Leukocyte CD18 monoclonal antibody worsens endotoxemia and cardiovascular injury in canines with septic shock

Abstract

We investigated the effects of a murine monoclonal antibody directed against the canine leukocyte CD11/18 adhesion complex (MAb R15.7) in a canine model of septic shock. Awake 2-yr-old purpose-bred beagles were studied 7 days before and 1, 2, 4, and 10 days after intraperitoneal placement of an Escherichia coli-infected fibrin clot. Starting 12 h before clot placement, animals received 0.5-1 mg/kg iv every 12 h (4 doses total) of either MAb R15.7 (MAb group, n = 8) or, as controls, murine serum protein (n = 8). After infected clot placement, all animals received antibiotic (ceftriaxne, 100 mg.kg-1.day-1 for 4 days). Two of eight control animals and four of eight MAb animals died (P = 0.4). During the first 8 h after clot placement, MAb animals, compared with control animals, had greater (P < 0.06) increases in serum endotoxin levels and higher (P < 0.05) neutrophil counts. Day 1 after clot placement, MAb animals, compared with control animals, had decreased (P < 0.05) central venous pressure and arterial pH and increased (P < 0.05) arterial lactate. Day 2 after clot placement, MAb animals, compared with control animals, had decreased (P < 0.05) cardiac index and mean arterial pressure. In summary, MAb R15.7, although associated with increased neutrophil counts, worsened serum endotoxemia, acidosis, and cardiovascular function in this canine model of septic shock. These data suggest that in septic shock, antibody directed against this leukocyte membrane protein complex may be harmful, possibly via impairment of normal leukocyte function.

E. colipneumonia induces CD18-independent airway neutrophil migration in the absence of increased lung vascular permeability

“…Neutralizing anti-CD18 antibodies may have other effects, such as cross-linking of the antigen, which could modify the adhesion pathway (7,25,44). CD18 deficiency may result in activation of compensatory mechanisms, and there are known phenotypic alterations, including soft tissue infections and neutrophilia, which may confound comparisons with the effects of anti-CD18 antibodies (34).…”

Granulocyte Colony-Stimulating Factor Has Differing Effects Comparing Intravascular versus Extravascular Models of Sepsis

“…33 Furthermore, in our canine and rat sepsis models, neutrophil inhibition with similar adhesion molecule-directed mAbs worsened survival rates with intraperitoneal and intrabronchial E. coli challenges, respectively. 21,23,34 Overall, our studies with G-CSF and adhesion molecule-directed mAbs suggest that the effects All animals had received daily treatment with G-CSF (5 g/kg/day) or control protein for 9 days prior to these measurements. Before E. coli challenge, TNF levels were similar comparing all animals in these two prior studies as well as in the present study (Table 2).…”

“…Tumor necrosis factor levels were determined with a cytotoxicity assay using the WEHI 164 cell line as previously described. 21 Plasma endotoxin concentrations were determined using a kinetic, chromogenic limulus lysate assay as previously described. 22 …”

Invited review: Compartmentalization of the inflammatory response in sepsis and SIRS

“…159,160 Similarly, anti-LFA-1 did not protect against a lethal injection of LPS in mice, 158 and anti-CD18 worsened cardiovascular function in a canine model of septic shock. 161 The involvement of different adhesion molecules may be specific to the different compartments and probably also depends upon the experimental model used. This complexity is underscored by experiments in which antibody blockade or absence of ICAM-1 (gene knock-out) abrogated LPS-induced cardiac dysfunction but did not reduce neutrophil accumulation.…”