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: 10614591
• 负责人: Joren C Madsen
• 金额: $ 242.63万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614591
• 关键词: Acute; Adrenal Cortex Hormones; Affect; Allografting; Anti-Inflammatory Agents; Antibodies; Antibody Formation; Assessment tool; Autoimmune Diseases; B cell differentiation; Biological Markers; Biopsy; Blocking Antibodies; Cell Count; Cells; Cessation of life; Chronic; Chronic Childhood Arthritis; Clinical; Detection; Diagnostic tests; Disease; Dose; Epitopes; Equilibrium; Experimental Models; FDA approved; FOXP3 gene; Fibrosis; Future; Generations; Heart; Heart Diseases; Heart Transplantation; Histologic; Human; IL-6 inhibitor; Immune; Immune response; Immune system; Immunity; Immunosuppression; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Innate Immune Response; Innate Immune System; Interferon Type II; Interleukin 6 Receptor; Interleukin-6; International; Isoantibodies; Jordan; Kidney; Link; Lung Transplantation; Maintenance; Measurement; Mediating; Memory B-Lymphocyte; Monoclonal Antibodies; Morbidity - disease rate; Natural Killer Cells; Nature; Outcome; Pathogenicity; Pathway interactions; Patients; Phase; Placebos; Plasmablast; Production; Quality of life; Randomized; Receptor Signaling; Refractory; Regimen; Regulatory T-Lymphocyte; Reperfusion Injury; Reporting; Research Personnel; Rheumatoid Arthritis; Risk Assessment; Saline; Societies; T cell response; T-Lymphocyte; Tacrolimus; Testing; Time; Transplant Recipients; Transplantation; Vascular Diseases; adaptive immune response; allograft rejection; antibody-mediated rejection; biomarker selection; cell free DNA; cytokine; design; donor-specific antibody; heart allograft; hemodynamics; immune activation; immunoregulation; improved; improved outcome; inflammatory milieu; insight; isoimmunity; kidney allograft; mycophenolate mofetil; novel; optimal treatments; post-transplant; predictive test; preservation; prevent; primary endpoint; programs; prospective; randomized placebo-controlled clinical trial; randomized, clinical trials; response; retransplantation; secondary endpoint; standard of care; tocilizumab; trial design

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.

项目总结/摘要 心脏移植是治疗不可逆终末期心脏病的最佳方法。然而，在这方面， 长期结果受到早期发生的广泛炎症和免疫反应的限制 移植后。这些包括缺血再灌注损伤、先天性免疫激活、急性细胞免疫损伤和急性细胞免疫损伤。 排斥反应和抗体介导的排斥反应，所有这些都导致晚期心脏移植物血管病变， 纤维化（慢性排斥）。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免疫反应， 排斥，在预防慢性排斥和实现可接受的长期存活方面是不成功的。 白细胞介素-6（IL-6）是一种独特的多效性细胞因子，其增强和连接 适应性、先天性和炎症反应。IL-6在每个免疫系统中的独特和关键的参与， 上述炎症途径使其成为特别有吸引力的靶细胞因子。Tocilizumab （Actemra®）是一种针对IL-6受体（IL-6 R）的一流的人源化单克隆抗体。是 FDA批准用于治疗难治性炎症性疾病。在实验模型中，托珠单抗（TCZ） 已显示使Th 17/Treg平衡偏向于调节性细胞定型，从而扩增Treg 数量，减少同种异体移植排斥，减少记忆B细胞数量和抗体形成（初级 （回忆）。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。 TCZ在人类移植受者中的首次使用最近由共同研究者S。约旦.不仅 在降低高致敏肾移植受者的同种抗体水平方面是否安全有效，但 能够改善患有最严重形式的慢性抗体的肾脏接受者的移植物和患者存活率- 介导的排斥考虑到通过阻断IL-6/IL-6 R通路实现的免疫调节的广度，我们 假设在移植后早期，在常规免疫抑制剂的基础上加入TCZ， 减少促炎、适应性和先天性免疫反应，同时增强调节机制。这 将启动保护/抗炎环境，对宿主的免疫系统产生持久的影响 和同种异体移植物，从而提高移植物和患者的长期存活率。为了验证这一假设，我们将进行一次 随机临床试验，1）确定早期TCZ治疗对心脏移植结果的影响， 至少一年，2）研究TCZ治疗对炎症和同种免疫反应的影响 心脏移植受者，和3）定义几种非侵入性生物标志物作为风险评估的效用， 用于预测心脏移植受者结局的诊断和预测性测试策略。我们 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，这些研究将通过指导未来的试验设计而使心脏受者受益。

项目成果

Comorbidities and Age Are Associated With Persistent COVID-19 PCR Positivity.

• DOI: 10.3389/fcimb.2021.650753
• 发表时间: 2021
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Aldhaeefi M;Tahir Z;Cote DJ;Izzy S;El Khoury J
• 通讯作者: El Khoury J