Targeting LFA-1 synergizes with CD40/CD40L blockade for suppression of both CD4-dependent and CD8-dependent rejection

Yue Wang, Donghong Gao, Keri E. Lunsford, Wendy L. Frankel, Ginny L. Bumgardner

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Allogeneic hepatocytes elicit CD4-dependent and (CD4-independent) CD8 + T-cell-initiated graft rejection. The (CD4-independent) CD8 + T-cell pathway is resistant to immunosuppressive strategies that readily and indefinitely suppress CD4+ T-cell-dependent rejection responses. Consequently, successful immunoregulation of hepatocyte-initiated immune responses requires a strategy which regulates both CD4-dependent and CD8-dependent rejection responses. Interference with CD40/CD40 ligand (CD40L) costimulation only transiently suppresses CD4- and CD8-dependent hepatocyte rejection. Interference with CD28/B7 costimulation transiently suppresses CD4-dependent hepatocyte rejection, but is ineffective for suppression of CD8-dependent hepatocyte rejection. To date, hepatocyte survival > 60 days post-transplant has not been achieved by any immunotherapeutic strategy. In the current study, we evaluated a novel immunosuppressive strategy which targets both LFA-1 and CD40L-mediated signals. Targeting LFA-1 suppressed (CD4-independent) CD8+ T-cell-initiated hepatocyte rejection such that allogeneic hepatocyte survival > 60 days was achieved in 70% of CD4 KO mice. Targeting both LFA-1-mediated signals and CD40/CD40L costimulation resulted in synergistic effects, such that hepatocellular survival > 60 days was achieved in 100% of C57BL/6 mice (which have both CD4- and CD8-dependent T-cell pathways available).

Original languageEnglish (US)
Pages (from-to)1251-1258
Number of pages8
JournalAmerican Journal of Transplantation
Volume3
Issue number10
DOIs
StatePublished - Oct 2003

Keywords

  • Costimulation
  • Rodent
  • T lymphocytes
  • Transgenic/knockout
  • Transplantation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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