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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Acute rejection and cardiac graft vasculopathy in the absence of donor-derived ICAM-1 or P-selectin

      Abstract

      Background: ICAM-1 and P-selectin are molecules that facilitate adhesion of circulating leukocytes to vessel walls. We have investigated the role of donor-derived ICAM-1 and P-selectin in acute and chronic cardiac allograft rejection.

      Methods

      C57BL/6J (H-2b) mice were used as donors for heterotopic heart transplantation into CBA/Ca (H-2k) recipients. The donors were wild-type or homozygous for gene mutations of ICAM-1 or P-selectin. We measured acute rejection in non-immunosuppressed recipients by daily palpation and sacrificed mice at Days 2, 4, and 6 for immunohistochemical analysis. For chronic rejection, recipients received monoclonal antibody against CD4+ T cells. We removed hearts at Days 60 to 62 for histologic assessment of vasculopathy using quantitative morphometry to measure intimal thickening.

      Results

      Time (days) to rejection was 7.1 ± 0.57 for wild-type (n = 10), 7.0 ± 0.71 for ICAM-1 −/− (not significantly different, n = 7) and 6.1 ± 0.33 (p = 0.001) for P-selectin −/− donors. ICAM-1 deficiency was associated with delayed infiltrate at Day 4 compared with wild-type. In the model of chronic rejection, elastin-positive vessels showed a mean occlusion of 34% ± 3% in transplanted wild-type hearts; vessels were divided into those showing 0% to 20%, 20% to 50%, and 50% to 100% occlusion. We observed no difference in the number of affected vessels or the amount of vascular thickening in donors lacking ICAM-1 or P-selectin compared with wild-type controls.

      Conclusions

      The absence of ICAM-1 or P-selectin in donor tissues neither lengthens the time of allograft survival nor inhibits the vascular lesions associated with chronic rejection. Indeed, the absence of P-selectin may exacerbate alloimmune injury.
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