EVALUATION OF RECOMBINANT HUMAN SOLUBLE DIMERIC TUMOR NECROSIS FACTOR RECEPTOR FOR PREVENTION OF OKT3-ASSOCIATED ACUTE CLINICAL SYNDROME1,2:
TRANSPLANTATION(1996)
Abstract
Tumor necrosis factor alpha (TNFa) has been shown to be the primary cytokine responsible for the OKT3-induced acute clinical syndrome (OKT3-ACS). Recombinant human soluble tumor necrosis factor receptor (TNFR:Fc) is a dimer of the p80 TNF receptor, which binds both TNFa and lymphotoxin (LT), Renal allograft recipients undergoing OKT3 therapy for steroid-resistant rejection were randomized to receive OKT3 alone or in combination with TNFR:Fc to determine its safety and efficacy in decreasing the severity of OKT3-ACS and in restoring renal function, Six of 12 patients were given TNFR:Fc prior to each of the first two injections of OKT3. All patients were monitored for manifestations of OKT3-ACS and changes in renal function. In addition, serial serum samples were assayed for TNFa and TNFR:Fc levels (ELISA) and TNFa bioactivity (L929). No adverse side effects were identified in patients receiving TNFR:Fc. Patients treated with TNFR:Fc had significantly fewer symptoms by day 2 of OKT3, and had a lower overall incidence of chills and arthralgias. Renal dysfunction reversed within 24 hr in the TNFR:Fc-treated group in contrast to the 48-72-hr delay in the control group, Antigenic TNFa levels increased in the control group from <10 pg/ml pre OKT3 to a mean peak level of 30+/-13 pg/ml on day 1 and decreased to pretreatment levels by day 2, TNFR:Fc-treated patients had a mean peak TNFa level of 235+/-135 pg/ml, suggesting a carrier effect of TNFR: Fc, In contrast, bioactivity was barely detectable (mean 20+/-14 pg/ml) in the day 1 samples from TNFR: Fc-treated patients, whereas significant bioactivity (peak mean 60+/-35 pg/ml) was detected in sera from control patients, TNF receptor levels reached 600 ng/ml in treated patients and remained elevated for up to 18 days confirming the long half-life of TNFR:Fc, This phase 1 trial demonstrates that TNFR:Fc is well tolerated and may limit the severity of OKT3-ACS, The most significant observation was a more rapid improvement in renal function in the TNFR:Fc-treated patients. The absence of TNFa bioactivity indicates that TNFR:Fc functions as a TNF antagonist. Further evaluation of higher doses of TNFR:Fc in OKT3-treated patients is currently in progress.
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