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

Graca, Luis; Daley, Stephen; Fairchild, Paul J.; Cobbold, Stephen P.; Waldmann, Herman

Description

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.authorGraca, Luis
dc.contributor.authorDaley, Stephen
dc.contributor.authorFairchild, Paul J.
dc.contributor.authorCobbold, Stephen P.
dc.contributor.authorWaldmann, Herman
dc.date.accessioned2016-01-06T00:30:26Z
dc.date.available2016-01-06T00:30:26Z
dc.identifier.issn14712172
dc.identifier.urihttp://hdl.handle.net/1885/95286
dc.description.abstractBACKGROUND 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.sponsorshipWork supported by grants from the Medical Research Council, U.K.
dc.publisherBioMed 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.sourceBMC Immunology
dc.subjectanimals
dc.subjectanimals, congenic
dc.subjectantibodies, monoclonal
dc.subjectantigens, cd4
dc.subjectantigens, cd8
dc.subjectbone marrow transplantation
dc.subjectcd40 ligand
dc.subjectcrosses, genetic
dc.subjectdrug synergism
dc.subjectfemale
dc.subjectgraft survival
dc.subjecth-2 antigens
dc.subjecthistocompatibility
dc.subjectimmunosuppression
dc.subjectlymphocyte activation
dc.subjectlymphocyte depletion
dc.subjectmale
dc.subjectmice
dc.subjectmice, inbred balb c
dc.subjectmice, inbred c57bl
dc.subjectmice, inbred cba
dc.subjectradiation chimera
dc.subjectskin transplantation
dc.subjectspecific pathogen-free organisms
dc.subjectt-lymphocyte subsets
dc.subjecttransplantation, homologous
dc.subjectimmune tolerance
dc.subjecttransplantation conditioning
dc.titleCo-receptor and co-stimulation blockade for mixed chimerism and tolerance without myelosuppressive conditioning
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume7
dc.date.issued2006-04-25
local.identifier.absfor110708
local.identifier.ariespublicationu4133361xPUB138
local.publisher.urlhttp://www.biomedcentral.com/
local.type.statusPublished Version
local.contributor.affiliationGraca, Luis, University of Oxford, United Kingdom
local.contributor.affiliationDaley, Stephen, College of Medicine, Biology and Environment, CMBE John Curtin School of Medical Research, Immunology and Infectious Disease, The Australian National University
local.contributor.affiliationFairchild, Paul J, University of Oxford, United Kingdom
local.contributor.affiliationCobbold, Stephen P, Oxford University, United Kingdom
local.contributor.affiliationWaldmann, Hermann, University of Oxford, United Kingdom
local.identifier.essn1471-2172
local.bibliographicCitation.issue1
local.bibliographicCitation.startpage9
local.bibliographicCitation.lastpage8
local.identifier.doi10.1186/1471-2172-7-9
dc.date.updated2016-02-24T10:36:38Z
local.identifier.scopusID2-s2.0-33646671989
CollectionsANU Research Publications

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