IMMUNOSUPPRESSION - PRE-CLINICAL AGENTS

A. Knöfel¹, N. Madrahimov², K. Dreckmann³, M. Avsar³, W. Sommer², D. Jonigk⁴, A. Haverich⁵, M. Strueber², G. Warnecke^2
1Httg, MHH, Hannover/GERMANY, ², Hannover Medical School, Hannover/GERMANY, ³Department Of Cardiothoracic, Transplantation And Vascular Surgery, Hannover Medical School, Hannover/GERMANY, ⁴, Pathologie, Hannover/GERMANY, ⁵Heart Transplant Surgery, Medical School Hannover, Hannover/GERMANY

Body: 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 porcine bronchus and allogeneic PBMC transfer into immune deficient mice. Methods: Porcine bronchi were transplanted under the skin of NODrag-/-gammac-/- mice. 5x10⁶ porcine PBMC were injected per animal in 5 groups (n=4-19). Group A received no PBMC, for group B cells and vessels were collected from the same pig. For group C cells and vessels were collected from two MHC mismatched pigs, group D recipients received allogeneic PBMC depleted of CD4⁺CD25⁺ T cells; group E 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 (n=19) 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 (n=5) epithelial loss, cell infiltration and luminal obliteration were low (p=0,0002). In group C (n=13) epithelial loss was pronounced and cell infiltration and histological changes were severe. In group D (n=10) these changes were even more severe. In group E (n=4), cell infiltration was reduced and histological damage to the allografts was less severe, as was the epithelial loss. Conclusion: Thus, heterotopic non-vascularized transplantation of a porcine bronchus graft and reconstitution with allogeneic porcine 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.

Disclosure: All authors have declared no conflicts of interest.