The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.
Transplant immunology| Volume 20, ISSUE 3, P340-349, March 2001

Download started.


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


      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.


      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.


      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.


      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.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Journal of Heart and Lung Transplantation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Springer T.A
        Traffic signals for lymphocyte recirculation and leukocyte migration.
        Cell. 1994; 76: 301-314
        • Belilacqua M.P
        • Nelson R.M
        J Clin Invest. 1993; 91: 379-387
        • Palabrica T
        • Lobb R
        • Furie B.C
        • et al.
        Leukocye accumulation which promotes fibrin deposition is mediated in vivo by P-selectin (CD62) on adherent platelets.
        Nature. 1992; 359: 848-851
        • Rothlein R
        • Dustin M.L
        • Marlin S.D
        • Springer T.A
        A human intercellular adhesion molecules (ICAM-1) distinct from LFA-1.
        J Immunol. 1986; 137: 1270-1276
        • Springer T.A
        Adhesion receptors of the immune system.
        Nature. 1990; 346: 425-434
        • Wagner D.D
        The Weibel palade body.
        Thromb Haemost. 1993; 70: 105-110
        • Weller A
        • Isenmann S
        • Vestweber D
        Cloning of the mouse endothelial selectins. Expression of both E- and P-selectin is inducible by tumour necrosis factor α.
        J Biol Chem. 1992; 267: 15176-15183
        • Isobe M
        • Yagita H
        • Okumura K
        • Ihara A
        Specific acceptance of cardiac allograft treatment with antibodies to ICAM-1 and LFA-1.
        Science. 1992; 255: 1125-1128
        • Schowengerdt K.O
        • Zhu J.Y
        • Stepowski S.M
        • Tu Y
        • Entamn M.L
        • Ballantyne C.M
        Cardiac allograft survival in mice deficient in intercellular adhesion molecule-1.
        Circulation. 1995; 92: 82-87
        • Kusaka M
        • Zandi-Nejad K
        • Kato S
        • et al.
        Exploitation of the continuum between early ischemia/reperfusion injury and host alloresponsiveness.
        Transplantation. 1999; 67: 1255-1261
        • Yamasaki S
        • Isobe M
        • Susuki J
        • et al.
        Role of selectin-dependent adhesion in cardiac allograft rejection.
        J Heart Lung Transplant. 1998; 17: 1007-1016
        • Corry R.J
        • Winn H.J
        • Russell P.S
        Primarily vascularised allografts of hearts in mice. The role of H-2D, H-2K and non-H-2 antigens in rejection.
        Transplantation. 1973; 16: 343-350
        • Raisanen-Sokolowski A
        • Glysing-Jensen T
        • Mottram P
        • Russell M
        Sustained anti-CD4/CD8 blocks inflammatory activation and intimal thickening in mouse heart allografts.
        Arterioscler Thromb Vasc Biol. 1997; 17: 2115-2122
        • Raisanen-Sokolowski A
        • Glysing-Jensen T
        • Koglin J
        • Russel M.E
        Reduced transplant arteriosclerosis in murine cardiac allografts placed in interferon-γ knock-out recipients.
        Am J Pathol. 1998; 152: 359-365
        • Lawson C
        • Ainsworth M
        • Yacoub M.H
        • Rose M.L
        Ligation of ICAM-1 on endothelial cells leads to expression of VCAM-1 via a nuclear factor -κB-independent mechanism.
        J Immunol. 1999; 162: 2990-2996
        • Taylor P.M
        • Rose M.L
        • Yacoub M.H
        Coronary artery immunogenecity.
        Transplant Immunol. 1993; 1: 294-301
        • Poston R.N
        • Haskard D.O
        • Croucher J.R
        • Gall N.P
        • Johnson-Tidey R.R
        Expression of intercellular adhesion molecule-1 in atherosclerotic plaques.
        Am J Pathol. 1992; 140: 665-673
        • Taniya Y
        • Yamamoto N
        • Ude T
        Protective effects of monoclonal antibody against LFA-1 and ICAM-1 on myocardial reperfusion injury following global ischaemia in rat hearts.
        Immunopharmacology. 1995; 29: 53-60
        • Poston R.N
        • Johnson-Tidey R.R
        Localized adhesion of monocytes to human atherosclerotic plaques demonstrated in vitro.
        Am J Pathol. 1996; 149: 73-80
        • Austrup F
        • Vestweber D
        • Borges E
        • et al.
        P- and E-selectin mediate recruitment of T helper-1 but not T-helper-2 cells into inflamed tissues.
        Nature. 1997; 385: 81-83
        • Borges E
        • Tietz W
        • Steegmaier M
        • et al.
        P-selectin glycoprotein ligand (PSGL-1) on T helper–1 but not on T helper–2 cells binds to P-selectin and supports migration into inflamed skin.
        J Exp Med. 1997; 185: 573-578
        • Rosencrantz A.R
        • Mendrick D.L
        • Cotran R.S
        • Mayadas T.N
        P-selectin deficiency exacerbates experimental glomerulonephritis.
        J Clin Invest. 1999; 103: 649-659
      1. Samuel SL, Hicks MJ, Lindsey JR, Bullard DC. P-selectin deficiency results in accelerated lethality in MRL/Mpj-Faslpr mice. FASEB J 1999;13:A855–56.

        • Bullard D.C
        • Qin L
        • Lorenzo I
        • et al.
        P-selectin/ICAM-1 double mutant mice.
        J Clin Invest. 1995; 95: 1782-1788
        • Raisanen-Sokolowski A
        • Glysing-Jensen T
        • Russell M.E
        Donor and recipient contributions of ICAM-1 and P-selectin in parenchymal rejection and graft arteriosclerosis.
        J Heart Lung Transplant. 1999; 18: 735-743
        • Russell P.S
        • Chase C.M
        • Colvin R.B
        Alloantibody and T cell mediated immunity in the pathogenesis of transplant arteriosclerosis.
        Transplantation. 1997; 64: 1531-1536
        • Schroeder J.S
        • Gao S.Z
        Accelerated graft coronary artery disease in heart-transplant recipients.
        Coron Artery Dis. 1995; 6: 226-233
        • Shi C
        • Feinberg M.W
        • Zhang D
        • et al.
        Donor MHC and adhesion molecules in transplant arteriosclerosis.
        J Clin Invest. 1999; 103: 469-474
        • Dietrich M
        • Hu Y
        • Zou Y
        • et al.
        Mouse model of transplant arteriosclerosis. Role of intercellular adhesion molecule-1.
        Arterioscler Throm Vasc Biol. 2000; 20: 343-352
        • McManus B.M
        • Malcom G
        • Kendall T.J
        • et al.
        Prominence of coronary arterial wall lipids in human heart allografts.
        Am J Pathol. 1995; 147: 292-300
        • Russel P.S
        • Chase C.M
        • Colvin R.B
        Accelerated atheromatous lesions in mouse hearts transplanted to apolipoprotein-E-deficient recipients.
        Am J Pathol. 1996; 149: 91-99
      2. Shi C, Lee Wen-Sen, Russel ME, et al. Hypercholesterolemia exacerbates transplant arteriosclerosis via increased neointimal smooth muscle cell accumulation. Circulation 1997;96:2722–8.

        • Isobe M
        • Suzuki J.I
        • Yamazaki S
        • Horie S
        • Okubo Y
        • Sekiguchi M
        Assessment of tolerance induction to cardiac allograft by anti-ICAM-1 and anti-LFA-1 monoclonal antibodies.
        J Heart Lung Transplant. 1997; 16: 1149-1156
        • Sadahiro M
        • McDonald T.O
        • Nelson K
        • Thomas R
        • Allen M.D
        Leukocyte CD18 receptors may be a better target than ICAM-1 for reducing histologic evidence of cellular and vascular rejection in the rabbit.
        Transplant Int. 1995; 8: 452-458
        • Damle N.K
        • Klussman K
        • Linsley P.S
        • et al.
        Differential costimulatory effects of adhesion molecules B7, ICAM-1, LFA-3, and VCAM-1 on resting and antigen primed CD4+ T lymphocytes.
        J Immunol. 1992; 148: 1985-1992
        • De Fougerolles A.R
        • Stacker S.A
        • Schwarting R
        • Springer T.A
        Characterisation of ICAM-2 and evidence for a third counter receptor for LFA-1.
        J Exp Med. 1991; 174: 253-267