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

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.