Abstract
Recent evidence strongly suggest that alloimmunity induced autoimmune process plays an important role in the development of chronic rejection following human lung transplantation. We have previously shown that intrabronchial administration of MHC Class I antibodies (Abs) to mice causes obliterative airway disease (OAD, which is considered as a model for chronic rejection following human lung transplantation. Our goal is to study the impact of FoxP3+ regulatory T-cells (Tregs) in this established murine model of OAD. FoxP3DTR transgenic Bl/6 mice (kindly provided by Dr. Rudensky), following diphtheria toxin (DT) administration the Treg frequency at 48hrs decreased by 98%. Intrabronchial administration of H2Kb Abs into DT treated mice demonstrated a 3 fold increase in airway lesions and fibrous deposition over non-Treg depleted animals. Antibody concentrations to self antigens increased from 154 ± 32 to 265 ± 48 µg/mL for Collagen-V and 243 ± 43 to 394 ± 48 µg/mL for K- α1Tubulin. ELISpot analysis for Th-precursor frequency showed enhanced levels of IFN-γ (2.3 fold), IL-17 (3.3 fold) and decreased levels of IL-10 (4.1 fold) in Treg depleted cohort. RT-PCR analysis on lung tissue demonstrated upregulation of chemokines and pro-fibrotic growth factors in Treg depleted cohort. We conclude that depletion of T reg increases the severity of OAD as well as development of autoimmune responses to self-antigens leading to pathogenesis of chronic rejection.