Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients

Abstract

Background We recently demonstrated that donor-derived modified immune cells (MICs)—PBMCs that acquire immunosuppressive properties after a brief treatment— induced specific immunosuppression against the allogeneic donor when administered prior to kidney transplantation. We found an up to 68-fold increase in CD19+CD24hiCD38hi transitional B lymphocytes compared with transplanted controls. Methods Ten patients from a phase I clinical trial who had received MIC infusions before kidney transplantation were followed to posttransplant day 1080. Results Patients treated with MICs had a favorable clinical course, showing no donor-specific HLA antibodies or acute rejections. The four patients who had received the highest dose of MICs 7 days before surgery and were on reduced immunosuppressive therapy showed an absence of in vitro lymphocyte reactivity against stimulatory donor blood cells, whereas reactivity against third-party cells was preserved. In these patients, numbers of transitional B lymphocytes were 75-fold and 7-fold higher than in 12 long-term survivors on minimal immunosuppression and four operationally tolerant patients, respectively (P<0.001 for both). In addition, we found significantly higher numbers of other regulatory B lymphocyte subsets, and a gene expression signature suggestive of operational tolerance in three of four patients. In MIC-treated patients, in vitro lymphocyte reactivity against donor blood cells was restored after B lymphocyte depletion, suggesting a direct pathophysiological role of regulatory B lymphocytes in donor-specific unresponsiveness. Conclusions These results indicate that donor-specific immunosuppression after MIC infusion is long-lasting and associated with a striking increase in regulatory B lymphocytes. Donor-derived MICs appear to be an immunoregulatory cell population which, when administered to recipients prior to transplantation, may exert a beneficial effect on kidney transplants.

Individualised immunosuppression with intravenously administered donor-derived modified immune cells compared with standard of care in living donor kidney transplantation (TOL-2 Study): protocol for a multicentre, open-label, phase II, randomised controlled trial

“…The majority of Breg produced the immunosuppressive cytokine interleukin (IL) 10 3. Clinical and immunological findings in the 10 patients were stable with now more than 5 years of follow-up4 (unpublished results). In summary, MIC therapy was well tolerated in the phase I clinical trial and did not lead to humoral sensitisation or rejections.…”

“…We have recently shown that administration of modified immune cells (MIC) prior to kidney transplantation led to specific immunosuppression against the allogeneic donor, which may allow reduction of conventional immunosuppressive therapy 3 4. MIC are donor-derived peripheral blood mononuclear cells (PBMC) that are treated ex vivo by an alkylating agent.…”

Immune Modulatory Cell Therapy in Kidney Transplantation: Hints of a Durable Mechanism of Action

“…In the current issue of JASN , Morath et al 5 take a step toward addressing this challenge in their report of 3-year clinical and immunologic outcomes for a group of ten living donor kidney transplant recipients who participated in a previously described phase 1 clinical trial of donor-derived modified immune cells (MICs). 2 The cell therapy for the trial consisted of donor-derived PBMCs (monocytes and lymphocytes) that were collected by leukapheresis, treated briefly with the cytotoxic agent mitomycin C, washed, resuspended in buffer, and administered directly to the transplant recipient as a single intravenous infusion either 2 or 7 days prior to transplantation.…”

“…Tregs have also been proposed as a primary active mediator of immune regulation induced by tolerogenic cell therapies, including donor-derived apoptotic cells 12 and mesenchymal stromal cells. 3 Morath et al 5 analyzed the longitudinal Treg profiles of their trial participants, finding that, despite an early expansion of Tregs during the first post-transplant year, the longer-term proportions of the circulating level of Treg were rather low. It is possible, therefore, that an early interplay between Tregs and Bregs participates in the initial induction of donor-specific hyporesponsiveness following MIC administration.…”

“…Thus, the association could reflect a confounding effect of immunosuppression. 10 To address this issue within the context of their clinical trial, Morath et al 5 compared TrB cells among different groups of subjects and confirmed significantly higher proportions of circulating TrB cells in the four MIC-treated patients compared with groups of healthy subjects, patients on dialysis, short-term transplant recipients on full immunosuppression, long-term transplant survivors receiving either full-dose or minimal immunosuppression, transplant recipients with chronic rejection, and spontaneous operationally tolerant recipients. 5 Furthermore, in addition to an increase in IL-10-producing TrB cells in these four patients, they also observed significant increases in other peripheral Breg subsets.…”