和2）研究TCZ对炎症和同种免疫应答的作用来检验我们的核心假设。