Donor and recipient contributions of ICAM-1 and P-selectin in parenchymal rejection and graft arteriosclerosis: insights from double knockout mice.
BACKGROUND
Mice with target gene deletions were used in an immunosuppressed, heterotopic mouse cardiac transplant model to investigate the effects of simultaneous deficiencies of ICAM-1 and P-selectin on late cardiac rejection.


METHODS
To determine the contribution of donor sources of ICAM-1 and P-selectin, ICAM-1/P-selectin gene deficient (I/P -/-) (n = 7) or wild type (n = 6) donor hearts were placed into CBA recipients. To study recipient sources of ICAM-1 and P-selectin, wild type donor hearts were placed into I/P -/- (n = 7) or wild type (n = 13) recipients. Recipients received a 30-day course of anti-CD4/8 mAb.


RESULTS
I/P -/- donor allografts had prolonged survival (52-57 days) compared with wild type allografts (49-51 days). I/P -/- donor allografts underwent parenchymal rejection with mononuclear cell infiltration and developed alpha-smooth muscle actin positive vascular thickening (30 +/- 7% luminal occlusion, n = 78 vessels). Wild type allografts had parenchymal rejection with vascular medial necrosis and an absence of arteriosclerotic thickening (10 +/- 8%, n = 75, p = 0.008). Using the reverse combination, allografts from I/P -/- or wild type recipients had similar graft survival (50-57 days), comparable but variable degrees of parenchymal rejection, and comparable vascular occlusion (22 +/- 15% vs 28 +/- 19%, p = 0.442).


CONCLUSIONS
We have shown that donor and recipient sources of ICAM-1 and P-selectin may have independent roles in leukocyte trafficking to the graft. Simultaneous interruption of donor ICAM-1 and P-selectin delays onset of parenchymal rejection. However, donor I/P deficiency permits arteriosclerotic development, perhaps by attenuating the alloimmune injury. In contrast, recipient deficiency alone does not altergraft outcomes suggesting that the donor is the critical site of ICAM-1 and P-selectin.
Räisänen-Sokolowski
A
A
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, USA.
Glysing-Jensen
T
T
Russell
M E
ME
D000199:Actins / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D006083:Graft Occlusion, Vascular / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D006084:Graft Rejection / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival; D016027:Heart Transplantation; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout / Q000235:genetics / Q000276:immunology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D019007:P-Selectin / Q000502:physiology*; D014019:Tissue Donors; D014184:Transplantation, Homologous
D000199:Actins; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1