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BACKGROUND: A major challenge in the application of marrow transplantation as a route to immunological tolerance of a transplanted organ is to achieve hematopoietic stem cell (HSC) engraftment with minimal myelosuppressive treatments. RESULTS: We here describe a combined antibody protocol which can achieve long-term engraftment with clinically relevant doses of MHC-mismatched bone marrow, without the need for myelosuppressive drugs. Although not universally applicable in all strains, we achieved reliable engraftment in permissive strains with a two-stage strategy: involving first, treatment with anti-CD8 and anti-CD4 in advance of transplantation; and second, treatment with antibodies targeting CD4, CD8 and CD40L (CD154) at the time of marrow transplantation. Long-term mixed chimerism through co-receptor and co-stimulation blockade facilitated tolerance to donor-type skin grafts, without any evidence of donor-antigen driven regulatory T cells. CONCLUSION: We conclude that antibodies targeting co-receptor and co-stimulatory molecules synergise to enable mixed hematopoietic chimerism and central tolerance, showing that neither cytoreductive conditioning nor 'megadoses' of donor bone marrow are required for donor HSC to engraft in permissive strains.

Original publication

DOI

10.1186/1471-2172-7-9

Type

Journal article

Journal

BMC Immunol

Publication Date

25/04/2006

Volume

7

Keywords

Animals, Animals, Congenic, Antibodies, Monoclonal, Antigens, CD4, Antigens, CD8, Bone Marrow Transplantation, CD40 Ligand, Crosses, Genetic, Drug Synergism, Female, Graft Survival, H-2 Antigens, Histocompatibility, Immune Tolerance, Immunosuppression, Lymphocyte Activation, Lymphocyte Depletion, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred CBA, Radiation Chimera, Skin Transplantation, Specific Pathogen-Free Organisms, T-Lymphocyte Subsets, Transplantation Conditioning, Transplantation, Homologous