Rejection of Tracheal Allograft by Intrapulmonary Lymphoid Neogenesis in the Absence of Secondary Lymphoid Organs

Background. Obliterative bronchiolitis after lung transplantation is associated with intrapulmonary lymphoid neogenesis. The purpose of this study was to examine the role of lymphoid neogenesis, especially its relationship with secondary lymphoid organs (SLOs) in allograft airway rejection. Methods. A murine intrapulmonary tracheal transplant model and a conventional subcutaneous tracheal transplant model were tested using wild-type control mice and splenectomized lymphotoxin alpha knockout (LT-/-) mice deficient in SLOs as recipients. Results. In both subcutaneous and intrapulmonary tracheal transplant models using wild-type animals, tracheal isografts remained open without rejection, whereas allografts showed progressive luminal obliteration after transplantation. Lymphoid neogenesis containing alloreactive T cells was observed in the lungs, which received an intrapulmonary tracheal allograft. Despite a lack of SLOs, intrapulmonary allografts in splenectomized LT-/- mice were rejected and obliterated by day 28, but the rejection of subcutaneous allografts was significantly delayed. Extensive lymphoid neogenesis was observed in the lungs of both intrapulmonary and subcutaneous allograft LT-/- recipients. Increased proliferation of CD4(+) T cells and B220(+) B cells was observed in the lungs but not in the thymus or bone marrow. Conclusions. Intrapulmonary lymphoid neogenesis is capable of mounting alloimmune responses without SLOs. Tracheal allograft rejection occurs as efficiently as in wild-type animals when it is placed in the lungs. Tracheal allograft rejection in the subcutaneous tissue occurs in a delayed manner without SLO in association with intrapulmonary lymphoid neogenesis.