Inhibition of monocyte/macrophage migration to a spinal cord injury site by an antibody to the integrin alpha D: A potential new anti-inflammatory treatment

The inflammatory response that ensues during the initial 48 to 72 h after s pinal cord injury causes considerable secondary damage to neurons and glia. Infiltration of proinflammatory-activated neutrophils and monocytes/macrop hages into the cord contributes to spinal cord injury-associated secondary damage. beta2 integrins play an essential role in leukocyte trafficking and activation and arbitrate cell-cell interactions during inflammation. The b eta2 integrin, alphaD beta2, is expressed on monocytes/macrophages and neut rophils and binds to vascular adhesion molecule-1 (VCAM-1). The increased e xpression of VCAM-1 during central nervous system (CNS) inflammation likely contributes to leukocyte extravasation into the CNS, Accordingly, blocking the interaction between alphaD beta2 and VCAM-1 may attenuate the inflamma tory response at the SCI site. We investigated whether the administration o f monoclonal antibodies (mAbs) specific for the rat alphaD subunit would re duce the inflammatory response after a spinal cord transection injury in ra ts. At a 1 mg/kg dose two of three anti-alphaD mAbs caused a significant (s imilar to 65%) reduction in the number of macrophages at the injury site an d one anti-alphaD mAb led to a similar to 43% reduction in the number of ne utrophils at the SCI site. Thus, our results support the concept that the a lphaD beta2 integrins play an important role in the trafficking of leukocyt es to a site of central nervous system inflammation. This study also offers preliminary evidence that anti-alphaD mAbs can reduce the extravasation of macrophages and, to a lesser extent, neutrophils, to the SCI site. (C) 200 0 Academic Press.