title: CTLA4Ig-induced linked regulation of allogeneic T cell responses.
abstract: The mechanisms by which CTLA4Ig exerts its powerful immunomodulatory effects are not clear. We show here that CTLA4Ig can induce linked regulation of allogeneic porcine T cell responses in vitro. Naive miniature swine SLA(dd) T cells were rendered hyporesponsive to specific allogeneic Ag after coculturing with MHC-mismatched SLA(cc) stimulators in the presence of CTLA4Ig. These Ag-specific hyporesponsive T cells were subsequently able to actively inhibit the allogeneic responses of naive syngeneic T cells in an MHC-linked fashion, as the responses of naive SLA(dd) responders against specific SLA(cc) and (SLA(ac))F(1) stimulators were inhibited, but allogeneic responses against a 1:1 mixture of SLA(aa) (I(a), II(a)) and SLA(cc) (I(c), II(c)) were maintained. This inhibition could be generated against either class I or class II Ags, was radiosensitive, and required cell-cell contact. Furthermore, the mechanism of inhibition was not dependent upon a deletional, apoptotic pathway, but it was reversed by anti-IL-10 mAb. These data suggest that CTLA4Ig-induced inhibition of naive allogeneic T cell responses can be mediated through the generation of regulatory T cells via an IL-10-dependent mechanism.
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Lee
authors.forename: J R
authors.initials: JR
authors.lastname: Rusche
authors.forename: M E
authors.initials: ME
authors.lastname: Maloney
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
authors.forename: M H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: J C
authors.initials: JC
authors.lastname: Madsen
mesh_terms: D000069594:Abatacept; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology; D060908:CTLA-4 Antigen; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000528:radiation effects; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007114:Immunization; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D007399:Interphase / Q000276:immunology; D007519:Isoantigens / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects; D008213:Lymphocyte Activation / Q000276:immunology / Q000528:radiation effects; D007959:Lymphocyte Culture Test, Mixed; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D008969:Molecular Sequence Data; D013552:Swine; D013556:Swine, Miniature; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018984:Epitopes, T-Lymphocyte; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007519:Isoantigens; D016753:Interleukin-10; D000069594:Abatacept; D007371:Interferon-gamma