Disruption of IL-4 responses in STAT6-knock out mice does not alter graft vasculopathy

389 Background. Development of graft vasculopathy is proposed to be regulated by the balance of Th1- and Th2-forces. Interleukin-4 (IL-4) is a major inducer of Th2-differentiation. These and other IL-4 responses have been shown to be mediated by the transcription factor STAT6. Hence, STAT6-deficient lymphocytes fail to differentiation into Th2 cells in response to IL-4. Methods. To determine whether STAT6-mediated IL-4 responses regulate the development of graft vasculopathy, we compared heterotopic vascularized transplants (CBA) placed into STAT6-knock out mice (STAT6-/, C57BL6×129, n=11) with those placed into wildtype controls (WT, C57BL6×129, n=7). Grafts were harvested at day 55 from recipients treated with anti-CD4/8 for 30 days. Frequency and severity of graft vasculopathy was assessed by computer-assisted analysis in all elastin stained vessels of both groups (n=177). To assess allograft-specific cytokine-activation patterns, we compared corrected transcript levels by 32P-RT-PCR. Results. Histologic evaluation showed comparable rejection in all grafts from both groups (ISHLT scores: STAT6-/- 1.6±0.2, WT 1.4±0.2). Grafts from both STAT6-/- and WT recipients developed graft vasculopathy with a comparable frequency (STAT6-/- 62±8% of all vessels, WT 70±12%) and severity (STAT6-/- 28±6% luminal occlusion, WT 25±6%). Grafts from STAT6-/- had significantly lower mean transcript levels for IL-4 (0.13±0.04 relative units) compared to WT (0.44±0.14 relative units, p=0.03). However, mean transcript levels for other Th2 cytokines (interleukin-5 (p=0.7) and -10 (p=0.5)) were comparable in both groups. Conclusion. Disruption of IL-4 responses by targeted deletion of the specific transcription factor STAT6 does not alter the frequency and severity of graft vasculopathy. Furthermore, the degree of parenchymal rejection was comparable in grafts from STAT6-deficient and wild type recipients. While essential for the development of Th2 responses in other disease models, STAT6-deficiency does not alter all Th2 forces in the transplanted heart. This extends our previous studies using recipients mice with targeted deletion of IL-4 suggesting that graft vasculopathy in the chronically rejecting is an interleukin-4-independent process.