OKT3-associated morbidity: interrelated function of complement and reactive oxygen intermediates in the generation of enhanced leukocyte adhesiveness

OKT3 is frequently and very successfully used in anti-rejection therapy after solid-organ transplantation, but there is considerable morbidity associated with the administration of the first dose, affecting virtually all treated patients. With this study we want to provide insights into the complex molecular and cellular mechanisms underlying the generation of early OKT3-related side effects, with emphasis on the frequently occurring respiratory manifestations. In spite of ample evidence for an important role of cytokines derived from OKT3-activated mononuclear cells in the generation of OKT3 first-dose reactions, immediate respiratory symptoms shortly following OKT3 administration have been linked to complement activation and pulmonary sequestration of granulocytes. Adhesive/aggregative events of leukocytes appear to be essential for the development of diverse OKT3-induced pulmonary pathologies, including a decrease in arterial P02, dyspnoe, wheezing, lung edema and even life-threatening respiratory distress. On the basis of our previous results on the directly stimulating effect of OKT3 on neutrophil oxidative burst and degranulation, the known complement-activating properties of reactive oxygen intermediates, and the aforementioned conditions, we postulate essential functional crossconnections between these components in the development of immediate reactions to OKT3. To test our hypothesis, we intend to perform studies on the intertwined influence of reactive oxygen intermediates and complement on leukocyte activation by OKT3, with subsequent functional proof of enhanced adhesiveness, in terms of homo-/heterotypic aggregation and adhesion to endothelium. With our results, we expect to provide evidence for the clinical relevance of the described mechanisms in monoclonal antibody therapy.