Phase I trial of donor-derived modified immune cell infusion in kidney transplantation

摘要

abstract_textpBACKGROUND. Preclinical experiments have shown that donor blood cells, modified in vitro by an alkylating agent (modified immune cells MICs), induced long-term specific immunosuppression against the allogeneic donor./ppMETHODS. In this phase I trial, patients received either 1.5 x 10(6) MICs per kg BW on day -2 (n = 3, group A), or 1.5 x 10(8) MICs per kg BW on day -2 (n = 3, group B) or day -7 (n = 4, group C) before living donor kidney transplantation in addition to post-transplantation immunosuppression. The primary outcome measure was the frequency of adverse events (AEs) until day 30 (study phase) with follow-up out to day 360./ppRESULTS. MIC infusions were extremely well tolerated. During the study phase, 10 treated patients experienced a total of 69 AEs that were unlikely to be related or not related to MIC infusion. No donor-specific human leukocyte antigen Abs or rejection episodes were noted, even though the patients received up to 1.3 x 10(10) donor mononuclear cells before transplantation. Group C patients with low immunosuppression during follow-up showed no in vitro reactivity against stimulatory donor blood cells on day 360, whereas reactivity against third-party cells was still preserved. Frequencies of CD19(+)CD24(hi)CD38(hi) transitional B lymphocytes (Bregs) increased from a median of 6 before MIC infusion to 20 on day 180, which was 19- and 68-fold higher, respectively, than in 2 independent cohorts of transplanted controls. The majority of Bregs produced the immunosuppressive cytokine IL-10. MIC-treated patients showed the Immune Tolerance Network operational tolerance signature./ppCONCLUSION. MIC administration was safe and could be a future tool for the targeted induction of tolerogenic Bregs./p/abstract_text