Induction of Alloantigen-Specific T Cell Tolerance Through the Treatment of Human T Lymphocytes with Wortmannin

Dennis D. Taub, William J Murphy, Osamu Asai, Robert G. Fenton, Gary Peltz, Michael L. Key, Susan Turcovski-Corrales, Dan L. Longo

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Signaling through the CD28 molecule on T cells by its natural ligand, B7, on APCs has recently been shown to require the presence of an active phosphatidylinositol 3-kinase pathway to mediate some of its costimulatory activities (1-7). Using the phosphatidylinositol 3-kinase inhibitor, wortmannin (WN) (8), on human and murine T cells, we have inhibited B7-1-mediated T cell activation and induced Ag-specific tolerance. The addition of WN and/or the B7-1 antagonist, CTLA4Ig, to primary human T cell cultures stimulated with B7-1-transfected allogeneic melanoma cell lines inhibited the generation of alloantigen-specific proliferative and cytolytic responses in vitro. Subsequent examination of these WN- and CTLA4Ig-treated primary T cell cultures revealed that these lymphocyte populations were tolerized to rechallenge with the priming alloantigens in secondary cultures in the absence of additional inhibitor(s). However, reactivity to a third party allogeneic stimulator remained intact. This WN-induced tolerance was reversed by the addition of high dose IL-2, but not IL-4 or IL-7, to the primary cultures, indicating that T cell anergy, not deletion, was responsible for this phenomenon. In vivo studies using a murine graft-vs-host disease (GVHD) model demonstrated that WN treatment of allogeneic donor lymphocytes in vitro failed to generate a significant GVHD in irradiated mouse recipients compared with control allogeneic donor lymphocytes. These findings suggest potentially novel therapeutic strategies for the prevention of GVHD.

Original languageEnglish (US)
Pages (from-to)2745-2755
Number of pages11
JournalJournal of Immunology
Volume158
Issue number6
StatePublished - Mar 15 1997
Externally publishedYes

ASJC Scopus subject areas

  • Immunology

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    Taub, D. D., Murphy, W. J., Asai, O., Fenton, R. G., Peltz, G., Key, M. L., Turcovski-Corrales, S., & Longo, D. L. (1997). Induction of Alloantigen-Specific T Cell Tolerance Through the Treatment of Human T Lymphocytes with Wortmannin. Journal of Immunology, 158(6), 2745-2755.