Interleukin-6, A Cytokine Critical to Mediation of Inflammation, Autoimmunity and Allograft Rejection

Abstract

The success of kidney transplants is limited by the lack of robust improvements in long-term survival. It is now recognized that alloimmune responses are responsible for the majority of allograft failures. Development of novel therapies to decrease allosensitization is critical. The lack of new drug development in kidney transplantation necessitated repurposing drugs initially developed in oncology and autoimmunity. Among these is tocilizumab (anti-IL-6 receptor [IL-6R]) which holds promise for modulating multiple immune pathways responsible for allograft injury and loss. Interleukin-6 is a cytokine critical to proinflammatory and immune regulatory cascades. Emerging data have identified important roles for IL-6 in innate immune responses and adaptive immunity. Excessive IL-6 production is associated with activation of T-helper 17 cell and inhibition of regulatory T cell with attendant inflammation. Plasmablast production of IL-6 is critical for initiation of T follicular helper cells and production of high-affinity IgG. Tocilizumab is the first-in-class drug developed to treat diseases mediated by IL-6. Data are emerging from animal and human studies indicating a critical role for IL-6 in mediation of cell-mediated rejection, antibody-mediated rejection, and chronic allograft vasculopathy. This suggests that anti-IL-6/IL-6R blockade could be effective in modifying T- and B-cell responses to allografts. Initial data from our group suggest anti-IL-6R therapy is of value in desensitization and prevention and treatment of antibody-mediated rejection. In addition, human trials have shown benefits in treatment of graft versus host disease in matched or mismatched stem cell transplants. Here, we explore the biology of IL-6/IL-6R interactions and the evidence for an important role of IL-6 in mediating allograft rejection.

Assessment of Tocilizumab (Anti–Interleukin-6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy in HLA-Sensitized Renal Allograft Recipients

“…IL-6 is an important mediator of inflammation that is critical to shaping T cell immunity and inhibiting Tregs while increasing T helper 17 cell (Th17) populations (18,19). IL-6 is also critical for the progression of na€ ıve B cells to plasmablasts and mature plasma cells.…”

“…It is accepted that IL-6 drives CD4 T cells toward Th17 phenotype while negating Treg differentiation (18,19). Neutralization of IL-6 reduces allograft rejection by allowing emergence of Tregs (19,31).…”

“…We have shown that IL-6-IL-6 receptor (IL-6R) interactions are critical for alloantibody generation in an animal model of alloimmunity (17). Thus, IL-6 shapes T cell immunity and is a powerful stimulant for pathogenic IgG production (18,19). Thus, IL-6 shapes T cell immunity and is a powerful stimulant for pathogenic IgG production (18,19).…”

Desensitization: Overcoming the Immunologic Barriers to Transplantation

“…However, excessive and unregulated production of IL-6 result in a number of chronic immune disorders, including a role in the chronic inflammation seen in transplant rejection, patients on dialysis, in crescentic glomerulonephritis, and graft versus host disease (GVHD) [43–45]. IL-6 is one of the major cytokines involved in differentiation of B cells to IgG-secreting plasmablasts and finally to plasma cells [46, 47]. In addition, IL-6 stimulates Th17 cells that increase inflammation and allograft rejection and inhibits the generation of Treg cells [48].…”

Anti-Interleukin-6 Promotes Allogeneic Bone Marrow Engraftment and Prolonged Graft Survival in an Irradiation-Free Murine Transplant Model

“…The pro-inflammatory cytokine interleukin-6 (IL-6) is a critical player in T cell and B cell (allo)immunity (18, 19). IL-6 is known for its versatile immunological functions, including its role as a key regulator of the Treg/Th17 balance where it prevents Treg development while promoting the differentiation of naïve T cells into Th17 cells (20, 21).…”