Tocilizumab and Active Antibody-Mediated Rejection in Kidney Transplantation: A Literature Review

Abstract

IntroductionChronic kidney disease (CKD) is a major public-health problem that increases the risk of end-stage kidney disease (ESKD), cardiovascular diseases, and other complications. Kidney transplantation is a renal-replacement therapy that offers better survival compared to dialysis. Antibody-mediated rejection (ABMR) is a significant complication following kidney transplantation: it contributes to both short- and long-term injury. The standard-of-care (SOC) therapy combines plasmapheresis and Intravenous Immunoglobulins (IVIg) with or without steroids, with or without rituximab: however, despite this combined treatment, ABMR remains the main cause of graft loss. IL-6 is a key cytokine: it regulates inflammation, and the development, maturation, and activation of T cells, B cells, and plasma cells. Tocilizumab (TCZ) is the main humanized monoclonal aimed at IL-6R and appears to be a safe and possible strategy to manage ABMR in sensitized recipients. We conducted a literature review to assess the place of the anti-IL-6R monoclonal antibody TCZ within ABMR protocols.Materials and MethodsWe systematically reviewed the PubMed literature and reviewed six studies that included 117 patients and collected data on the utilization of TCZ to treat ABMR.ResultsMost studies report a significant reduction in levels of Donor Specific Antibodies (DSAs) and reduced inflammation and microvascular lesions (as found in biopsies). Stabilization of the renal function was observed. Adverse events were light to moderate, and mortality was not linked with TCZ treatment. The main side effect noted was infection, but infections did not occur more frequently in patients receiving TCZ as compared to those receiving SOC therapy.ConclusionTCZ may be an alternative to SOC for ABMR kidney-transplant patients, either as a first-line treatment or after failure of SOC. Further randomized and controlled studies are needed to support these results.

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

“…Subsequently, there have been many other reports demonstrating benefits in treatment of AMR, cAMR, and CMR with tocilizumab in adult and pediatric kidney transplant patients. Treatment of AMR/cAMR with long‐term administration of tocilizumab had been overall safe and without significant side effects in our hands 30–36 . A recent report by Cabezas et al 35 evaluated the reported an evaluation of published literature from case studies regarding the efficacy of tocilizumab in treating cAMR.…”

“…However, boosting endogenous Tregs with immunomodulatory therapies in vivo is an attractive alternative which would eliminate current limitations associated with performing adoptive cell therapy and could be widely clinical applicable. We and others have shown IL‐6 inhibits Treg differentiation and its inhibition with anti–IL‐6/IL‐6R treatment increases Treg numbers in animal models and human studies in vivo 28,32,35,38 . Granofszky et al 41 evaluated treatment with anti–IL‐6 instead of Treg transfer to determine if this would lead to multi‐lineage chimerism in recipients of fully mismatched BMT.…”

“…Treatment of AMR/cAMR with long-term administration of tocilizumab had been overall safe and without significant side effects in our hands. [30][31][32][33][34][35][36] A recent report by Cabezas et al 35 evaluated the reported an evaluation of published literature from case studies regarding the efficacy of tocilizumab in treating cAMR. They evaluated 117 cases of cAMR and their conclusion showed that in most cases there was a significant reduction in levels of DSAs and reduced inflammation and microvascular lesions on biopsies after tocilizumab treatment.…”

“…Importantly, the investigators allowed patients treated with placebo in the randomized portion of the study Treg numbers in animal models and human studies in vivo. 28,32,35,38 Granofszky et al 41…”

STAT3 Inhibitors: A Novel Insight for Anticancer Therapy of Pancreatic Cancer

“…Tocilizumab is a highly specific monoclonal antibody that recognizes IL-6R [ 93 ]. Serum levels of IL-6 and soluble IL-6R are elevated in RA patients after treatment with tocilizumab, which is currently approved by the FDA for the treatment of RA and juvenile idiopathic arthritis [ 94 , 95 ]. The effects of tocilizumab in cancer disease are similar to those of RA, with patients receiving tocilizumab experiencing functional IL-6R blockade, increased serum IL-6 and soluble IL-6R levels, decreased levels of phosphorylated STAT3, and more active T-cell function in vivo, secreting more interferon-gamma and tumor necrosis factor-alpha [ 96 ].…”