Association of B7-1 co-stimulation with the development of graft arterial disease. Studies using mice lacking B7-1, B7-2, or B7-1/B7-2.
To investigate the roles of B7-1 and/or B7-2 co-stimulatory molecule in the development of graft arterial disease (GAD), major histocompatibility complex (MHC) class II-mismatched allograft hearts were transplanted into wild-type, B7-1(-/-), B7-2(-/-), or B7-1/B7-2(-/-) recipient mice. Grafts were explanted at 4 or 8 weeks and used for histological and immunohistochemical analyses, RNase protection assay, and flow cytometry of graft infiltrating cells. Grafts in wild-type recipients showed macrophage, recipient MHC class II, and B7 molecule co-localization by immunohistochemistry to GAD lesions. Flow cytometry revealed that CD11b(+) and MHC class II(+) graft infiltrating cells expressed B7-1 more than B7-2, whereas B7-2 expression was predominant in CD11b(-) cells at 4 and 8 weeks. GAD was significantly attenuated in the allografts in B7-1(-/-) and B7-1/B7-2(-/-) but not in B7-2(-/-) recipients compared to wild-type hosts. Interferon-gamma mRNA levels were comparable in all graft combinations, whereas interleukin-4 mRNA levels decreased in grafts in B7-2 deficient hosts, but did not correlate with GAD attenuation. The findings indicate distinct roles for B7-1 and B7-2 co-stimulatory molecules in the development of GAD, potentially because of differential expression of B7-1 and B7-2 molecules on distinct stimulator and/or effector cell populations.
Department of Medicine, Cardiovascular Division, Vascular Medicine and Atherosclerosis Unit, Immunology Research Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Y
Y
Furukawa
D A
DA
Mandelbrot
P
P
Libby
A H
AH
Sharpe
R N
RN
Mitchell
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D015703:Antigens, CD / Q000032:analysis / Q000235:genetics / Q000502:physiology; D001402:B-Lymphocytes / Q000737:chemistry / Q000166:cytology; D018122:B7-1 Antigen / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000166:cytology; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005838:Genotype; D006083:Graft Occlusion, Vascular / Q000209:etiology*; D006084:Graft Rejection / Q000150:complications / Q000503:physiopathology; D016027:Heart Transplantation; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007150:Immunohistochemistry; D008264:Macrophages / Q000737:chemistry / Q000166:cytology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors; D014184:Transplantation, Homologous
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D018925:Chemokines; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins