MAST CELLS IN ACUTE AND CHRONIC REJECTION OF RAT CARDIAC ALLOGRAFTS???A MAJOR SOURCE OF BASIC FIBROBLAST GROWTH FACTOR1

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Abstract
Studies of cardiac allograft arteriosclerosis, i.e., chronic rejection, have largely focused on mononuclear inflammatory cell infiltrates in the vascular wall and periphery of the occluded vessels. The purpose of this study was to investigate the role of mast cells in the development of acute and chronic rejection in rat cardiac allografts. In the acute rejection model, transplant recipients were not treated with immunosuppressants, and the grafts were removed 5 days after transplantation at the time of severe acute rejection. In the chronic rejection model, the recipients were administered triple-drug immunosuppression, and the grafts were removed 90 days after transplantation. During acute rejection, the number of mast cells was not increased, but the localization pattern differed from that of syngeneic grafts. In acute rejection, mast cells were located in the perivascular region of the allografts, but in syngeneic grafts, mast cells had a more interstitial location. In the chronic rejection model, the cardiac allografts with severe intimal thickening showed large numbers of mast cells at perivascular sites of occluded intramyocardial vessels and in the interstitium. Linear regression analysis revealed a significant correlation between the numbers of perivascular and interstitial mast cells and the intensity of intimal thickening. The majority of mast cells showed positive immunoreactivity to basic fibroblast growth factor (bFGF). Macrophage bFGF expression was not so prominent, but macrophages were more frequent in numbers. Tumor necrosis factor-alpha expression was detected mainly in macrophages and in only a few mast cells. When the intensity of arteriosclerosis was decreased by an increase in the intensity of immunosuppression, the numbers of intragraft mast cells and other mononuclear cells, and also the production of their respective cytokines, bFGF and tumor necrosis factor-alpha, gradually diminished. Taken together, our data show that the intensity of intramyocardial mast cell infiltration was associated with the intensity of chronic inflammation and allograft arteriosclerotic changes, but not with acute rejection, and that mast cells, in addition to macrophages, are a major source of myocardial bFGF. The results also demonstrate that when the T-cell activation pathway is blocked using cyclosporin, the number of mast cells is decreased. Cyclosporin may have affected the cytokine production that interfered with both the mast cell-dependent initiation and the leukocyte- and mast cell-dependent amplification and progression of the immune responses influenced by mast cell-leukocyte cytokine cascades. bFGF produced by mast cells may contribute to enhanced inflammation, neovascularization, and fibrosis during cardiac allograft arteriosclerosis.

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