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Blockade of chronic graft-versus-host disease by alloantigen-induced CD4+CD25+Foxp3+ regulatory T cells in nonlymphopenic hosts.
J Leukoc Biol. 2007 Nov; 82(5):1053-61.JL

Abstract

CD4(+)CD25(+) regulatory T cells (Tregs) are well known to suppress immunopathology induced in lymphopenic animals following T cell reconstitution, including acute graft-versus-host disease (GVHD) post-bone marrow transplantation. The regulatory potential of this subset in nonlymphopenic hosts and in chronic, Th2-mediated GVHD is less clear. We have generated alloantigen-specific cells from CD4(+)CD25(+) populations stimulated with MHC-disparate dendritic cells and found them to express a stable Treg forkhead box p3(+) phenotype with enhanced suppressive activity mediated by cell contact. When transferred into nonlymphopenic F1 hosts, nonspecific Tregs proliferated as rapidly as CD4(+)CD25(-) cells but displayed distinct growth kinetics in vitro. Tregs, expanded in response to alloantigen in vitro, displayed greatly enhanced suppressive activity, which was partially antigen-specific. They were effective inhibitors of chronic GVHD, blocking donor cell engraftment, splenomegaly, autoantibody production, and glomerulonephritis. CD25(+) and CD25(-) cells were equally susceptible to inhibition by immunosuppressive drugs targeting TCR signaling and rapamycin, but Tregs were resistant to inhibition by dexamethasone. The data indicate that alloantigen-driven expansion, rather than homeostatic proliferation, is key to the effectiveness of CD4(+)CD25(+) Tregs in GVHD and suggest that cellular therapy with alloantigen-induced Tregs in combination with glucocorticoid treatment would be effective in prevention of chronic GVHD after immune reconstitution.

Authors+Show Affiliations

Allergy, and Respiratory Science, King's College London, 5th Floor Thomas Guy House, Guy's Hospital Campus, London, UK.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17684039

Citation

Giorgini, A, and A Noble. "Blockade of Chronic Graft-versus-host Disease By Alloantigen-induced CD4+CD25+Foxp3+ Regulatory T Cells in Nonlymphopenic Hosts." Journal of Leukocyte Biology, vol. 82, no. 5, 2007, pp. 1053-61.
Giorgini A, Noble A. Blockade of chronic graft-versus-host disease by alloantigen-induced CD4+CD25+Foxp3+ regulatory T cells in nonlymphopenic hosts. J Leukoc Biol. 2007;82(5):1053-61.
Giorgini, A., & Noble, A. (2007). Blockade of chronic graft-versus-host disease by alloantigen-induced CD4+CD25+Foxp3+ regulatory T cells in nonlymphopenic hosts. Journal of Leukocyte Biology, 82(5), 1053-61.
Giorgini A, Noble A. Blockade of Chronic Graft-versus-host Disease By Alloantigen-induced CD4+CD25+Foxp3+ Regulatory T Cells in Nonlymphopenic Hosts. J Leukoc Biol. 2007;82(5):1053-61. PubMed PMID: 17684039.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blockade of chronic graft-versus-host disease by alloantigen-induced CD4+CD25+Foxp3+ regulatory T cells in nonlymphopenic hosts. AU - Giorgini,A, AU - Noble,A, Y1 - 2007/08/07/ PY - 2007/8/9/pubmed PY - 2007/12/7/medline PY - 2007/8/9/entrez SP - 1053 EP - 61 JF - Journal of leukocyte biology JO - J. Leukoc. Biol. VL - 82 IS - 5 N2 - CD4(+)CD25(+) regulatory T cells (Tregs) are well known to suppress immunopathology induced in lymphopenic animals following T cell reconstitution, including acute graft-versus-host disease (GVHD) post-bone marrow transplantation. The regulatory potential of this subset in nonlymphopenic hosts and in chronic, Th2-mediated GVHD is less clear. We have generated alloantigen-specific cells from CD4(+)CD25(+) populations stimulated with MHC-disparate dendritic cells and found them to express a stable Treg forkhead box p3(+) phenotype with enhanced suppressive activity mediated by cell contact. When transferred into nonlymphopenic F1 hosts, nonspecific Tregs proliferated as rapidly as CD4(+)CD25(-) cells but displayed distinct growth kinetics in vitro. Tregs, expanded in response to alloantigen in vitro, displayed greatly enhanced suppressive activity, which was partially antigen-specific. They were effective inhibitors of chronic GVHD, blocking donor cell engraftment, splenomegaly, autoantibody production, and glomerulonephritis. CD25(+) and CD25(-) cells were equally susceptible to inhibition by immunosuppressive drugs targeting TCR signaling and rapamycin, but Tregs were resistant to inhibition by dexamethasone. The data indicate that alloantigen-driven expansion, rather than homeostatic proliferation, is key to the effectiveness of CD4(+)CD25(+) Tregs in GVHD and suggest that cellular therapy with alloantigen-induced Tregs in combination with glucocorticoid treatment would be effective in prevention of chronic GVHD after immune reconstitution. SN - 0741-5400 UR - https://www.unboundmedicine.com/medline/citation/17684039/Blockade_of_chronic_graft_versus_host_disease_by_alloantigen_induced_CD4+CD25+Foxp3+_regulatory_T_cells_in_nonlymphopenic_hosts_ L2 - https://doi.org/10.1189/jlb.0407227 DB - PRIME DP - Unbound Medicine ER -