Targeting Inflammation and Alloimmunity in Heart Transplant Recipients with Tocilizumab

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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.