title: Murine T lymphocytes incapable of producing macrophage inhibitory protein-1 are impaired in causing graft-versus-host disease across a class I but not class II major histocompatibility complex barrier.
abstract: The routine use of bone marrow transplantation is limited by the occurrence of acute and chronic graft-versus-host disease (GVHD). Current approaches to decreasing the occurrence of GVHD after allogeneic transplantation use T-cell depletion, use immunosuppressive agents, or block costimulatory molecule function. The role of proteins in the recruitment of alloreactive lymphocytes has not been well characterized. Chemokines are a large family of proteins that mediate recruitment of mononuclear cells in vitro and in vivo. To investigate the role of T-cell production of the chemokine macrophage inhibitory protein-1 (MIP-1) in the occurrence of GVHD, splenocytes either from wild-type or from MIP-1-/- mice were administered to class I (B6.C-H2(bm1)) and class II disparate mice (B6-C-H2(bm12)). The incidence and severity of GVHD was markedly reduced in bm1 mice receiving splenocytes from MIP-1-/- mice as compared with mice receiving wild-type splenocytes. Bm1 mice receiving MIP-1-/- splenocytes had significantly less weight loss and markedly reduced inflammatory responses in the lung and liver than mice receiving C57BL/6 splenocytes. Bm1 mice receiving MIP-1-/- splenocytes had a markedly decreased production of antichromatin autoantibodies and impaired generation of bm1-specific T lymphocytes versus wild-type mice. However, MIP-1-/- splenocytes easily induced GVHD when administered to bm12 mice. This data show that blockade of chemokine production or function may provide a new approach to the prevention or treatment of GVHD but that chemokines that recruit both CD4(+) and CD8(+) lymphocytes may need to be targeted.
authors.affiliation: Lineberger Comprehensive Cancer Center, and the Departments of Medicine, Microbiology, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. serody@med.unc.edu
authors.forename: J S
authors.initials: JS
authors.lastname: Serody
authors.forename: D N
authors.initials: DN
authors.lastname: Cook
authors.forename: S L
authors.initials: SL
authors.lastname: Kirby
authors.forename: E
authors.initials: E
authors.lastname: Reap
authors.forename: T C
authors.initials: TC
authors.lastname: Shea
authors.forename: J A
authors.initials: JA
authors.lastname: Frelinger
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology; D054407:Chemokine CCL4; D005260:Female; D006086:Graft vs Host Disease / Q000453:epidemiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D015994:Incidence; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology; D015431:Weight Loss / Q000276:immunology
chemical_list: D001323:Autoantibodies; D054407:Chemokine CCL4; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D019402:Macrophage Inflammatory Proteins