An Inhibitor of CD28–CD80 Interactions Impairs CD28-Mediated Costimulation of Human CD4 T Cells

We have identified and characterized a microbial extract-derived inhibitor of T cell CD28-dependent costimulation, NP1835-2, utilizing anin vitrosystem in which anti-human CD3 antibody and a human CD80-Ig fusion protein are immobilized on protein A-coated microspheres. This system is CD28-CD80-depen...

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Veröffentlicht in:Cellular immunology 1999-01, Vol.191 (1), p.49-59
Hauptverfasser: Fine, Jay S., Macosko, Heather D., Justice, Luminita, Chou, Chuan-Chu, Jenh, Chung-Her, Narula, Satwant K., Zavodny, Paul J.
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container_end_page 59
container_issue 1
container_start_page 49
container_title Cellular immunology
container_volume 191
creator Fine, Jay S.
Macosko, Heather D.
Justice, Luminita
Chou, Chuan-Chu
Jenh, Chung-Her
Narula, Satwant K.
Zavodny, Paul J.
description We have identified and characterized a microbial extract-derived inhibitor of T cell CD28-dependent costimulation, NP1835-2, utilizing anin vitrosystem in which anti-human CD3 antibody and a human CD80-Ig fusion protein are immobilized on protein A-coated microspheres. This system is CD28-CD80-dependent, as judged by the specific ability of anti-CD80 antibody or cytotoxic T lymphocyte antigen-4-Ig to block human CD4 T cell responses. Activation of CD4 T cells in this system in presence of NP1835-2 resulted in a concentration-dependent inhibition of T cell proliferation (IC50of 1–4 μg/ml), surface activation marker expression, and the production of many T cell cytokines, with the exception of TGFβ. Impairment of T cell activation correlated with a blockade of cell cycle progression at G0/G1and was only partly restored by addition of 100 U/ml IL-2. No inhibition by NP1835-2 of T cell proliferation stimulated by plate-bound anti-CD3 antibody, phorbol 12-myristate 13-acetate + A23187, or P815 cells expressing the costimulatory molecule CD58 was observed. NP1835-2 was unable to modulate anti-IgM-stimulated B cell proliferation or LPS-induced monocyte activation. Suboptimal concentrations of NP1835-2 and cyclosporin together were able to impair T cell activation in an additive fashion. NP1835-2 was also able to inhibit the primary human MLR. These data indicate that NP1835-2 may belong to a class of molecules capable of selectively impairing CD28-mediated T cell costimulation and suggest its potential usefulness in the treatment of a variety of T cell-dependent diseases. Moreover, NP1835-2 may serve as a useful probe for investigating the mechanisms involved in T cell nonresponsiveness.
doi_str_mv 10.1006/cimm.1998.1403
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This system is CD28-CD80-dependent, as judged by the specific ability of anti-CD80 antibody or cytotoxic T lymphocyte antigen-4-Ig to block human CD4 T cell responses. Activation of CD4 T cells in this system in presence of NP1835-2 resulted in a concentration-dependent inhibition of T cell proliferation (IC50of 1–4 μg/ml), surface activation marker expression, and the production of many T cell cytokines, with the exception of TGFβ. Impairment of T cell activation correlated with a blockade of cell cycle progression at G0/G1and was only partly restored by addition of 100 U/ml IL-2. No inhibition by NP1835-2 of T cell proliferation stimulated by plate-bound anti-CD3 antibody, phorbol 12-myristate 13-acetate + A23187, or P815 cells expressing the costimulatory molecule CD58 was observed. NP1835-2 was unable to modulate anti-IgM-stimulated B cell proliferation or LPS-induced monocyte activation. 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ispartof Cellular immunology, 1999-01, Vol.191 (1), p.49-59
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subjects Abatacept
Antigens, CD
Antigens, Differentiation - pharmacology
B7-1 Antigen - physiology
CD28 Antigens - physiology
CD4-Positive T-Lymphocytes - drug effects
CD4-Positive T-Lymphocytes - immunology
Cell Cycle - drug effects
CTLA-4 Antigen
Cyclosporine - pharmacology
Cytokines - biosynthesis
Humans
Immunoconjugates
Immunosuppressive Agents - pharmacology
Lymphocyte Activation - drug effects
Receptors, Interleukin-2 - biosynthesis
title An Inhibitor of CD28–CD80 Interactions Impairs CD28-Mediated Costimulation of Human CD4 T Cells
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