Role of polymorphic Fc receptor Fc gamma RIIa in cytokine release and adverse effects of murine IgG1 anti-CD3/T cell receptor antibody (WT31)

Anti-CD3 monoclonal antibody (mAb) OKT3 is immunosuppressive, but causes severe adverse effects during the first administration (''first-dose reaction''). These adverse effects are presumably caused by cytokilae release that results from T-cell activation, In vitro, T-cell activation by anti-CD3 mAb requires interaction with monocyte Fc receptors, The Fc receptor for murine IgG1, Fc gamma RIIa, is polymorphic. In some individuals, murine IgG1 anti-CD3 mAb causes T-cell proliferation and cytokine release in vitro (high responders [HR]), whereas in individuals with the low-responder (LR) phenotype it does not. We have now investigated the role of this Fc gamma RIIa polymorphism in the release of cytokines in vivo and the occurrence of adverse effects after the administration of WT31, a murine IgG1 anti-CD3/T cell receptor mAb. WT31 caused an increase of plasma tumor necrosis factor-alpha in all four HR patients and none of the five LR patients, In all HR patients except one, plasma gamma-interferon and interleukin 6 also increased, and a first-dose response was observed, whereas no cytolrine release or adverse effects occurred in any of the LR patients. WT31 caused lymphopenia in all HR and none of the LR patients, FAGS analysis demonstrated that in HR patients, after the initial disappearance of CD3(+) cells from peripheral blood, modulation of CD3 occurred, whereas in LR patients a high degree of coating of the lynzphocytes was observed. Surprisingly, WT31 also induced a marked granulocytopenia, as well as a decrease of thrombocytes, in three of the four HR patients (and in none of the LR patients). These data provide direct clinical evidence that Fe receptor interaction determines the release of cytolrines and the occurrence of adverse effects after administration of anti CD3rr cell receptor mAb, Furthermore, these data suggest that tumor necrosis factor-alpha by itself is not sufficient to induce the first-dose reaction.