*Purpose: In highly HLA sensitized patients, both memory B and T cells responding to donor-specific HLA in addition to plasma cells secreting anti-HLA Abs are targets for desensitization intended to persistently eliminate anti-HLA Abs. After treatment with rituximab, a depletion/reduction of naive and memory CD20+ B cells in the blood has been observed even at long-term follow-up. Although plasma cells are resistant to rituximab, short-lived plasma cells likely exhaust their lifespans shortly after rituximab treatment. In cases where short-lived plasma cells exclusively produce DSA, desensitization should be complete after rituximab treatment and sequential plasmapheresis. We have recently demonstrated that B cell depletion with rituximab exacerbates anti-donor CD4+ T-Cell responses in highly HLA sensitized patients by using MLR assay using CFSE-technique, possibly because rituximab-treatment undesirably depletes specific B cell subsets that can regulate T cell responses to allo-antigens. Hence, inhibiting T cells by antithymocyte globulin is needed during the desensitization. In cases where long-lived plasma cells are also responsible for DSA production, an additional immunomodulatory therapy with bortezomib is required to complete desensitization. To avoid either persistent immune dysfunction or hypogammaglobulinemia, identifying immune recovery via periodic monitoring is prudent before starting therapy with bortezomib. We found that IgM+ CD19+ mature B cells recovered more rapidly, returning to baseline by 6 months, whereas IgM+ CD27+ memory B cells remained low at 2 years after rituximab treatment. Hence, the period after rituximab treatment characterized by the presence of mature B cells but the absence of memory B cells may represent an appropriate therapeutic window for the subsequent bortezomib treatment.

*Methods: The step-wise desensitization treatment has been applied to 16 highly sensitized living donor kidney transplant (LDLT) candidates who had DSA resulting in positive lymphocytotoxicity crossmatches with their donors.

*Results: In 8 patients among them, DSA values were significantly decreased, and cross-match tests were consistently negative. All 8 patients underwent LDLT. They showed immediate and persistent renal function, and both DSA and non-DSA were persistently undetectable during the observation period. Neither AMR, ACR nor sever infectious complication was encountered in those patients. There was the minimal impact of the desensitization on Abs specific for varicella zoster virus and cytomegalovirus despite its remarkable depleting effects on both DSA and non-DSA. The remaining other 8 patients are currently taking additional bortezomib cycles.

*Conclusions: The present cases demonstrate that a step-wise use of rituximab, antithymocyte globulin and bortezomib can safely desensitize highly HLA-sensitized kidney transplant candidates.

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