Using recipient mice with targeted deletion of IFN-γ in our mouse transplant model, we showed that allograft vessel thickening and neointimal smooth muscle cell expansion are reduced when IFN-γ–mediated Th1 responses are absent. 6 Recently, we 7 and others 8 have collected in vivo evidence that Th1 forces promote arteriosclerotic lesion development. 5 Th1 cells produce interferon gamma (IFN-γ), interleukin (IL)-2, and tumor necrosis factor-β (TNF-β), whereas Th2 cells produce IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. One area of active investigation has focused on cytokine pathways because activated CD4 cells differentiate into distinct Th1 and Th2 subsets. However, less is known about the specific molecular mechanisms through which these T-cell effects are conferred. 3 4 Depletion or inhibition of CD4 cells prevents or significantly reduces neointimal thickening. 1 2 The importance of CD4-positive T cells in this cascade has been established using rodent models. Alloimmune responses are believed to initiate an inflammatory cascade culminating in neointimal smooth muscle cell proliferation, perivascular fibrosis, and expansion of extracellular matrix. Transplant arteriosclerosis is an accelerated form of intimal thickening that develops after cardiac transplantation.
This effect is associated with attenuation of Th1 forces. Hence, when present, immune sources of TGF-β 1 attenuate transplant arteriosclerosis. Using 32P-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). To determine whether TGF-β 1 deficiency altered CD4 activation patterns, we studied intragraft cytokine expression. 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). At 55 days, allografts in TGF-β 1–deficient recipients had increased concentric intimal thickening. 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). 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). Besides its parenchymal effects, transforming growth factor-β 1 (TGF-β 1) mediates immunosuppressive effects on proliferation and activation of CD4 cells.
Circ: Cardiovascular Quality & Outcomes.
Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB).