A pilot trial of recombinant human interleukin-10 in kidney transplant recipients receiving OKT3 induction therapy.
BACKGROUND
We conducted a randomized, double-blind, placebo-controlled, rising single-dose study to investigate the effects of recombinant human (rh) interleukin (IL) 10 in renal transplant patients who received OKT3 as induction therapy.


METHODS
Patients received 0.1 (n=6), 1 (n=6), or 10 microg/kg (n=3) rhIL-10 or placebo (n=6) intravenously 30 min before the first injection of 5 mg of OKT3. We monitored IL-10 serum levels, the effect of rhIL-10 on OKT3-induced cytokine production, clinical toxicity, and the incidence of immunization against OKT3.


RESULTS
Serum IL-10 levels in the three experimental groups reached 0.8+/-0.2, 7.9+/-1.3, and 118.6+/-7.3 ng/ml (mean+/-SEM), respectively, 30 min after rhIL-10 injection. Peak plasma levels of tumor necrosis factor-alpha (TNF-alpha) were reduced from 2953+/-1599 pg/ml in patients injected with OKT3 and placebo to 447+/-155, 703+/-246, and 459+/-246 pg/ml in patients injected with 0.1, 1, and 10 microg/kg rhIL-10, respectively. Values for 24-hr TNF-alpha area under the curve decreased from 8988+/-3551 pg x hr/ml in control patients to 2284+/-494, 3950+/-955, and 2420+/-931 pg x hr/ml for the 0.1, 1, and 10 microg/kg rhIL-10 dose groups, respectively (P=0.045). There was also a trend toward reduced plasma levels of IL-2, IL-8, and interferon-gamma in rhIL-10-pretreated patients. Although none of the patients who received placebo or 0.1 or 1 microg/kg rhIL-10 developed an IgM antibody response directed against OKT3 during the first 10 days, this occurred in all three patients who received the highest rhIL-10 dose. In two of these patients, neutralization of OKT3 was associated with a reversible acute rejection episode.


CONCLUSIONS
Pretreatment with doses of up to 1 microg/kg rhIL-10 is safe and reduces the release of TNF-alpha induced by OKT3. However, higher doses might promote early sensitization to OKT3.
Wissing
K M
KM
Department of Nephrology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. wissing@ulb.ac.be
Morelon
E
E
Legendre
C
C
De Pauw
L
L
LeBeaut
A
A
Grint
P
P
Maniscalki
M
M
Ickx
B
B
Vereerstraeten
P
P
Chatenoud
L
L
Kreis
H
H
Goldman
M
M
Abramowicz
D
D
D000328:Adult; D000917:Antibody Formation; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005334:Fever / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007075:Immunoglobulin M / Q000097:blood; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D016853:Muromonab-CD3 / Q000009:adverse effects*; D010865:Pilot Projects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016207:Cytokines; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016209:Interleukin-8; D016853:Muromonab-CD3; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma