Induction of tolerance to recombinant therapeutic proteins.
The specific IgM and IgG antibody responses to subcutaneous (s.c.) treatment of mice with recombinant human IFN-alpha2a (rHuIFN-alpha2a) or IFN-beta were inhibited in a dose-dependent manner by prior oromucosal (o.m.) administration of rHuIFN-alpha2a or IFN-beta, respectively. Pretreatment of animals once a day for 7 days by the o.m. route with the highest dose of IFN-alpha2a tested (10(7) IU) resulted in complete inhibition of the peak IFN-alpha2a-specific IgG antibody response detected 28 days after subsequent s.c. injection of IFN-alpha2a (p < 0.001). Similarly, prior o.m. administration of 1-10 microg rHuGM-CSF per day for 7 days resulted in a statistically significant (p < 0.001) inhibition of the peak GM-CSF-specific IgG antibody response detected 28 days after s.c. administration of GM-CSF. In contrast, prior o.m. treatment with a quantity of bovine serum albumin (BSA) (100 microg) or human serum albumin (HSA) (10 microg) equivalent, respectively, to the protein content of the highest dose of IFN-alpha2a or GM-CSF administered by the o.m. route, did not affect significantly the IFN-alpha2a-specific or GM-CSF-specific IgG antibody responses detected on subsequent s.c. administration of IFN-alpha2a or GM-CSF. Oromucosal administration of IFN-alpha2a, IFN-beta, or GM-CSF alone did not induce detectable IFN-alpha2a-specific, IFN-beta-specific, or GM-CSF-specific IgM or IgG antibody responses at any of the time points tested. These results suggest that short-term o.m. administration of a recombinant protein is an effective means of inducing peripheral tolerance to subsequent parenteral administration of a therapeutic protein.
Meritet
J F
JF
Laboratory of Viral Oncology, UPR 9045 CNRS, Institut André Lwoff/IFR 2249, 94801 Villejuif, France.
Maury
C
C
Tovey
M G
MG
D000281:Administration, Intranasal; D000818:Animals; D004361:Drug Tolerance; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007279:Injections, Subcutaneous; D007370:Interferon Type I / Q000008:administration & dosage / Q000494:pharmacology; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009297:Nasal Mucosa; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007370:Interferon Type I; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor