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Open Access Research article

Co-receptor and co-stimulation blockade for mixed chimerism and tolerance without myelosuppressive conditioning

Luis Graca123*, Stephen Daley1, Paul J Fairchild1, Stephen P Cobbold1 and Herman Waldmann1*

Author Affiliations

1 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK

2 Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, P1649-028 Lisbon, Portugal

3 Instituto Gulbenkian de Ciência, P2780-156 Oeiras, Portugal

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BMC Immunology 2006, 7:9  doi:10.1186/1471-2172-7-9

Published: 25 April 2006

Abstract

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.