Immune sources of transforming growth factor-beta1 reduce transplant arteriosclerosis: insight derived from a knockout mouse model.
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-beta1 (TGF-beta1) mediates immunosuppressive effects on proliferation and activation of CD4 cells. This study was designed to assess immune contributions of TGF-beta1 to arteriosclerosis by comparing the effect of TGF-beta1-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-beta1 (n=7) and was compared with those placed into wild-type recipients (n=11). At 55 days, allografts in TGF-beta1-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-beta1-deficient recipients compared with wild-type recipients (47.4+/-4.1%, P=0.003). To determine whether TGF-beta1 deficiency altered CD4 activation patterns, we studied intragraft cytokine expression. Using 32P-reverse-transcriptase polymerase chain reaction assays, we show that TGF-beta1-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-beta1 attenuate transplant arteriosclerosis. This effect is associated with attenuation of Th1 forces.
Koglin
J
J
From the Cardiovascular Biology Laboratory, Harvard School of Public Health, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
Glysing-Jensen
T
T
Räisänen-Sokolowski
A
A
Russell
M E
ME
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology*; D004195:Disease Models, Animal; D016027:Heart Transplantation / Q000009:adverse effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology*; D014184:Transplantation, Homologous / Q000473:pathology
D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta