ROLE OF POLYMORPHIC FC RECEPTOR FC-GAMMA-RIIA IN CYTOKINE RELEASE ANDADVERSE-EFFECTS OF MURINE IGG1 ANTI-CD3 T CELL-RECEPTOR ANTIBODY (WT31)/

Anti-CD3 monoclonal antibody (mAb) OKT3 is immunosuppressive, but caus es severe adverse effects during the first administration (''first-dos e reaction''). These adverse effects are presumably caused by cytokila e release that results from T-cell activation, In vitro, T-cell activa tion by anti-CD3 mAb requires interaction with monocyte Fc receptors, The Fc receptor for murine IgG1, Fc gamma RIIa, is polymorphic. In som e individuals, murine IgG1 anti-CD3 mAb causes T-cell proliferation an d cytokine release in vitro (high responders [HR]), whereas in individ uals with the low-responder (LR) phenotype it does not. We have now in vestigated the role of this Fc gamma RIIa polymorphism in the release of cytokines in vivo and the occurrence of adverse effects after the a dministration of WT31, a murine IgG1 anti-CD3/T cell receptor mAb. WT3 1 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 exce pt one, plasma gamma-interferon and interleukin 6 also increased, and a first-dose response was observed, whereas no cytolrine release or ad verse effects occurred in any of the LR patients. WT31 caused lymphope nia in all HR and none of the LR patients, FAGS analysis demonstrated that in HR patients, after the initial disappearance of CD3(+) cells f rom peripheral blood, modulation of CD3 occurred, whereas in LR patien ts a high degree of coating of the lynzphocytes was observed. Surprisi ngly, WT31 also induced a marked granulocytopenia, as well as a decrea se of thrombocytes, in three of the four HR patients (and in none of t he LR patients). These data provide direct clinical evidence that Fe r eceptor interaction determines the release of cytolrines and the occur rence of adverse effects after administration of anti CD3rr cell recep tor mAb, Furthermore, these data suggest that tumor necrosis factor-al pha by itself is not sufficient to induce the first-dose reaction.