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Master Thesis

Améliorer l’accès à la transplantation rénale des sujets hyperimmunisés : quelle place pour le Tocilizumab dans les protocoles de désimmunisation ?

Abstract : Kidney transplantation is recognized as the best replacement therapy for end-stage renal disease. However, its access, already limited by the shortage of grafts, will be even more restricted for so-called "immunized" kidney transplant candidates (KTC), i.e. those who have developed anti-HLA antibodies after a past immunological event (transplantation, pregnancy, transfusion). Desensitization (DES) aims to remove these anti-HLA antibodies and block their production in order to increase the number of compatible grafts. The standard-of-care (SOC) of DES (apheresis, rituximab, +/- intravenous immunoglobulin) is based on a few small, non-randomized studies. The results of DES, mainly supported in the field of living donor transplantation, are encouraging but the search for new therapies remains an important issue. Tocilizumab (TCZ) (anti-IL-6R monoclonal antibody) is a candidate of choice because of the central role of IL-6 in the immune response (differentiation of plasmacells ; orientation of T helper lymphocytes towards a Th17 rather than a regulatory T profile, etc). To date, only one clinical study tested the efficacy of TCZ as a treatment for DES. It was used as a 2nd line treatment in subjects who were resistant to SOC. Therefore, we conducted a prospective, non-randomized, exploratory study to evaluate the efficacy and safety of a TCZ-only DES protocol to improve kidney transplantation access for hyperimmunized subjects. Fourteen patients were included between 2016 and 2020 and treated with tocilizumab alone (8mg/kg monthly, for at least 6 months). The primary endpoint was the evolution of MFI (mean fluorescent intensity) of the immunodominant anti-HLA antibody between the beginning and the end of the TCZ treatment. We observed a decrease in the MFI of the immunodominant antibody in class I (7780 vs 10548; p = 0.00085) and in class II (6267 vs 7191; p = 0.019). In addition, there was a significant decrease in the mean MFI of all anti-HLA antibodies (with an initial MFI > 2000) in class I (7102 vs 7999; p = 0.012), as well as in the number of anti-HLA antibodies with MFI ≥ 10,000 in class I (14 vs 18; p = 0.0059) and class II (13 vs 19; p = 0.021). Finally, the safety profile was favorable with only one serious adverse event (spondylodiscitis). However, if statistically significant, the effect of TCZ alone was not clinically relevant because more than half of the patients retained at least one anti-HLA antibody with an MFI ≥ 10,000, and more than 80% of them had the MFI of their immunodominant antibody remain above 3,000. Thus, only one patient (7%) could be transplanted without further DES therapy. In contrast, eleven patients (79%) subsequently received a standard DES protocol, and eight of these were able to be transplanted. Our study therefore suggests that TCZ alone is not sufficient to improve access to transplantation for hyperimmunized KTC. Its place could be in association with the standard DES protocol, in order to improve its short-term efficacy (reduction of immunization and obtaining a compatible graft) but also - and above all - its long-term efficacy (reduction of the rebound of anti-HLA antibodies, of the risk of humoral rejection). This last hypothesis is supported by the study of lymphocyte phenotypes under TCZ which shows a blockage of the maturation of the B lineage. It would be relevant to test this last hypothesis with further studies.
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Master Thesis
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https://dumas.ccsd.cnrs.fr/dumas-03468544
Contributor : Jean-Hugues Morneau Connect in order to contact the contributor
Submitted on : Tuesday, December 7, 2021 - 11:04:19 AM
Last modification on : Saturday, January 1, 2022 - 3:10:33 AM

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  • HAL Id : dumas-03468544, version 1

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Jules Weinhard. Améliorer l’accès à la transplantation rénale des sujets hyperimmunisés : quelle place pour le Tocilizumab dans les protocoles de désimmunisation ?. Médecine humaine et pathologie. 1994. ⟨dumas-03468544⟩

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