Immunosuppression and Induction of Anergy by CTLA4Igin Vitro: Effects on Cellular and Antibody Responses of Lymphocytes from Rats with Experimental Autoimmune Myasthenia Gravis

KEVIN R. MCINTOSH, PETER S. LINSLEY, Daniel B Drachman

Research output: Contribution to journalArticle

Abstract

The pathogenic antibody response to acetylcholine receptor (AChR) in experimental autoimmune myasthenia gravis (EAMG) is T cell dependent. Therefore, it should be possible to design specific immunotherapeutic approaches to treat EAMG (and human MG) by interfering with AChR-specific helper T cells. Productive T cell activation by antigen requires at least two signals: one signal delivered through the T cell receptor by antigen and a second costimulatory signal delivered through the CD28 receptorviathe B7 counterreceptor expressed on antigen-presenting cells. Here we show that interference with the B7 costimulatory signal, using a soluble CD28 analogue, CTLA4Ig, resulted in a profound decrease in IL2 production and significantly decreased lymphoproliferative responses and antibody responses by primed lymph node cells from rats with EAMG, when stimulated with AChRin vitro.Nonclonal AChR-specific T cell lines, when stimulated with AChR in the presence of CTLA4Ig, were also inhibited in their ability to proliferate and to produce the cytokines IL2 and IFN-γ. They remained deficient in their ability to produce IL2 when restimulated with AChR plus fresh antigen-presenting cells and showed variable inhibition of proliferation. The induction of hyporesponsiveness was accompanied by the expression of functional IL2 receptors, as shown by vigorous proliferative responses to addition of exogenous IL2. These results indicate that specific antigen stimulation in the presence of CTLA4Ig can induce certain features typical of anergy. CTLA4Ig provides a promising approach for the immunomodulation of MG and other antibody-mediated autoimmune diseases.

Original languageEnglish (US)
Pages (from-to)103-112
Number of pages10
JournalCellular Immunology
Volume166
Issue number1
DOIs
StatePublished - Nov 1995

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Autoimmune Experimental Myasthenia Gravis
Cholinergic Receptors
Immunosuppression
Antibody Formation
Interleukin-2
Lymphocytes
Antigen-Presenting Cells
CD27 Antigens
T-Lymphocytes
Immunomodulation
Interleukin-2 Receptors
Helper-Inducer T-Lymphocytes
T-Cell Antigen Receptor
Autoimmune Diseases
Lymph Nodes
Cytokines
Antigens
Cell Line
Antibodies

ASJC Scopus subject areas

  • Immunology
  • Cell Biology

Cite this

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title = "Immunosuppression and Induction of Anergy by CTLA4Igin Vitro: Effects on Cellular and Antibody Responses of Lymphocytes from Rats with Experimental Autoimmune Myasthenia Gravis",
abstract = "The pathogenic antibody response to acetylcholine receptor (AChR) in experimental autoimmune myasthenia gravis (EAMG) is T cell dependent. Therefore, it should be possible to design specific immunotherapeutic approaches to treat EAMG (and human MG) by interfering with AChR-specific helper T cells. Productive T cell activation by antigen requires at least two signals: one signal delivered through the T cell receptor by antigen and a second costimulatory signal delivered through the CD28 receptorviathe B7 counterreceptor expressed on antigen-presenting cells. Here we show that interference with the B7 costimulatory signal, using a soluble CD28 analogue, CTLA4Ig, resulted in a profound decrease in IL2 production and significantly decreased lymphoproliferative responses and antibody responses by primed lymph node cells from rats with EAMG, when stimulated with AChRin vitro.Nonclonal AChR-specific T cell lines, when stimulated with AChR in the presence of CTLA4Ig, were also inhibited in their ability to proliferate and to produce the cytokines IL2 and IFN-γ. They remained deficient in their ability to produce IL2 when restimulated with AChR plus fresh antigen-presenting cells and showed variable inhibition of proliferation. The induction of hyporesponsiveness was accompanied by the expression of functional IL2 receptors, as shown by vigorous proliferative responses to addition of exogenous IL2. These results indicate that specific antigen stimulation in the presence of CTLA4Ig can induce certain features typical of anergy. CTLA4Ig provides a promising approach for the immunomodulation of MG and other antibody-mediated autoimmune diseases.",
author = "MCINTOSH, {KEVIN R.} and LINSLEY, {PETER S.} and Drachman, {Daniel B}",
year = "1995",
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