IL-6 Directed Therapy in Transplantation

Abstract

Purpose of Review IL-6 is a pleiotropic, pro-inflammatory cytokine that plays an integral role in the development of acute and chronic rejection after solid organ transplantation. This article reviews the experimental evidence and current clinical application of IL-6/IL-6 receptor (IL-6R) signaling inhibition for the prevention and treatment of allograft injury. Recent Findings There exists a robust body of evidence linking IL-6 to allograft injury mediated by acute inflammation, adaptive cellular/humoral responses, innate immunity, and fibrosis. IL-6 promotes the acute phase reaction, induces B cell maturation/antibody formation, directs cytotoxic T-cell differentiation, and inhibits regulatory T-cell development. Importantly, blockade of the IL-6/IL-6R signaling pathway has been shown to mitigate its harmful effects in experimental studies, particularly in models of kidney and heart transplant rejection. Currently, available agents for IL-6 signaling inhibition include monoclonal antibodies against IL-6 or IL-6R and janus kinase inhibitors. Recent clinical trials have investigated the use of tocilizumab, an anti-IL-6R mAb, for desensitization and treatment of antibody-mediated rejection (AMR) in kidney transplant recipients, with promising initial results. Further studies are underway investigating the use of alternative agents including clazakizumab, an anti-IL-6 mAb, and application of IL-6 signaling blockade to clinical cardiac transplantation. Summary IL-6/IL-6R signaling inhibition provides a novel therapeutic option for the prevention and treatment of allograft injury. To date, evidence from clinical trials supports the use of IL-6 blockade for desensitization and treatment of AMR in kidney transplant recipients. Ongoing and future clinical trials will further elucidate the role of IL-6 signaling inhibition in other types of solid organ transplantation.

Implantable Immunosuppressant Delivery to Prevent Rejection in Transplantation

“…Later on, more immunosuppressant types were developed. For instance, tofacitinib that inhibits the immune response through the janus kinase pathway, monoclonal antibodies (clazakizumab, tocilizumab) to inhibit inflammatory cytokines (such as interleukin (IL)-6), and multimeric Fas ligands (Adipogen) that can improve the survival of MSCs survival and support MSCs to induce T cells apoptosis (Figure 1) [23][24][25][26][27].…”

Imagining a Better Outcome for Chronic Antibody-Mediated Rejection—Will Blocking Interleukin-6 Signaling Help?

“…Blocking IL-6 signaling effectively reduces B cell activation, plasmablast differentiation, and antibody production. 5 In a mouse model of allosensitization, IL-6R blockade attenuated alloantibody recall responses by modulating T helper 17 cells, T follicular helper cells, regulatory T cells (Tregs), and long-lived plasma cells in the bone marrow. S1 IL-6 promotes T cell proliferation by producing IL-2 and activating STAT3.…”

“…S1 IL-6 promotes T cell proliferation by producing IL-2 and activating STAT3. 5 Together with transforming growth factor-b, IL-6 is involved in the differentiation of T helper 17 cells from naive T cells by enhancing RORgt expression. It inhibits Treg differentiation from naive T cells by transforming growth factor-b via STAT3.…”

“…S2 In the kidneys, IL-6 is secreted by multiple cell types and activates pathways involved in inflammation, ischemia-reperfusion injury, adaptive cellular and humoral responses, and fibrosis. 5 There may be theoretical reasons that blocking IL-6 makes inflammation worse. Natural killer (NK) cells-like cytotoxic T cells-can elaborate perforin and granzyme and can cause target cell apoptosis.…”

“…In human kidney transplant recipients with acute rejection, early reports have documented increased expression of IL-6 mRNA in kidney biopsies and increased serum and urine IL-6 levels. 5 In an initial study of 36 patients with CAAMR who failed standard treatment, tocilizumab was given as a rescue therapy. Significant reductions in donorspecific anti-HLA antibodies and stabilization of kidney function were observed at 2 years; graft and patient survival rates at 6 years were 80% and 91%, respectively.…”