The role of MIG/CXCL9 in cardiac allograft vasculopathy.
T lymphocytes play a critical role in chronic rejection of transplanted hearts, or cardiac allograft vasculopathy (CAV). However, the molecular mediators of T lymphocyte recruitment in CAV are incompletely defined. We hypothesized that the chemokine, monokine induced by interferon-gamma (MIG/CXCL9), which induces T lymphocyte migration in vitro, participates in T lymphocyte recruitment in CAV. In a previously characterized MHC II-mismatched murine model of CAV, intragraft MIG/CXCL9 gene transcript and protein levels increased on days 7, 14, and 24 days after transplantation, paralleling T lymphocyte recruitment and preceding intimal thickening. Antibody neutralization of MIG/CXCL9 significantly reduced CD4(+) T lymphocyte infiltration and intimal thickening in this model. MIG/CXCL9 was produced by graft-infiltrating MOMA-2+ macrophages in early and late stages of CAV. And, although T lymphocytes did not produce MIG/CXCL9, recipient CD4(+) T lymphocytes were required for sustained intragraft MIG/CXCL9 production and CAV development. These findings demonstrate that 1) MIG/CXCL9 plays an important role in CD4(+) T lymphocyte recruitment and development of CAV, 2) MOMA-2+ macrophages are the predominant recipient-derived source of MIG/CXCL9, and 3) recipient CD4 lymphocytes are necessary for sustained MIG/CXCL9 production and CAV development in this model. Neutralization of the chemokine MIG/CXCL9 may have therapeutic potential for the treatment of chronic rejection after heart transplantation.
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000502:physiology*; D003327:Coronary Disease / Q000276:immunology* / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology*; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011183:Postoperative Complications; D013997:Time Factors; D014184:Transplantation, Homologous / Q000473:pathology
C080810:CXCL9 protein, human; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma