IMMUNE SOURCES OF TRANSFORMING GROWTH FACTOR-BETA(1) REDUCE TRANSPLANT ARTERIOSCLEROSIS - INSIGHT DERIVED FROM A KNOCKOUT MOUSE MODEL

Activated CD4-positive T cells are essential in the early stages of ar teriosclerotic lesion development after cardiac transplantation. Besid es its parenchymal effects, transforming growth factor-beta(1) (TGF-be ta(1)) mediates immunosuppressive effects on proliferation and activat ion of CD4 cells. This study was designed to assess immune contributio ns of TGF-beta(1) to arteriosclerosis by comparing the effect of TGF-b eta(1)-deficient and -competent infiltrating inflammatory cells on the development of intimal thickening in a heterotopic mouse transplant m odel (CBA to C57B6), Transplant arteriosclerosis was evaluated in card iac grafts placed into knockout recipients heterozygous for TGF-beta(1 ) (n=7) and was compared with those placed into wild-type recipients ( n=11). At 55 days, allografts in TGF-beta(1)-deficient recipients had increased concentric intimal thickening. Computer-assisted analysis of all elastin-positive vessels (n=173) showed significantly increased l uminal occlusion (67.8+/-5.6%) in grafts from TGF-beta(1)-deficient re cipients compared with wild-type recipients (47.4+/-4.1%, P=0.003). To determine whether TGF-beta(1) deficiency altered CD4 activation patte rns, we studied intragraft cytokine expression. Using P-32-reverse-tra nscriptase polymerase chain reaction assays, we show that TGF-beta(1)- deficient recipients had an increased expression of the transcription factor STAT 4, interferon gamma, and interleukin-2. (Th1-type respons e) and unaltered or reduced expression of the transcription factor STA T 6, interleukin-4, and interleukin-10 (Th2-type response). Hence, whe n present, immune sources of TGF-beta(1) attenuate transplant arterios clerosis, This effect is associated with attenuation of Th1 forces.