Allogeneic CD4+CD25+ T Cells Regulate Rejection of Bronchus Transplants in Humanised Mice

Abstract

Introduction: Long term survival following lung transplantation is limited by bronchiolitis obliterans. In our porcine allogeneic lung transplantation model, we have previously shown that long term graft acceptance correlated with the frequency of circulating CD4+CD25+ regulatory T cells. It is not known whether this type of T cell regulation is the cause for, or an epiphenomenon of, long term allograft survival. Therefore, we investigated the role of T cell regulation in an adoptive transfer system using human bronchus and allogeneic PBMC transfer into immune deficient mice. Methods: human bronchi were transplanted under the skin of NODrag-/-gammac−/− mice. 5×106 porcine PBMC were injected per animal in 5 groups (n=4-15). Group A received no PBMC, for group B cells and vessels were collected from two different people, group C recipients received allogeneic PBMC depleted of CD4+CD25+ T cells; group D recipients received allogeneic PBMC enriched of CD4+CD25+ T cells. Alloinjury of the heterotopic bronchus grafts was assessed by histology of the graft on postoperative day 28. Results: In the control group A epithelial loss (p< 0,0001), cell infiltration and luminal obstruction (p< 0,0001) were absent and structural damage to the cartilage and the epithelium was low. In group B epithelial loss was pronounced and cell infiltration and histological changes were severe. In group C these changes were even more severe. In group D, cell infiltration was reduced and histological damage to the allografts was less severe, as was the epithelial loss. Conclusion: Thus, heterotopic transplantation of a human bronchus graft and reconstitution with allogeneic human PBMC in NODrag−/− gammac−/− mice represents a valuable tool for transplant research. In this model, we could show in vivo that rejection of bronchus transplants, that is histologically reminiscent of bronchiolitis obliterans, is controlled by CD4+CD25+ T cell regulation.