CD154 blockade abrogates allospecific responses and enhances CD4 + regulatory T-cells in mouse orthotopic lung transplant

J. M. Dodd-O, E. A. Lendermon, H. L. Miller, Q. Zhong, E. R. John, W. M. Jungraithmayr, F. R. D'Alessio, J. F. McDyer

Research output: Contribution to journalArticle

Abstract

Acute cellular rejection (ACR) is a common and important clinical complication following lung transplantation. While there is a clinical need for the development of novel therapies to prevent ACR, the regulation of allospecific effector T-cells in this process remains incompletely understood. Using the MHC-mismatched mouse orthotopic lung transplant model, we investigated the short-term role of anti-CD154 mAb therapy alone on allograft pathology and alloimmune T-cell effector responses. Untreated C57BL/6 recipients of BALB/c left lung allografts had high-grade rejection and diminished CD4 +: CD8 + graft ratios, marked by predominantly CD8 +> CD4 + IFN-γ + allospecific effector responses at day 10, compared to isograft controls. Anti-CD154 mAb therapy strikingly abrogated both CD8 + and CD4 + alloeffector responses and significantly increased lung allograft CD4 +: CD8 + ratios. Examination of graft CD4 + T-cells revealed significantly increased frequencies of CD4 +CD25 +Foxp3 + regulatory T-cells in the lung allografts of anti-CD154-treated mice and was associated with significant attenuation of ACR compared to untreated controls. Together, these data show that CD154/CD40 costimulation blockade alone is sufficient to abrogate allospecific effector T-cell responses and significantly shifts the lung allograft toward an environment predominated by CD4 + T regulatory cells in association with an attenuation of ACR. The authors find that CD154/CD40 costimulation blockade alone in a mouse model of orthotopic lung transplant results in abrogation of allospecific T-cell responses and increased regulatory T cells.

Original languageEnglish (US)
Pages (from-to)1815-1824
Number of pages10
JournalAmerican Journal of Transplantation
Volume11
Issue number9
DOIs
StatePublished - Sep 1 2011

Keywords

  • Allograft rejection
  • CD154
  • effector T-cell
  • mouse orthotopic lung transplantation
  • regulatory T-cell

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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