title: Interleukin-6, A Cytokine Critical to Mediation of Inflammation, Autoimmunity and Allograft Rejection: Therapeutic Implications of IL-6 Receptor Blockade.
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.
authors.affiliation: 1 Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Jordan
authors.forename: Jua
authors.initials: J
authors.lastname: Choi
authors.forename: Irene
authors.initials: I
authors.lastname: Kim
authors.forename: Gordon
authors.initials: G
authors.lastname: Wu
authors.forename: Mieko
authors.initials: M
authors.lastname: Toyoda
authors.forename: Bonga
authors.initials: B
authors.lastname: Shin
authors.forename: Ashley
authors.initials: A
authors.lastname: Vo
mesh_terms: D064591:Allografts; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D015551:Autoimmunity / Q000187:drug effects*; D015195:Drug Design; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D058990:Molecular Targeted Therapy; D016377:Organ Transplantation / Q000009:adverse effects*; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors