Intestinal irradiation and fibrosis in a Th1-deficient environment.

Abstract

Changes in the Th1/Th2 immune balance may play a role in increasing the incidence of radiation-induced toxicity. This study evaluates the consequences of Th1 deficiency on intestinal response (fibrosis and T cell trafficking) to abdominal irradiation and examines in mucosa and mesenteric lymph nodes (MLN) the differential involvement of the two Th1 pathways, T-bet/STAT1 and IL-12/STAT4, in controlling this balance in mice. Using T-bet-deficient mice (T-bet-/-), we evaluated the mRNA and protein expression of the Th1 pathways (IFN-γ, T-bet/STAT1, and IL-12/STAT4) and the CD4+ and CD8+ populations in ileal mucosa and MLN during the first 3 months after 10 Gy abdominal irradiation. The T-bet-deficient mice showed an increased fibrotic response to radiation, characterized by higher TGF-β1, col3a1 expression, and collagen deposition in mucosa compared with wild-type mice. This response was associated with drastically lower expression of IFN-γ, the hallmark Th1 cytokine. Analysis of the Th1 expression pathways, T-bet/STAT1 and IL-12/STAT4, showed their equal involvement in the failure of Th1 polarization. A minimal IFN-γ level depended on the IL-23-p19/STAT4 level. In addition, the radiation-induced deficiency in the priming of Th1 by IFN-γ was related to the defective homing capacity of CD8+ cells in the mucosa. Irradiation induces Th2 polarization, and the Th2 immune response may play a role in potentiating irradiation-induced intestinal collagen deposition.