Monokine induced by IFN-gamma is a dominant factor directing T cells into murine cardiac allografts during acute rejection.
The use of chemokine antagonism as a strategy to inhibit leukocyte trafficking into inflammatory sites requires identification of the dominant chemokines mediating recruitment. The chemokine(s) directing T cells into cardiac allografts during acute rejection remain(s) unidentified. The role of the CXC chemokines IFN-gamma inducible protein 10 (IP-10) and monokine induced by IFN-gamma (Mig) in acute rejection of A/J (H-2(a)) cardiac grafts by C57BL/6 (H-2(b)) recipients was tested. Intra-allograft expression of Mig was observed at day 2 posttransplant and increased to the time of rejection at day 7 posttransplant. IP-10 mRNA and protein production were 2.5- to 8-fold lower than Mig. Whereas allografts were rejected at day 7-9 in control recipients, treatment with rabbit antiserum to Mig, but not to IP-10, prolonged allograft survival up to day 19 posttransplant. At day 7 posttransplant, allografts from Mig antiserum-treated recipients had marked reduction in T cell infiltration. At the time of rejection in Mig antiserum-treated recipients (i.e., days 17-19), intra-allograft expression of macrophage-inflammatory protein-1alpha, -1beta, and their ligand CCR5 was high, whereas expression of CXCR3, the Mig receptor, was virtually absent. Mig was produced by the allograft endothelium as well as by recipient allograft-infiltrating macrophages and neutrophils, indicating the synergistic interactions between innate and adaptive immune compartments during acute rejection. Collectively, these results indicate that Mig is a dominant recruiting factor for alloantigen-primed T cells into cardiac allografts during acute rejection. Although Mig antagonism delays acute heart allograft rejection, the results also suggest that the alloimmune response circumvents Mig antagonism through alternative mechanisms.
Miura
M
M
Urological Institute and Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Morita
K
K
Kobayashi
H
H
Hamilton
T A
TA
Burdick
M D
MD
Strieter
R M
RM
Fairchild
R L
RL
D000208:Acute Disease; D000595:Amino Acid Sequence; D000818:Animals; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology*; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins; D007519:Isoantigens / Q000276:immunology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism; D011184:Postoperative Period; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000235:genetics; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous / Q000276:immunology
C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C515188:Cxcr3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D007519:Isoantigens; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine