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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Abatacept
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Amino Acid Sequence
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Animals
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Antibodies, Monoclonal / pharmacology
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Antigens, CD
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Antigens, Differentiation / pharmacology*
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Apoptosis / immunology
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CTLA-4 Antigen
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Cell Communication / immunology
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Cells, Cultured
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Coculture Techniques
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Epitopes, T-Lymphocyte / immunology
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Epitopes, T-Lymphocyte / radiation effects
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Flow Cytometry
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Humans
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Immune Tolerance / immunology
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Immunization
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Immunoconjugates*
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Immunosuppressive Agents / pharmacology*
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Interferon-gamma / metabolism
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Interleukin-10 / immunology
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Interleukin-10 / metabolism
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Interleukin-2 / pharmacology
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Interphase / immunology
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Isoantigens / immunology*
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Isoantigens / metabolism
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Isoantigens / radiation effects
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Lymphocyte Activation / immunology
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Lymphocyte Activation / radiation effects
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Lymphocyte Culture Test, Mixed
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Major Histocompatibility Complex / genetics
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Major Histocompatibility Complex / immunology
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Major Histocompatibility Complex / radiation effects
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Molecular Sequence Data
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Swine
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Swine, Miniature
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / radiation effects
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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T-Lymphocytes, Regulatory / radiation effects
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, Differentiation
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CTLA-4 Antigen
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CTLA4 protein, human
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Epitopes, T-Lymphocyte
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Immunoconjugates
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Immunosuppressive Agents
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Interleukin-2
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Isoantigens
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Interleukin-10
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Abatacept
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Interferon-gamma