This application aims at studying alloantigen dependent graft vasculopathy by focusing on the involvement of Th1 and Th2 cytokines in a murine cardiac allograft model. The applicant has established a reproducible wild type and knockout recipient models of murine cardiac allograft arteriosclerosis using a 28 day course of anti CD4/CD8 mAb or a two day course of CTLA4 Ig immunosuppression. Vascular arteriosclerosis is evaluated at a fixed time point [55 days] after transplantation. The applicant proposes to use targeted gene deletions in inbred mice [Th1: STAT4-/-, IFNg-/-, IL2-/-; Th2: IL4-/-, IL10-/-] and computer-linked image analysis microscopy to evaluate graft arteriosclerosis in the established model. It is proposed that since Ag- activated CD4 T cells are important in the development of graft vasculopathy, selected Th1 and Th2 cytokines therefore have causal rather than incidental roles in the genesis of graft arteriosclerosis. Using knockout mice, the preliminary data which have been published and summarized show that while IFNg mediated Th1 responses promote vascular thickening through VSMC uncontrolled proliferation, IL-10 mediated Th2 responses suppress CD45+ inflammatory cellular infiltration. These interesting observations that Th1 cytokines play an important role in transplant arteriosclerosis are significant and persuasive.
| Russell, M E (2000) Cardiac allograft vasculopathy--a changing perspective. Z Kardiol 89 Suppl 9:IX/6-10 |
| Koglin, J; Glysing-Jensen, T; Gadiraju, S et al. (2000) Attenuated cardiac allograft vasculopathy in mice with targeted deletion of the transcription factor STAT4. Circulation 101:1034-9 |
