Different routes of donor-derived hematopoietic stem cell transplantation for donor-specific chimerism induction across MHC barrier

Abstract

Transplantation of donor-derived stem cells can improve organ allograft survival in animal models. This study was designed to investigate the effect of different routes of bone marrow cell (BMC) transplantation on donor-specific tolerance induction across MHC barrier under short-term CsA monotherapy and αβTCR/CsA treatment protocols. Forty-eight BMC transplantations were performed between BN(RT1 n) donors and LEW(RT1 1) recipients. Intraosseous and intravenous BMC transplantation was studied in six groups of eight animals each receiving 35 × 10 6 ( n = 4) and 70 × 10 6 ( n = 4) bone marrow cells. Groups I and II (controls) received BMC transplantation but no treatment, groups III and IV CsA monotherapy, and groups V, VI αβTCR/CsA protocol for 7 days. Flow cytometry monitored immunodepletion and donor-specific chimerism for MHC class I RT1 n/CD4, RT1 n/CD8 and RT1 n/CD45RA antigens. All animals survived without graft-versus-host disease. At day 63 under CsA monotherapy a low level of chimerism for RT1 n/CD4 was induced after intraosseous (1.9%) and intravenous (0.8%) transplantation of (70 × 10 6) BMC. Under αβTCR/CsA protocol chimerism for RT1 n/CD4 revealed 6.5% and 0.9% in intraosseous and intravenous (70 × 10 6) BMC transplantation, respectively. The total number of chimerism in intraosseous and intravenous (70 × 10 6) BMC transplantation groups was 9.9% and 3.4%, respectively. Following intraosseous BMC transplantation under αβTCR/CsA protocol chimerism was 50% higher in a group receiving 70 × 10 6 (9.9%) vs 35 × 10 6 (4.9%) BMC. Intraosseous transplantation of donor BMC under αβTCR/CsA protocol was 75% more efficient in induction of donor-specific chimerism compared to intravenous transplantation.