Abstract
Purpose: :
Corneal allograft rejection is T cell-mediated, including Th1-dependent and Th2-dependent pathways. Stat6 is a transcription factor involved in the signaling pathway of IL-4 production by Th2 cells and Stat6-/- mice are unable to respond to IL-4 in in vitro and in vivo assays. These mice show a striking defect in the generation of Th2 cells. We hypothesized that tilting towards the Th1 pathway in Stat6-/- mice would favor corneal allograft rejection.
Methods: :
Corneal allotransplants were performed on BALB/c (Th2-biased), C57BL/6 (Th1-biased) and Stat6-/- (BALB/c background) mice as well as age-matched syngeneic transplants as controls. Corneal grafts were evaluated twice a week and a clinical score for opacification was given using slit lamp biomicroscopy. At post operative day (POD) 14, lymphocytes from corneal grafts, spleens and lymph nodes were harvested. ELISPOT was performed to detect T cell priming by IL-2, IL-4 and INF-γ production.
Results: :
In Th1-biased C57BL/6 mice, the corneal allografts started rejection at POD15 and were 100% rejected by POD28. In contrast, in Th2-biased BALB/c mice allografts started to reject by POD30 and 75% were rejected by POD60 . In Stat6-/- mice the tempo of graft rejection was slower than C57BL/6 (P<0.01) but faster than BALB/c (P<0.01). The grafts started to reject by POD20 and were 100% rejected by POD40. Lymphocytes were harvested from Stat6-/- mice with corneal transplants at POD14. ELISPOT data showed Th1 priming (IL2 and INFγ) but no Th2 priming (IL4) which confirmed that corneal allografts rejection in stat6-/- Balb/c mice was Th1 cells mediated.
Conclusions: :
The tempo of graft rejection in Th1-biased C57BL/6 mice is faster than in Th2-biased BALB/c mice. Stat6 deficiency in BALB/c mice favors switching from Th2 to Th1, which promotes graft rejection. Therefore, our data suggest that Th2 cells are involved in corneal allograft survival. The use of Th2-enhancing agents could provide new clinical options to prevent graft rejection in humans.
Keywords: transplantation • cornea: basic science • immunomodulation/immunoregulation