B G Exner1, Y L Colson, H Li, S T Ildstad. 1. Institute for Cellular Therapeutics, Allegheny University of the Health Sciences, Philadelphia, Pa. 19102, USA.
Abstract
BACKGROUND: Solid organ transplantation has become the preferred approach for the treatment of end-stage organ failure. However, the toxicity associated with the nonspecific immunosuppression essential to graft survival is substantial. Bone marrow transplantation (BMT) can overcome these limitations by the induction of donor-specific tolerance. The morbidity and mortality associated with fully ablative conditioning used to achieve engraftment has prevented the clinical application of BMT for induction of tolerance for solid organ transplantation. Although it was previously believed that fully ablative conditioning was essential to achieve engraftment, it has recently become apparent that partial conditioning may be sufficient to achieve chimerism and tolerance. The focus of this study was to characterize which cells in the host microenvironment must be eliminated for engraftment of MHC-disparate bone marrow to be achieved. METHODS: C57BL/10SnJ mice were depleted of CD4+, CD8+, or both cell types with monoclonal antibodies before irradiation with 300 centigray (cGy) and transplantation of 15 x 10(6) allogeneic (B10.BR) bone marrow cells. Two days after transplantation the animals were treated with 200 mg/kg cyclophosphamide. Animals were typed for chimerism at 28 days and monthly thereafter. RESULTS: The combination of CD4+ and CD8+ depletion resulted in multilineage engraftment in 76.5% of the animals at a level of 57.1 +/- 17.7%. The depletion of CD4+ cells alone was not sufficient to allow engraftment, whereas depletion of CD8+ cells alone was. CONCLUSIONS: T cells in the recipient's marrow space play an important role in hindering allogeneic engraftment in the mouse. The T-cell subset responsible appears to be CD8+ cells rather than CD4+ cells.
BACKGROUND: Solid organ transplantation has become the preferred approach for the treatment of end-stage organ failure. However, the toxicity associated with the nonspecific immunosuppression essential to graft survival is substantial. Bone marrow transplantation (BMT) can overcome these limitations by the induction of donor-specific tolerance. The morbidity and mortality associated with fully ablative conditioning used to achieve engraftment has prevented the clinical application of BMT for induction of tolerance for solid organ transplantation. Although it was previously believed that fully ablative conditioning was essential to achieve engraftment, it has recently become apparent that partial conditioning may be sufficient to achieve chimerism and tolerance. The focus of this study was to characterize which cells in the host microenvironment must be eliminated for engraftment of MHC-disparate bone marrow to be achieved. METHODS: C57BL/10SnJ mice were depleted of CD4+, CD8+, or both cell types with monoclonal antibodies before irradiation with 300 centigray (cGy) and transplantation of 15 x 10(6) allogeneic (B10.BR) bone marrow cells. Two days after transplantation the animals were treated with 200 mg/kg cyclophosphamide. Animals were typed for chimerism at 28 days and monthly thereafter. RESULTS: The combination of CD4+ and CD8+ depletion resulted in multilineage engraftment in 76.5% of the animals at a level of 57.1 +/- 17.7%. The depletion of CD4+ cells alone was not sufficient to allow engraftment, whereas depletion of CD8+ cells alone was. CONCLUSIONS: T cells in the recipient's marrow space play an important role in hindering allogeneic engraftment in the mouse. The T-cell subset responsible appears to be CD8+ cells rather than CD4+ cells.
Authors: Hong Xu; Yiming Huang; Paula M Chilton; Lala-Rukh Hussain; Michael K Tanner; Jun Yan; Suzanne T Ildstad Journal: J Immunol Date: 2008-11-01 Impact factor: 5.422