Abstract
Blockade of the CD40 and CD28 costimulatory pathways significantly prolongs allograft survival; however, certain strains of mice (i.e., C57BL/6) are relatively resistant to the effects of combined CD40/CD28 blockade. We have previously shown that the costimulation blockade-resistant phenotype can be attributed to a subset of CD8+ T cells and is independent of CD4+ T cell-mediated help. Here we explore the role of the IL-2 pathway in this process using mAbs against the high affinity IL-2R, CD25, and IL-2 in prolonging skin allograft survival in mice receiving combined CD40/CD28 blockade. We have also investigated the effects of treatment on effector function by assessment of cytotoxicity and the generation of IFN-gamma-producing cells in response to allogeneic stimulators as well as proliferation in an in vivo graft-vs-host disease model. We find that additional blockade of either CD25 or IL-2 significantly extends allograft survival beyond that in mice receiving costimulation blockade alone. This correlates with diminished frequencies of IFN-gamma-producing allospecific T cells and reduced CTL activity. Anti-CD25 therapy also synergizes with CD40/CD28 blockade in suppressing proliferative responses. Interestingly, depletion of CD4+ T cells, but not CD8+ cells, prevents prolongation in allograft survival, suggesting an IL-2-independent role for regulation in extended survival.
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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Animals
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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal / pharmacology
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Antigens, CD
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Antigens, Differentiation / administration & dosage
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CD4-Positive T-Lymphocytes / immunology
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CD40 Ligand / immunology
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CD8-Positive T-Lymphocytes / immunology
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CTLA-4 Antigen
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Cytotoxicity Tests, Immunologic
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Down-Regulation / immunology
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Drug Synergism
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Graft Rejection / immunology*
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Graft Rejection / prevention & control*
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Graft Survival / immunology
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Graft vs Host Disease / immunology
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Immune Sera / administration & dosage
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Immunoconjugates*
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Immunosuppressive Agents / pharmacology
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Injections, Intraperitoneal
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / biosynthesis
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / immunology
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Interleukin-2 / physiology*
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Lymphocyte Activation / immunology*
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Lymphocyte Culture Test, Mixed
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Receptors, Interleukin-2 / immunology
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Signal Transduction / immunology*
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Skin Transplantation / immunology
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Transplantation, Homologous / immunology*
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, mouse
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Immune Sera
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Immunoconjugates
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Immunosuppressive Agents
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Interleukin-2
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Receptors, Interleukin-2
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CD40 Ligand
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Abatacept
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Interferon-gamma