title: CD154 blockade abrogates allospecific responses and enhances CD4(+) regulatory T-cells in mouse orthotopic lung transplant.
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.
authors.affiliation: Department of Anesthesiology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Dodd-o
authors.forename: E A
authors.initials: EA
authors.lastname: Lendermon
authors.forename: H L
authors.initials: HL
authors.lastname: Miller
authors.forename: Q
authors.initials: Q
authors.lastname: Zhong
authors.forename: E R
authors.initials: ER
authors.lastname: John
authors.forename: W M
authors.initials: WM
authors.lastname: Jungraithmayr
authors.forename: F R
authors.initials: FR
authors.lastname: D'Alessio
authors.forename: J F
authors.initials: JF
authors.lastname: McDyer
mesh_terms: D000818:Animals; D016516:CD4-CD8 Ratio; D023201:CD40 Ligand / Q000276:immunology*; D003470:Culture Media; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000276:immunology; D016040:Lung Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D003470:Culture Media; D023201:CD40 Ligand; D007371:Interferon-gamma