Reduction of central nervous system ischemic injury in rabbits using leukocyte adhesion antibody treatment.

Abstract

Activated leukocytes appear to be directly involved in ischemic central nervous system injury. A surface glycoprotein (CD18) on the leukocyte is required for endothelial adherence and subsequent function and can be blocked with leukocyte adhesion antibody treatment. We used two animal models to determine the efficacy of anti-CD18 antibody treatment in preserving neurologic function after central nervous system ischemia. We gave a dose of 1 mg/kg anti-CD18 to treatment rabbits 30 minutes before inducing irreversible ischemia in the brain with intraarterial microspheres or in the spinal cord using reversible aortic occlusion. Treatment with anti-CD18 produced a significant reduction in neurologic deficits in the reversible spinal cord model, but not in the irreversible microsphere model. This protective effect supports the active role of leukocytes in central nervous system reperfusion ischemic injury and offers potential for future therapy. {Stroke 1991;22:877-883) T he appearance of leukocytes in injured ischemic tissue traditionally has been believed to represent a pathophysiologic response to existing injury. Recent evidence indicates they also may be important in the pathogenesis and extension of ischemic injury. "4 Two proposed mechanisms of leukocyte potentiation of ischemia are 1) microvascular occlusion from direct mechanical obstruction and cytotoxic effects on the endothelium, and 2) central nervous system (CNS) tissue infiltration and neuronal cytotoxic injury. "7 The leukocyte-mediated tissue damage may be irreversible even if blood flow is restored. Leukocyte adhesion is an early step in both of these mechanisms.Recent studies have identified a specific leukocyte membrane glycoprotein complex (CD 18) that is critically important for adherence. Monoclonal antibodies (anti-CD 18) to these glycoproteins have been Received October 1, 1990; accepted March 27, 1991. shown to inhibit adherence-dependent leukocyte functions in vitro. 89 In vivo studies using anti-CD18 have shown a reduction of ischemic injury and decreased leukocyte tissue infiltration in heart, lung, intestinal, and systemic shock models.10 -14 These data indicate that leukocyte endothelial adhesion is probably a critical early event in the process leading to neutrophil-mediated tissue reperfusion injury. To date, there have been no published studies using anti-CD 18 to reduce CNS ischemic injury. It is not known how the blood-brain barrier influences leukocyte adhesion and migration or if it would alter anti-CD 18 effects. Because neutrophil infiltratiori is present early in CNS ischemic injury, 15 -17 it is anticipated that leukocytes also will have a critical role in CNS ischemic injury. To test this hypothesis, we evaluated the therapeutic efficacy of anti-CD18 in two models of selective CNS ischemia in rabbits. These models were chosen to compare the treatment efficacy of anti-CD 18 in a reperfusion model versus an irreversible microemboli model. Materials and MethodsWe used male New Zealand White rabbits weighing 2-3 kg. We select...

CD18-Mediated Neutrophil Recruitment Contributes to the Pathogenesis of Reperfused but Not Nonreperfused Stroke

“…28 However, it has been difficult to tease out the pathogenic role of CD18 in PMN recruitment in stroke using blocking antibodies. Administration of a blocking antibody to CD18 (clone designate R 3.3) demonstrated therapeutic efficacy effective in an ischemiareperfusion model of spinal cord injury 29 but not in a model of irreversible cerebral embolic stroke. 16 In the latter study, administration of a monoclonal antibody to CD18 (clone designate MoAb 60.3) did not improve CBF or evoked potentials.…”

The incidence and characteristics of silent cerebral infarction in elderly diabetic patients: association with serum-soluble adhesion molecules

“…A new concept for the onset of ischaemic stroke has been proposed in recent reports as follows: ICAM-1 is expressed on the cell surface by exposure to cytokines such as tumour necrosis factor-a and interleukin-1b during ischaemia [42] or by free radicals induced after reperfusion [39], which contributes not only to neutrophil adherence to the endothelial cells but also to the migration and infiltration of neutrophils. This vicious circle of neutrophils and ICAM-1 may physically plug and obstruct the microvasculature [38,39,43,44]. However, most of these reports describe the expression and changes in adhesion molecules during the acute stroke phase [41] or under experimental ischaemic conditions [38,44], and nothing has been reported on alterations in adhesion molecules under chronic conditions such as SCI.…”

Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke.

“…The pathogenic relevance of adhesion molecule expression in the brain remains controversial, however; data from a trial of a monoclonal anti-ICAM-1 antibody in stroke in humans are not yet available (Rothlein, R., personal communication). In animal models, there is conflicting experimental evidence regarding the effectiveness of anti-adhesion molecule strategies in the treatment of experimental stroke (21)(22)(23). To determine whether ICAM-1 participates in the pathogenesis of postischemic cerebral injury, the experiments reported here were undertaken in a murine model of focal cerebral ischemia and reperfusion so that the role of a single, critical mediator of PMN adhesion (ICAM-1) could be determined.…”