Abstract
Purpose: :
Three categories of CD4+ T lymphocytes have been implicated in allograft rejection: Th1, Th2, and Th17 cells. This study examined the role of Th17 cells in corneal allograft rejection.
Methods: :
C57BL/6 corneas were grafted to BALB/c mice that were treated with anti-IL-17, anti-interferon-γ (IFN-γ) or isotype control antibodies. CD4+ splenocytes collected from mice following corneal allograft rejection were stimulated with C57BL/6 alloantigens and cytokine production was quantified by ELISA. Signal transducer and activator of transcription 6 (STAT6) is essential for the induction of Th2 cells. Corneal allografts were transplanted to STAT6 knockout (KO) BALB/c mice to assess the role of Th2 cells in corneal graft rejection.
Results: :
Untreated mice had a 50% incidence of rejection and produced a typical Th1 cytokine profile. By contrast, mice treated with anti-IFN-γ did not generate Th1 immune responses, yet rejected 90% of their allografts, indicating that Th1 cells are not required for rejection. The cytokine profile of these mice was characterized by a preponderance of Th2 cytokines but no IL-17 or IFN-γ. Mice treated with anti-IL-17 rejected 90% of their corneal allografts and produced a Th2 cytokine profile and no detectable IFN-γ. Mice were treated with anti-IFN-γ and anti-IL-17 to block both Th1 and Th17 immune responses. Instead of blocking rejection, combined antibody treatment resulted in a 90% incidence of graft rejection and a Th2 cytokine profile, suggesting that Th2 cells mediated rejection. STAT6 KO mice treated with anti-IL-17 antibody, displayed a 50% incidence of rejection, and a Th1 cytokine profile. Cytokine profiles for all of the experiments revealed a steep elevation of IL-17 in mice with surviving allografts and undetectable IL-17 in rejector mice.
Conclusions: :
In this study rejection occurred in hosts with disabled Th1, Th2, or Th17 cell populations, suggesting that rejection might be mediated by Th1, Th2, or Th17 cells. However, we found no evidence that Th17 cells were capable of mediating corneal allograft rejection, and instead, the weight of evidence suggests that IL-17 promotes immune privilege and favors corneal allograft survival.
Keywords: transplantation • immune tolerance/privilege • immunomodulation/immunoregulation