Absence of recipient CCR5 promotes early and increased allospecific antibody responses to cardiac allografts.
Acute rejection is mediated by T cell infiltration of allografts, but mechanisms mediating the delayed rejection of allografts in chemokine receptor-deficient recipients remain unclear. The rejection of vascularized, MHC-mismatched cardiac allografts by CCR5(-/-) recipients was investigated. Heart grafts from A/J (H-2(a)) donors were rejected by wild-type C57BL/6 (H-2(b)) recipients on day 8-10 posttransplant vs day 8-11 by CCR5(-/-) recipients. When compared with grafts from wild-type recipients, however, significant decreases in CD4(+) and CD8(+) T cells and macrophages were observed in rejecting allografts from CCR5-deficient recipients. These decreases were accompanied by significantly lower numbers of alloreactive T cells developing to IFN-gamma-, but not IL-4-producing cells in the CCR5(-/-) recipients, suggesting suboptimal priming of T cells in the knockout recipients. CCR5 was more prominently expressed on activated CD4(+) than CD8(+) T cells in the spleens of allograft wild-type recipients and on CD4(+) T cells infiltrating the cardiac allografts. Rejecting cardiac allografts from wild-type recipients had low level deposition of C3d that was restricted to the graft vessels. Rejecting allografts from CCR5(-/-) recipients had intense C3d deposition in the vessels as well as on capillaries throughout the graft parenchyma similar to that observed during rejection in donor-sensitized recipients. Titers of donor-reactive Abs in the serum of CCR5(-/-) recipients were almost 20-fold higher than those induced in wild-type recipients, and the high titers appeared as early as day 6 posttransplant. These results suggest dysregulation of alloreactive Ab responses and Ab-mediated cardiac allograft rejection in the absence of recipient CCR5.
Amano
Hiroyuki
H
Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Bickerstaff
Alice
A
Orosz
Charles G
CG
Novick
Andrew C
AC
Toma
Hiroshi
H
Fairchild
Robert L
RL
D000818:Animals; D000918:Antibody Specificity / Q000235:genetics; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007518:Isoantibodies / Q000096:biosynthesis* / Q000502:physiology; D007519:Isoantigens / Q000276:immunology*; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000172:deficiency* / Q000502:physiology; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D013997:Time Factors
C515188:Cxcr3 protein, mouse; D007518:Isoantibodies; D007519:Isoantigens; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine