Tolerance Induction With Hematopoietic Stem Cell for Kidney Transplantation

Abstract

Tolerance induction is considered to be a final goal in the field of organ transplantation. We have performed simultaneous bone marrow and kidney transplantation in MHC mismatched patients to induce transient mixed chimerism and donor-specific tolerance. From December 2011 to May 2014, seven MHC mismatched patients received simultaneous bone marrow and kidney transplantation. Median follow-up was 34 months after transplant. The preconditioning regimen consisted of cyclophosphamide, fludarabine, rituximab (375 mg/m2, −7 and −2 days before transplantation), antithymocyte globulin (1.5 mg/mg/day,-2 ~ 0 days) and thymic irradiation. Maintenance immunosuppressions were tacrolimus and steroids. Immunosuppression tapering was usually initiated when the patient sustained stable graft function for at least 12 months post-transplant. Immunosuppression was slowly tapered over 6 ~ 12 months. Four out of the seven patients were successfully tapered off immunosuppression. One patient is currently undergoing immunosuppression tapering. Two patients failed at immunosuppression withdrawal; Because of acute rejection and severe BK virus nephritis. 5 patients experienced BK viremia during their post-transplant period. We analyzed T cell reconstitution after bone marrow and kidney transplantation, showed a major expansion of CD8+ effector memory (CD45RA-CCR7-), end-stage effector (CD45RA + CCR7-) T cells, and late-differentiated CD27-CD28- cells. We screened BMTKT patients for the expression of an inhibitory receptor such as PD-1, 2B4, CD160, BTLA, TIGIT, Tim-3 and LAG-3. They were increased an expression of 2B4 and PD-1. And, we analyzed the functionally distinct subpopulations in regulatory T cells. Patients with experienced acute cellular rejection were more elevated CD45RA-Foxp3low non-suppressive Treg cells (Fr-III) than CD45RA-Foxp3high effector Treg cells (Fr-II). We have performed seven cases of simultaneous bone marrow and kidney transplantation in MHC mismatched patients. Four out of the seven patients achieved immunosuppression withdrawal and revealed increased CD45RA-Foxp3high effector Treg cells (Fr-II).