DONOR-SPECIFIC CYTOKINE PRODUCTION BY GRAFT-INFILTRATING LYMPHOCYTES INDUCES AND MAINTAINS GRAFT VASCULAR-DISEASE IN HUMAN CARDIAC ALLOGRAFTS

Background. The development of graft vascular disease (GVD) in the all ograft is a major impediment for long-term survival of heart transplan t recipients. GVD may be mediated by cellular processes, in response t o the transplanted heart, and regulated by cytokines. Methods. We stud ied donor-specific cytokine production patterns in graft-infiltrating lymphocyte cultures propagated from endomyocardial biopsies. The biops ies were derived from patients with and without signs of GVD, as diagn osed by angiography at 1 year after heart transplantation. Results. In the first year after transplantation, significantly more T-helper (Th ) 1 cytokines (interleukin [IL]-2: P=0.04; interferon-gamma: P=0.01), but not Th2 (IL-4 and IL-6) cytokines, were produced by cultures of pa tients with GVD compared with patients without GVD. Thereafter, the Th 1 cytokine levels in patients with GVD normalized to the levels of pat ients without GVD. Detectable levels of IL-6 were produced significant ly more often (P=0.009) by cultures obtained more than 1 year after tr ansplantation from patients with GVD. Conclusions. The results suggest that high levels of Th1 cytokines produced by graft-infiltrating lymp hocytes early after transplantation may be responsible for activation of vascular endothelium, leading to the migration and proliferation of smooth muscle cells that is characteristic of GVD. IL-6, produced lat er after transplantation, continues this process by promoting smooth m uscle cell proliferation.