Interleukin-6: An Important Mediator of Allograft Injury

Abstract

Interleukin-6 (IL-6) is a cytokine with critical innate and adaptive immunity functions. Its diverse immunological and physiological actions include direction of immune cell differentiation, initial response to invading pathogens and ischemic injury, sustained plasma cell growth, and immunoglobulin production. IL-6 transcriptional dysregulation is commonly seen in patients with autoimmune or inflammatory disorders. Emerging information suggests that IL-6 transcription is upregulated in patients with kidney and heart transplant rejection and may account for perpetuation of inflammatory responses in the allograft, leading to allograft rejection and vasculopathy. IL-6–directed therapeutics include monoclonal antibodies directed at IL-6, the IL-6 receptor (IL-6R), and Janus kinase inhibitors. IL-6–mediated signaling to cell targets is unique, involving classic signaling (IL-6->IL-6R) cell membrane receptors, transsignaling (IL-6->soluble IL-6R->gp130) which activates any cell, and the recently discovered IL-6/IL-6R transpresentation in which antigen-presenting cells synthesize and express IL-6/IL-6R complexes, which are transported through the cell membrane subsequently interacting with gp130 to costimulate T cells. Currently, there are new trials in autoimmunity and heart and kidney transplantation to determine effectiveness of inhibiting IL-6/IL-6R to ameliorate chronic allograft rejection and coronary allograft vasculopathy. Therapeutic trials aimed at prevention of ischemia/reperfusion injury to allografts based on animal data should be considered.

A perspective on the potential detrimental role of inflammation in pig orthotopic heart xenotransplantation

“…Interleukin‐6 receptor (IL‐6R) blockade with tocilizumab prevented a rise in C‐RP (Figure 1), but clearly did not completely prevent the inflammatory response because SAA remained elevated for several weeks or even months (Figure 4). 18,19 Although IL‐6R blockade with tocilizumab may have had a beneficial effect in suppressing T‐ and B‐cell activation, 30 and preventing IL‐6 binding to baboon tissues, it does not prevent binding to pig tissues 26,31 . We, therefore, suggest its administration could possibly be detrimental to the pig graft (as the level of plasma IL‐6 increases significantly as it can no longer bind to baboon tissues).…”

IL-6 Directed Therapy in Transplantation

“…Trans-signaling dramatically expands the activation capacities and pathological effects of IL-6 by enabling the transmission of IL-6R-initiated signals to cells that do not constitutively express the receptor. Indeed, sIL-6R and the widespread expression of gp130 enable IL-6 to activate nearly every cell in the body [27,28]. Trans-signaling is regulated by a soluble form of gp130 (sgp130), which forms a complex with IL-6/sIL-6R and prevents its binding to membrane-bound gp130 [29].…”

HLA Desensitization in Solid Organ Transplantation: Anti-CD38 to Across the Immunological Barriers

“…First, Interleukin 6 (IL-6) is a cytokine promoting Tfh and enhancing the progression of B cells to high-affinity antibodies producing PC (42). Tocilizumab, a first-in-class humanized monoclonal antibody (mAb) with specificity for IL-6R, reduce inflammation within the allograft during ABMR in heart and kidney transplantation (43) and induce circulating DSA reduction (44). Clazakizumab is a humanized IgG1 mAb with specificity for IL6 which can also induce circulating DSA reduction (45).…”