Immune responses following tocilizumab therapy to desensitize HLA-sensitized kidney transplant candidates

Abstract

Kidney transplant candidates (KTCs) who are HLA highly sensitized (calculated panel‐reactive alloantibodies >95%) have poor access to deceased kidney transplantation. In this single‐center prospective study, 13 highly sensitized desensitization‐naïve KTCs received IV tocilizumab (8 mg/kg) every 4 weeks. We evaluated tolerability as well as immune responses, that is, T cell, B cell, T follicular helper (Tfh) subsets, blood cytokines (IL‐6, soluble IL‐6 receptor‐sIL‐6R‐, IL‐21), blood chemokines (CXCL10, CXCL13), and anti‐HLA alloantibodies. Tocilizumab treatment was well‐tolerated except in one patient who presented spondylodiscitis, raising a note of caution. Regarding immune parameters, there were no significant changes of percentages of lymphocyte subsets, that is, CD3+, CD3+/CD4+, CD3+/CD8+ T cells, and NK cells. This was also the case for Tfh cell subsets, B cells, mature B cells, plasma cells, pre‐germinal center (GC) B cells, and post‐GC B cells, whereas we observed a significant increase in naïve B cells (p = .02) and a significant decrease in plasmablasts (p = .046) over the tocilizumab treatment course. CXCL10, CXCL13, IL‐21, total IgG, IgA, and IgM levels did not significantly change during tocilizumab therapy; conversely, there was a significant increase in IL‐6 levels (p = .03) and a huge increase in sIL‐6R (p = .00004). There was a marginal effect on anti‐HLA alloantibodies (class I and class II). To conclude in highly sensitized KTCs, tocilizumab as a monotherapy limited B cell maturation; however, it had almost no effect on anti‐HLA alloantibodies.

Multi-omics network characterization reveals novel microRNA biomarkers and mechanisms for diagnosis and subtyping of kidney transplant rejection

“…It is widely known that immune response is a leading factor affecting the function of allograft after kidney transplantation [ 29 , 30 ]. In this study immune-related BP terms, e.g., interferon-gamma-mediated signaling pathway, type I interferon signaling pathway, immune response, antigen processing and presentation, etc.…”

Tocilizumab in the Treatment of Chronic Antibody-Mediated Rejection Post Kidney Transplantation: Clinical and Histological Monitoring

“…It has been showed that TCZ significantly and nonspecifically reduce the IgG synthesis in highly sensitized kidney transplant recipients treated for cABMR (23). However, in highly sensitized kidney transplant candidates, tocilizumab as a monotherapy limited B cell maturation but however, it had almost no effect on anti-HLA alloantibodies (24). Chandran et al conducted a randomized controlled clinical trial of clinically stable kidney transplant recipients on calcineurin inhibitor, mycophenolate mofetil, and prednisone, with subclinical graft inflammation noted on surveillance biopsies during the first-year post-transplant: they were randomized to receive either TCZ (8 mg/kg every 4 weeks, six infusions) or placebo.…”

Tocilizumab Trough Levels Variability in Kidney-Transplant Candidates Undergoing Desensitization

“…In addition, our results must be weighed up against the modest overall effect of TCZ as the single desensitization strategy [ 9 , 10 ]. Previous studies have suggested that the response to TCZ in rheumatoid arthritis is greater when sIL-6R levels are low [ 23 ].…”

“…However, only half of these patients were able to receive a transplant (5/10 patients) and one patient developed antibody-mediated rejection after transplantation [ 5 ]. In our recently published experience, TCZ as a desensitization therapy failed to induce a clinically significant reduction in anti-HLA antibody mean fluorescent intensity (MFI) [ 9 ], but limited B-cell maturation [ 10 ].…”