Interleukin-6 Receptor Signaling Disruption Prevents Cardiac Allograft Deterioration in Mice

Abstract

Objectives: Interleukin-6, a pleiotropic cytokine that functions in both innate and adaptive immune responses, has been implicated in allograft rejection. We analyzed the efficacy of anti interleukin-6 receptor monoclonal antibody in delaying allograft rejection in a murine model of a heart. Materials and Methods: To investigate the role of interleukin-6 receptor signal transduction in acute and chronic allograft rejection, we blocked interleukin-6 receptor signaling to suppress the alloimmune response in C57BL/6 recipients of BALB/c cardiac allografts. Results: Administration of a high-dose α-interleukin-6 receptor monoclonal antibody prevented the intragraft infiltration of inflammatory cells and lymphocytes and prolonged allograft survival during the peritransplant period. However, all allografts were rejected by 23.5 days after transplant. In contrast, cardiac allograft recipients treated with a cytotoxic T-lymphocyte antigen 4-immunoglobulin plus continued administration of low-dose α-interleukin-6 receptor monoclonal antibody showed long-term graft survival compared with cytotoxic T-lymphocyte antigen 4-immunoglobulin monotherapy. A histologic analysis revealed that graft fibrosis was prevented in cytotoxic T-lymphocyte antigen 4-immunoglobulin plus highdose α-interleukin-6 receptor monoclonal antibody group, but not in the cytotoxic T-lymphocyte antigen 4-immunoglobulin alone group. This suggests that deterioration of graft function associated with chronic rejection could be prevented by blocking interleukin-6 receptor signaling. Conclusions: Disruption of interleukin-6 receptor signaling is an effective strategy for modulating proinflammatory immune responses and preventing chronic rejection.

RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection

“…The comparison of significantly dysregulated transcripts in transplanted mice and patients manifesting rejection yielded 70 common dysregulated mRNAs, with 33 of these 70 coding for proteins involved in the IL‐6 pathway. These findings are in line with previous reports on the role of IL‐6 in cardiac rejection 40, 41 and urge for further efforts to determine the true potential of IL‐6 targeting to prevent ACR. Importantly, the pro‐inflammatory effects of miR‐155 during ACR implicate that it targets mRNAs coding for anti‐inflammatory proteins.…”

Novel Application of Localized Nanodelivery of Anti–Interleukin-6 Protects Organ Transplant From Ischemia–Reperfusion Injuries

“…While animal studies have highlighted the importance of targeting IL‐6 to promote allograft survival , the impact of anti–IL‐6 in reducing IRI‐induced alloimmunity has not been shown previously. Our data indicate that anti–IL‐6 treatment abrogates this effect of IRI.…”

Anti-IL-6 eluting immunomodulatory biomaterials prolong skin allograft survival

“…Amongst the various inflammatory cytokines, IL-6 is one of the most pleotropic cytokines known 55,56 . IL-6 plays a critical role in the pathogenesis of allograft rejection in general, and targeting IL-6 results in reduced acute rejection and amelioration of chronic vascular injuries 56–63 . Targeting IL-6 also promotes the tolerogenic effect of co-stimulatory blockade 60,64 .…”