Tolerance Induction in HLA Disparate Living Donor Kidney Transplantation by Donor Stem Cell Infusion

Abstract

Background We recently reported that durable chimerism can be safely established in mismatched kidney recipients through nonmyeloablative conditioning followed by infusion of a facilitating cell (FC)-based hematopoietic stem cell transplant termed FCRx. Here we provide intermediate-term follow-up on this phase 2 trial. Methods Fifteen HLA mismatched living donor renal transplant recipients underwent low intensity conditioning (fludarabine, cyclophosphamide, 200cGyTBI), received a living donor kidney transplant on day 0, then infusion of cryopreserved FCRx on day +1. Maintenance immunosuppression(IS),consisting of tacrolimus and mycophenolate, was weaned over one year. Results All but one patient demonstrated peripheral blood macrochimerism post-transplantation. Engraftment failure occurred in a highly sensitized (PRA of52%) recipient. Chimerism was lost in 3patients at 2, 3, and 6 months post transplantation. Two of these subjects had received either a reduced cell dose or incomplete conditioning; the other 2 had PRA >20%. All demonstrated donor-specific hyporesponsiveness and were weaned from full dose immunosuppression. Complete immunosuppression withdrawal at one year post-transplant was successful in all patients with durable chimerism. There has been no GVHD or engraftment syndrome. Renal transplant loss occurred in 1 patient who developed sepsis following an atypical viral infection. Two subjects with only transient chimerism demonstrated subclinical rejection on protocol biopsy despite donor-specific hyporesponsiveness. Conclusions Low intensity conditioning plus FCRx safely achieved durable chimerism in mismatched allograft recipients. Sensitization represents an obstacle to successful induction of chimerism. Sustained T cell chimerism is a more robust biomarker of tolerance than donor-specific hyporeactivity.

Clonal Deletion Established via Invariant NKT Cell Activation and Costimulatory Blockade Requires In Vivo Expansion of Regulatory T Cells

“…These data collectively suggest that donorderived hematopoietic cells are necessary to maintain clonal anergy. Indeed, seminal works for clinical application of hematopoietic chimerism in humans have shown that the presence of macrochimerism was the most reliable predictor for establishment of tolerance (38,39).…”

Requirement for Interactions of Natural Killer T Cells and Myeloid-Derived Suppressor Cells for Transplantation Tolerance

“…Although many tolerance induction protocols have been successfully developed in laboratory animals, only a few, using hematopoietic cell transplantation to induce chimerism and tolerance have been applied to clinical trials (1–6). The conditioning regimen of total lymphoid irradiation (TLI) used with the T cell depletive reagent, anti-thymocyte globulin/serum (ATG/ATS), has been shown to induce tolerance in mice and humans after the development of persistent mixed chimerism (3, 4, 7–10).…”

Chimerism and Tolerance Induction in Kidney Transplantation

“…The conditioning regimen at NMH consisted of pre-transplant fludarabine, pre- and post-transplant cyclophosphamide, and 200 cGy total body irradiation. Eight of 15 HLA mismatched patients who underwent this protocol developed high-level (>90%) durable donor chimerism beginning 1 month after transplantation [23]. One patient developed atypical viral infection and bone marrow failure at 3 months post-transplant, which was rectified by infusion of autologous stem cells.…”

“…Durable mixed chimerism was noted in two patients. Three patients in the protocol had only transient donor chimerism lasting several months (2 had reduced doses of FCRx and 1 was highly sensitized with high PRA at the time of transplantation) but in vitro proliferative assay by MLR and CML also demonstrated DSH despite the loss of chimerism [23]. One of them was subsequently withdrawn from MMF and later Tacrolimus based on the in vitro testing, but later developed subclinical Banff 1A rejection in the 12-month protocol biopsy, which was treated successfully with intravenous corticosteroids and by increasing tacrolimus dosage to therapeutic range.…”