Jd. Eason et al., INHIBITION OF THE EFFECTS OF TNF IN RENAL-ALLOGRAFT RECIPIENTS USING RECOMBINANT HUMAN DIMERIC TUMOR-NECROSIS-FACTOR RECEPTORS, Transplantation, 59(2), 1995, pp. 300-305
Tumor necrosis factor alpha (TNFa) and lymphotoxin (LT) or TNF beta ar
e closely linked cytokines produced by macrophages and activated T lym
phocytes, which play important regulatory roles in the immune response
to allografts. They have also been implicated as mediators of the adv
erse reactions observed during OKT3 therapy. Therefore, anti-TNF agent
s could be useful both for immunosuppression and for limiting the syst
emic response observed in patients receiving OKT3. Recombinant TNFR:Fc
is a fusion protein that binds TNFa and LT, thereby neutralizing thei
r effects in vitro. The present study investigates the potential clini
cal application of TNFR:Fc in a nonhuman primate renal allograft model
. Cynomolgus renal allograft recipients were treated with TNFR:Fc indu
ction therapy alone or in combination with subtherapeutic doses of cyc
losporine. Control animals received no immunosuppression or subtherape
utic cyclosporine. TNFR:Fc, administered as the only immunosuppressive
agent, successfully prolonged renal allograft survival in the majorit
y of treated animals. The prolongation of allograft survival was even
more impressive when TNFR:Fc was combined with subtherapeutic doses of
cyclosporine. Onset of rejection was significantly delayed as well in
the TNFR:Fc treated groups. No adverse side effects were observed in
any of the TNFR:Fc treated animals. Precursor cytotoxic T cells were d
etected in peripheral blood samples of treated recipients but the leve
l of effector CTLs in vivo was below the threshold of detection. These
results demonstrate that TNFR:Fc can be safely administered and is ef
fective in prolonging renal allograft survival and in delaying the ons
et of rejection when administered alone or in combination with cyclosp
orine.