Inhibition of leucocyte and platelet adhesion reduces neointimal hyperplasia after arterial injury.

Restenosis following coronary angioplasty is though to result from migration and proliferation of medial smooth muscle cells. However, the factors that initiate this proliferation are still unknown. In a rabbit model of carotid artery injury, we tested the hypothesis that activated platelets and leucocytes might contribute to the development of neointimal hyperplasia. Following arterial injury, rabbits received either no treatment, R15.7, a monoclonal antibody against the leucocyte CD11/CD18 adhesion complex, aurintricarboxylic acid (ATA), a substance that inhibits platelet glycoprotein Ib-von Willebrand factor interaction, or the combination of R15.7 and ATA. After 21 days, the extent of neointimal hyperplasia was evaluated by planimetry on histological arterial sections. The area of neointima averaged 0.51 +/- 0.07 mm2 in control animals and it was significantly reduced by administration of either R15.7 or ATA alone to 0.12 +/- 0.05 and 0.20 +/- 0.01 mm2, respectively (p < 0.05 vs controls for both groups). The animals that received the combination of R15.7 and ATA showed a further reduction in neointimal hyperplasia, as compared to animals that received ATA alone (p < 0.05 vs ATA alone). These data indicate that platelets and leucocytes play an important role in the pathophysiology of neointimal hyperplasia in this experimental model. Interventions that reduce platelet and leucocyte adhesion to vessel wall might have beneficial effects in reducing restenosis following coronary angioplasty.

Fc gamma and CD11/CD18 receptor expression on normal density and low density human eosinophils.

We have studied the expression of Fc gamma receptors and leucocyte integrins (CD11/CD18 family) on human eosinophils using specific monoclonal antibodies (mAb) and flow cytometric analysis. Peripheral blood eosinophils of normal density and low density were compared with neutrophils and monocytes. Several properties of the human eosinophil were established. These were (i) that the eosinophil expressed Fc gamma RII (CDw32) only (unlike monocytes which bear Fc gamma RI and Fc gamma RII and neutrophils which bear Fc gamma RII and Fc gamma RIII); (ii) that the absence of Fc gamma RIII (CD16) on eosinophils served as a basis for distinguishing eosinophil and neutrophil populations by immunofluorescence; (iii) that the leucocyte adhesion glycoproteins, LFA-1 alpha (CD11a), CR3-alpha (CD11b), p150, 95-alpha (CD11c) and the common beta-chain (CD18), were expressed on the eosinophil as well as the neutrophil; (iv) that CD18 expression was significantly reduced on low-density eosinophils from the hypereosinophilic syndrome. Thus, our findings emphasize the unique phenotype of the human eosinophil in terms of Fc gamma receptor expression, the similarity of the eosinophil and neutrophil with regard to the leucocyte integrins and that eosinophils of low density do not differ greatly from those of normal density in terms of receptor expression.

A 19-year-old man with leucocyte adhesion deficiency. In vitro and in vivo studies of leucocyte function.

We describe a male patient with leucocyte adhesion molecule deficiency (LAD) of moderate phenotype. Although diagnosis was made only 2 years before his death, the patient survived until 19 years of age. This enabled us to perform a number of novel investigation, both in vivo and in vitro, relating to his leucocyte biology. Monocytes cultured in vitro matured into morphologically normal, phagocytically capable macrophages, which were able to recognize aged 'apoptotic' neutrophils. By injection of radiolabelled autologous neutrophils we demonstrated a prolonged neutrophil half-life, but normal margination, de-margination on exercise, and splenic pooling. Neutrophil adherence in vitro to vascular endothelium was normal. Histological examination of the patient's lungs at post-mortem showed intravascular aggregation of polymorphonuclear leucocytes but a paucity of cells in the interstitium and alveolar spaces. These findings indicate that the peripheral blood leucocytosis commonly observed in these patients may be due to prolonged intravascular neutrophil survival, and suggest that CD11/18 molecules have an important role in facilitating neutrophil emigration from blood vessels at sites of inflammation.

Haemodialysis monocytopenia: differential sequestration kinetics of CD14+CD16+ and CD14++ blood monocyte subsets.

In peripheral blood the majority of circulating monocytes present a CD14highCD16- (CD14++) phenotype, while a subpopulation shows a CD14lowCD16+ (CD14+CD16+) surface expression. During haemodialysis (HD) using cellulosic membranes transient leukopenia occurs. In contrast, synthetic biocompatible membranes do not induce this effect. We compared the sequestration kinetics for the CD14+CD16+ and CD14++ monocyte subsets during haemodialysis using biocompatible dialysers. Significant monocytopenia, as measured by the leucocyte count, occurred only during the first 30 min. However, remarkable differences were observed between the different monocyte subsets. CD14++ monocyte numbers dropped to 77 +/- 13% of the predialysis level after 15 min, increasing to > or = 93% after 60 min. In contrast, the CD14+CD16+ subset decreased to 33 +/- 15% at 30 min and remained suppressed for the course of dialysis (67 +/- 11% at 240 min). Approximately 6 h after the end of HD the CD14+CD16+ cells returned to basal levels. Interestingly, the CD14+CD16+ monocytes did not show rebound monocytosis while a slight monocytosis of CD14++ monocytes was occasionally observed during HD. A decline in CD11c surface density paralleled the sequestration of CD14+CD16+ monocytes. Basal surface densities of important adhesion receptors differed significantly between the CD14+CD16+ and CD14++ subsets. In conclusion, during HD the CD14+CD16+ subset revealed different sequestration kinetics, with a more pronounced and longer disappearance from the blood circulation, compared with CD14++ monocytes. This sequestration kinetics may be due to a distinct surface expression of major adhesion receptors which facilitate leucocyte-leucocyte, as well as leucocyte-endothelial, interactions.