Immune responses induced by intranasal imiquimod and implications for therapeutics in rhinovirus infections.
Notwithstanding the progress recently made in immunology and virology, there is yet no effective, specific treatment for the common cold. Symptomatic treatment is minimally effective. An anecdotal report of rapid clearing of the common cold of recent onset after intranasal application of imiquimod in several subjects by one of the authors, made us test the hypothesis that this treatment works through the secretion of interferon by the nasal mucosa. We decided to do an animal study in primates (Indian Macaca Mulata): 5 treatment and 3 control animals were used. Imiquimod or placebo was massaged into the nares of the animals and periodic samples of post-nasal fluid were taken and measurements for Interferon alpha (IFNalpha) and Tumor Necrosis Factor alpha (TNFalpha) were made by ELISA methods, and kinetic studies. mRNA IFNalpha was also isolated and analyzed by quantitative competitive RT-PCR. The internal standard was constructed to be complementary to and compete with oligonucleotide primers and for amplification of target sequences. One intranasal application of imiquimod rapidly (1-4 Hours) induced high levels of mRNA for IFNalpha, and minimal levels in the control animals. Rapid induction of INFalpha, and proportional increase of TNFalpha sustained for 4 and 6 hours respectively were noted. No adverse reactions to treatment were found in macaques during this short period of intranasal imiquimod usage (except in one macaque with a short period of lacrimation). No animal had cytotoxic effects when examined at 6 hr, 12 hr, 24 hr or 48 hr, except one animal, which had an episode of lacrimation for 6 hr post treatment. Thus both safety and efficacy of short treatment with imiquimod is proven in this animal model. Proof of principle for intranasal treatment of the common cold with imiquimod is shown. We think that this work will encourage a number of double blind clinical trials to confirm the effectiveness of the intranasal treatment of the common cold with imiquimod.
Clejan
Sanda
S
Department of Pathology & Laboratory Medicine, Tulane University School of Medicine and the General Clinical Research Center, New Orleans, LA, 70112-2699, USA. sclejan@tulane.edu
Mandrea
E
E
Pandrea
Ivona V
IV
Dufour
J
J
Japa
S
S
Veazey
R S
RS
D000276:Adjuvants, Immunologic / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000281:Administration, Intranasal; D000634:Aminoquinolines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D003139:Common Cold / Q000188:drug therapy*; D015870:Gene Expression / Q000187:drug effects; D000077271:Imiquimod; D016233:Immunotherapy, Active / Q000379:methods*; D007369:Interferon Inducers / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000378:metabolism; D008253:Macaca mulatta; D009297:Nasal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D007369:Interferon Inducers; D016898:Interferon-alpha; D008233:Lymphotoxin-alpha; D012333:RNA, Messenger; D000077271:Imiquimod