Importance of IL-6 inhibition in prevention and treatment of antibody-mediated rejection in kidney allografts

Abstract

However, persistent expression of high levels of IL-6 are associated with a number of pathologic conditions including autoimmune diseases and capillary leak syndrome.Importantly, in kidney transplant patients, IL-6 may play a role in mediation of cellmediated rejection (CMR) and antibody-mediated rejection (AMR). This is likely due to the importance of IL-6 in stimulating B cell responses with pathogenic donor-specific antibody (DSA) generation and stimulation of T effector cell responses while inhibiting T regulatory cells. Data from preliminary clinical trials and clinical observations show that tocilizumab (anti-IL-6R) and clazakizumab (anti-IL-6) may have promise in treatment of CMR, AMR and chronic (cAMR). This has led to a phase 3 placebo, randomized clinical trial of clazakizumab for treatment of cAMR, a condition for which there is currently no treatment. The identification of IL-6 production in vascular endothelia cells after alloimmune activation reveals another potential pathway for vasculitis as endothelia cell IL-6 may stimulate immune cell responses that are potentially inhibitable with anti-IL-6/IL-6R treatment. Importantly, anti-IL-6/IL-6R treatments have shown the ability to induce Treg and Breg cells in vivo which may have potential importance for prevention and treatment of DSA development and allograft rejection.

New treatment for antibody-mediated rejection: interleukin-6 inhibitors

“…In cases of rejection occurring more than 30 days after transplant, clinicians should focus on maintaining optimal immunosuppression while addressing any concomitant TCMR. For chronic rejection changes observed more than 30 days posttransplant, therapeutic options such as plasmapheresis, IVIG, high-dose steroids, or rituximab may be considered, particularly in the presence of preexisting DSAs [ 3 , 4 , 13 ].…”

“…This stimulates the maturation of B cells into memory B cells and IL-6–producing plasmablasts, which in turn promote the formation of germinal centers and the progression to antibody-producing plasma cells ( Fig. 3 ) [ 13 ].…”

Advances in desensitization for human leukocyte antigen incompatible kidney transplantation

“…Persistent IL-6/IL-6 receptor (IL-6R) signaling reduces T-regulatory (T reg ) cells, increasing pathogenic antibody production and inflammation [34]. Recent data suggest that targeting the IL-6/IL-6R signaling pathway may provide unique benefits in reducing pathogenic IgG antibodies, reducing T-effector/memory responses while increasing T reg populations and limiting endothelial cell activation and injury in response to DSA binding [35]. There are currently two agents that have been studied in transplantation, discussed below.…”

Chronic Active Antibody-mediated Rejection: Opportunity to Determine the Role of Interleukin-6 Blockade

“…17 Apparent AMR is actually frequently "mixed" and involves multiple effectors, including T cells, 18 complement, endothelial adhesion molecules, neutrophils, monocyte/macrophages, and IgGstimulated antibody-dependent cellular cytotoxicity by natural killer cells. 19,20 IL-6 is implicated in T-cell activation, reducing Treg, stimulating T-follicular helper cells and germinal centers, 21,22 as well as driving B-cell proliferation, maturation, and class-switching. [22][23][24][25] IL-6 also induces acute-phase reactants, activates endothelial cells, and promotes vascular injury.…”

“…19,20 IL-6 is implicated in T-cell activation, reducing Treg, stimulating T-follicular helper cells and germinal centers, 21,22 as well as driving B-cell proliferation, maturation, and class-switching. [22][23][24][25] IL-6 also induces acute-phase reactants, activates endothelial cells, and promotes vascular injury. 26,27 Not only can it act on multiple cell types by both direct and indirect pathways, 28 IL-6 can also be produced by many types of parenchymal cells, especially following ischemia.…”