Co-receptor and co-stimulation blockade for mixed chimerism and tolerance without myelosuppressive conditioning
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Graca, Luis; Daley, Stephen; Fairchild, Paul J.; Cobbold, Stephen P.; Waldmann, Herman
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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...[Show more]
dc.contributor.author | Graca, Luis | |
---|---|---|
dc.contributor.author | Daley, Stephen | |
dc.contributor.author | Fairchild, Paul J. | |
dc.contributor.author | Cobbold, Stephen P. | |
dc.contributor.author | Waldmann, Herman | |
dc.date.accessioned | 2016-01-06T00:30:26Z | |
dc.date.available | 2016-01-06T00:30:26Z | |
dc.identifier.issn | 14712172 | |
dc.identifier.uri | http://hdl.handle.net/1885/95286 | |
dc.description.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. | |
dc.description.sponsorship | Work supported by grants from the Medical Research Council, U.K. | |
dc.publisher | BioMed Central | |
dc.rights | © Graca et al. 2006 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | |
dc.source | BMC Immunology | |
dc.subject | animals | |
dc.subject | animals, congenic | |
dc.subject | antibodies, monoclonal | |
dc.subject | antigens, cd4 | |
dc.subject | antigens, cd8 | |
dc.subject | bone marrow transplantation | |
dc.subject | cd40 ligand | |
dc.subject | crosses, genetic | |
dc.subject | drug synergism | |
dc.subject | female | |
dc.subject | graft survival | |
dc.subject | h-2 antigens | |
dc.subject | histocompatibility | |
dc.subject | immunosuppression | |
dc.subject | lymphocyte activation | |
dc.subject | lymphocyte depletion | |
dc.subject | male | |
dc.subject | mice | |
dc.subject | mice, inbred balb c | |
dc.subject | mice, inbred c57bl | |
dc.subject | mice, inbred cba | |
dc.subject | radiation chimera | |
dc.subject | skin transplantation | |
dc.subject | specific pathogen-free organisms | |
dc.subject | t-lymphocyte subsets | |
dc.subject | transplantation, homologous | |
dc.subject | immune tolerance | |
dc.subject | transplantation conditioning | |
dc.title | Co-receptor and co-stimulation blockade for mixed chimerism and tolerance without myelosuppressive conditioning | |
dc.type | Journal article | |
local.description.notes | Imported from ARIES | |
local.identifier.citationvolume | 7 | |
dc.date.issued | 2006-04-25 | |
local.identifier.absfor | 110708 | |
local.identifier.ariespublication | u4133361xPUB138 | |
local.publisher.url | http://www.biomedcentral.com/ | |
local.type.status | Published Version | |
local.contributor.affiliation | Graca, Luis, University of Oxford, United Kingdom | |
local.contributor.affiliation | Daley, Stephen, College of Medicine, Biology and Environment, CMBE John Curtin School of Medical Research, Immunology and Infectious Disease, The Australian National University | |
local.contributor.affiliation | Fairchild, Paul J, University of Oxford, United Kingdom | |
local.contributor.affiliation | Cobbold, Stephen P, Oxford University, United Kingdom | |
local.contributor.affiliation | Waldmann, Hermann, University of Oxford, United Kingdom | |
local.identifier.essn | 1471-2172 | |
local.bibliographicCitation.issue | 1 | |
local.bibliographicCitation.startpage | 9 | |
local.bibliographicCitation.lastpage | 8 | |
local.identifier.doi | 10.1186/1471-2172-7-9 | |
dc.date.updated | 2016-02-24T10:36:38Z | |
local.identifier.scopusID | 2-s2.0-33646671989 | |
Collections | ANU Research Publications |
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01_Graca_Co-receptor_and_co-stimulation_2006.pdf | Published Version | 300.5 kB | Adobe PDF |
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