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.
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 vasculopathy (CAV). The goal of this project is to develop a clinical trial protocol for testing the efficacy of Tocilizumab (TCZ, Actemra(r)) in preventing CAV and improving outcomes in heart transplant recipients.
