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

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.

[Improving access to kidney transplantation for highly sensitized patients: What place for IL-6 pathway blockade in desensitization protocols?] / Améliorer l'accès à la transplantation rénale des sujets hyperimmunisés : quelle place pour un blocage de la voie de l'IL-6 dans les protocoles de désimmunisation ?

BACKGROUND: Desensitization allows kidney transplantation for HLA highly sensitized subjects. Due to the central role of IL-6 in immunological response, tocilizumab (monoclonal antibody directed against IL-6 receptor) could probably improve desensitization efficacy. METHODS: Pubmed systematic review by using MeSH terms: tocilizumab, clazakizumab, interleukin-6 blockade, kidney transplantation, kidney graft and desensitization. STUDIES: IL-6 plays a role in humoral response (plasmocyte differentiation induced by lymphocyte T, IL-21 secretion) as well as in cellular response (differentiation of LT Th17 rather than T reg). In desensitization field, tocilizumab was first studied as second-line treatment after failing of standard-of-care (apheresis, rituximab ± IgIV). Recent study showed that tocilizumab as a monotherapy attenuated anti-HLA antibodies rates but was not sufficient to allow transplantation. However, lymphocyte immunophenotyping showed that tocilizumab hindered B cells maturation. Thereby, tocilizumab could improve long-term efficacy of desensitization, by limiting the anti-HLA rebound and so avoiding antibody-mediated rejection. This hypothesis is supported by a recent study which used clazakizumab (monoclonal antibody directed against IL-6) in association with standard-of-care. In that study, clazakizumab was continued after kidney transplantation. Results were encouraging because 9/10 patients were transplanted and there was no donor-specific antibody at 6 months post-transplantation. CONCLUSION: IL-6 pathway blockade as a monotherapy fails to desensitize HLA highly sensitized kidney transplant candidates. In association with standard-of-care, it does not seem to significatively improve kidney allograft access (short-term efficacy) vs. standard-of-care only. However, it could improve long-term prognosis of HLA incompatible transplantation by orienting the response towards a tolerogenic profile, by hindering B-cell maturation and, thereby, avoiding DSA rebounds after transplantation. This hypothesis needs to be proven by further studies.

Tocilizumab and Desensitization in Kidney Transplant Candidates: Personal Experience and Literature Review.

Desensitization (DES) allows kidney transplantation for highly HLA-sensitized subjects. Due to the central role of IL-6 in the immunological response, tocilizumab may improve DES efficacy. Thus, we conducted a PubMed systematic review using the MeSH terms tocilizumab, interleukin-6, kidney transplantation, and desensitization. Tocilizumab (TCZ) was first studied for DES as the second-line treatment after failure of a standard DES protocol (SP) (apheresis, rituximab +/- IVIg). Although TCZ (as a monotherapy) attenuated anti-HLA antibody rates, it did not permit transplantation. However, lymphocyte immuno-phenotyping has shown that TCZ hinders B-cell maturation and thus could improve the long-term efficacy of DES by limiting anti-HLA rebound and so avoid antibody-mediated rejection. This hypothesis is supported by a recent study where clazakizumab, a monoclonal antibody directed against IL-6, was continued after kidney transplantation in association with an SP. Nine out of ten patients were then eligible for transplantation, and there were no donor-specific antibodies at 6 months post-transplantation. In association with an SP, tocilizumab does not seem to significantly improve kidney-allograft access (short-term efficacy) vs. a SP only. However, it could improve the long-term prognosis of HLA-incompatible transplantation by hindering B-cell maturation and, thereby, avoiding donor-specific antibody rebounds post-transplantation.