Previous studies have implicated the allogeneic immune response in the development of obliterative bronchiolitis after lung transplantation. However, the progression of specific pathogenic events leading to this form of chronic allograft dysfunction have not been well characterized. We used a murine tracheal transplantation model in which a single mismatched HLA-A2-transgenic molecule is indirectly recognized by the recipient CD4T cells to show that obliterative airway disease (OAD) that developed in these allografts was preceded by indirect recognition of the HLA-A2 molecule and subsequent development of anti-HLA-A2 antibodies.