Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia

Abstract

Lifelong immunosuppression is required for allograft survival after kidney transplantation but may not ultimately prevent allograft loss resulting from chronic rejection. We developed an approach that attempts to abrogate immune rejection and the need for post-transplantation immunosuppression in three patients with Schimke immuno-osseous dysplasia who had both T-cell immunodeficiency and renal failure. Each patient received sequential transplants of αβ T-cell-depleted and CD19 B-cell-depleted haploidentical hematopoietic stem cells and a kidney from the same donor. Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation. (Funded by the Kruzn for a Kure Foundation.).

Figure 1.. Sequential αβ T-Cell–Depleted and CD19 B-Cell–Depleted Haploidentical HSCT and Kidney Transplantation in Three Patients with SIOD.

Three patients with Schimke immuno-osseous dysplasia (SIOD) received a reduced-intensity conditioning regimen consisting of antithymocyte globulin, fludarabine (the dose of which was adjusted because of the patients’ renal insufficiency), cyclophosphamide, totalbody irradiation, and rituximab. The graft used for hematopoietic stem-cell transplantation (HSCT), which was obtained from one of the parents, was depleted of αβ T cells and CD19 B cells, and no immunosuppression was administered after the graft infusion. Each patient received a kidney transplant 5 to 10 months later from the parent who served as the donor for HSCT. A short course of immunosuppression was stopped by 30 days after kidney transplantation. All three patients have had normal kidney function without any immunosuppression for a period of follow-up ranging from 22 to 34 months. AUC denotes area under the curve.

Figure 2.. One-Way Mixed-Lymphocyte Cellular Assay of T-Cell Alloreactivity at 1 Year after Kidney Transplantation.

Peripheral blood mononuclear cells (PBMCs), which were used as responder cells, were isolated from the three patients at least 1 year after their kidney transplantation (KT). The PBMCs were stained with CellTrace Violet (Invitrogen) before coculture with stimulator Epstein–Barr virus (EBV)–transduced B lymphoblastoid cell lines (EBV-LCLs) previously generated from the parents of the patients or from an unrelated healthy third-party control. CellTrace Violet fluorescence intensity (on a logarithmic scale) for CD3+CD19− cells (x axis) is shown plotted against T-cell count (y axis); a loss of fluorescence indicates cell proliferation. T-cell proliferation was measured after 6 days of culture and obtained at a responder-to-stimulator ratio of 2:1. T cells of both of the two siblings (Patients 1 and 2) and of Patient 3 showed functional tolerance to EBV-LCLs derived from their respective donors, whereas they were immune competent and proliferated in the presence of EBV-LCLs derived from nondonor parents or a healthy, unrelated control. The plots in the first column show the absence of T-cell proliferation when PBMCs were cultured in medium alone. The results shown are representative of three replicates for each combination of stimulator and responder cells.