Immune Sources of Transforming Growth Factor-ß₁ Reduce Transplant Arteriosclerosis

Insight Derived From a Knockout Mouse Model

From the Cardiovascular Biology Laboratory, Harvard School of Public Health (J.K., T.G.-J., A.R.-S., M.E.R.), Brigham and Women's Hospital (M.E.R.), and Harvard Medical School (M.E.R.), Boston, Mass.

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-ß₁ (TGF-ß₁) mediates immunosuppressive effects on proliferation and activation of CD4 cells. This study was designed to assess immune contributions of TGF-ß₁ to arteriosclerosis by comparing the effect of TGF-ß₁–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-ß₁ (n=7) and was compared with those placed into wild-type recipients (n=11). At 55 days, allografts in TGF-ß₁–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-ß₁–deficient recipients compared with wild-type recipients (47.4±4.1%, P=0.003). To determine whether TGF-ß₁ deficiency altered CD4 activation patterns, we studied intragraft cytokine expression. Using ³²P-reverse-transcriptase polymerase chain reaction assays, we show that TGF-ß₁–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-ß₁ attenuate transplant arteriosclerosis. This effect is associated with attenuation of Th1 forces.

Key Words: heart transplantation • growth factor • Th1 cell • cytokine • graft rejection

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