Cutting edge: Targeted ligation of CTLA-4 in vivo by membrane-bound anti-CTLA-4 antibody prevents rejection of allogeneic cells

Kwang Woo Hwang, William B. Sweatt, Ian Elliott Brown, Christian Blank, Thomas F. Gajewski, Jeffrey A. Bluestone, Maria Luisa Alegre

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

Natural engagement of CTLA-4 on host B7 limits T cell activation. We hypothesized that therapeutic cross-linking of CTLA-4 in vivo may further inhibit T cell function and prevent allograft rejection. However, none of the currently available CTLA-4-binding reagents have ligating properties when injected in vivo. The observation that surface-immobilized anti-CTLA-4 mAb inhibits T cell activation in vitro prompted us to develop a membrane-bound single-chain anti-CTLA-4 Ab (7M). To model whether tissue expression of 7M could suppress allograft rejection, we examined the ability of H-2Ld-specific TCR-transgenic T cells to reject 7M-expressing allogeneic tumor cells injected s.c. Expression of 7M significantly inhibited allogeneic rejection in mice that received CTLA-4+/+ but not CTLA-4-/- T cells. Furthermore, CTLA-4+/+ T cells that had encountered 7M-expressing tumors in vivo acquired defects in cytokine production and cytotoxicity. Thus, deliberate ligation of CTLA-4 in vivo potently inhibits allogeneic T cell responses.

Original languageEnglish (US)
Pages (from-to)633-637
Number of pages5
JournalJournal of Immunology
Volume169
Issue number2
StatePublished - Jul 15 2002
Externally publishedYes

ASJC Scopus subject areas

  • Immunology

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