DONOR-SPECIFIC CYTOKINE PRODUCTION BY GRAFT-INFILTRATING LYMPHOCYTES INDUCES AND MAINTAINS GRAFT VASCULAR DISEASE IN HUMAN CARDIAC ALLOGRAFTS1

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Abstract
The development of graft vascular disease (GVD) in the allograft is a major impediment for long-term survival of heart transplant recipients. GVD may be mediated by cellular processes, in response to the transplanted heart, and regulated by cytokines. We studied donor-specific cytokine production patterns in graft-infiltrating lymphocyte cultures propagated from endomyocardial biopsies. The biopsies were derived from patients with and without signs of GVD, as diagnosed by angiography at 1 year after heart transplantation. In the first year after transplantation, significantly more T-helper (Th) 1 cytokines (interleukin [IL]-2: P =0.04; interferon-γ: P =0.01), but not Th2 (IL-4 and IL-6) cytokines, were produced by cultures of patients with GVD compared with patients without GVD. Thereafter, the Th1 cytokine levels in patients with GVD normalized to the levels of patients without GVD. Detectable levels of IL-6 were produced significantly more often ( P =0.009) by cultures obtained more than 1 year after transplantation from patients with GVD. The results suggest that high levels of Th1 cytokines produced by graft-infiltrating lymphocytes 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 later after transplantation, continues this process by promoting smooth muscle cell proliferation.