Immune Sources of Transforming Growth Factor-β 1 Reduce Transplant Arteriosclerosis

Abstract

Abstract —Activated CD4-positive T cells are essential in the early stages of arteriosclerotic lesion development after cardiac transplantation. Besides its parenchymal effects, transforming growth factor-β 1 (TGF-β 1 ) mediates immunosuppressive effects on proliferation and activation of CD4 cells. This study was designed to assess immune contributions of TGF-β 1 to arteriosclerosis by comparing the effect of TGF-β 1 –deficient and –competent infiltrating inflammatory cells on the development of intimal thickening in a heterotopic mouse transplant model (CBA to C57B6). Transplant arteriosclerosis was evaluated in cardiac grafts placed into knockout recipients heterozygous for TGF-β 1 (n=7) and was compared with those placed into wild-type recipients (n=11). At 55 days, allografts in TGF-β 1 –deficient recipients had increased concentric intimal thickening. Computer-assisted analysis of all elastin-positive vessels (n=173) showed significantly increased luminal occlusion (67.8±5.6%) in grafts from TGF-β 1 –deficient recipients compared with wild-type recipients (47.4±4.1%, P =0.003). To determine whether TGF-β 1 deficiency altered CD4 activation patterns, we studied intragraft cytokine expression. Using 32 P-reverse-transcriptase polymerase chain reaction assays, we show that TGF-β 1 –deficient recipients had an increased expression of the transcription factor STAT 4, interferon gamma, and interleukin-2 (Th1-type response) and unaltered or reduced expression of the transcription factor STAT 6, interleukin-4, and interleukin-10 (Th2-type response). Hence, when present, immune sources of TGF-β 1 attenuate transplant arteriosclerosis. This effect is associated with attenuation of Th1 forces.