Effect of anti-ICAM-1 antibodies on macromolecular leakage and leukocyte activation: A study of hindlimb allografts in the rat

We investigated the ability of anti-ICAM-1 monoclonal antibodies to reduce endothelial cell damage by assessing microvascular permeability and microci rculatory function during the acute phase of allograft rejection. The compo site rat hindlimb-cremaster muscle transplantation model was employed in th ree experimental groups of 18 animals each. Isograft control transplantatio ns were performed between genetically identical Lewis (LEW, RT11) rats. All ograft transplantations were performed across a major histocompatibility ba rrier between Lewis-Brown-Norway (LBN, RT-11+n), and Lewis (LEM, RT11) rats . In addition, a third group of animals receiving allografts was treated wi th 1 mg/kg/day of anti-ICAM-1 monoclonal antibody. After 24 hours, 72 hours , and 7 days, we measured microvascular permeability, leukocyte activation, functional capillary perfusion, red blood cell velocity, vessel diameters, and endothelial edema index in six animals per each follow-up period. Endo thelial cell damage was assessed by measuring graft permeability to fluores cein isothiocyanate-labeled albumin (0.2 ml/100 g body weight) with compute r-aided image analysis. Mean microvascular permeability was lower in the tr eated allograft group than in untreated controls at all follow-up times (p < 0.001). In addition, anti-ICAM I-l treatment significantly reduced the ac tivation of sticking leukocytes at 24 and 72 hours (p < 0.001) and the acti vation of transmigrating leukocytes at 72 hours and 7 days (p < 0.05). The allografts presented a characteristic microcirculatory pattern of acute rej ection as early as 24 hours after transplantation. The dysfunction of the e ndothelial cell barrier at all time points was indicated by significant inc reases in the degree of allograft macromolecular permeability and in the nu mber of activated sticking and transmigrating leukocytes. Treatment with an ti-ICAM-1 antibodies significantly reduced the surge of leukocytes in the a llograft transplants and protected the endothelial barrier from the acute e ffects of transplantation trauma.