title: Delivery of IL-12 intranasally leads to reduced IL-12-mediated toxicity.
abstract: Interleukin-12 (IL-12) is a heterodimeric cytokine that enhances immune responses to bacterial, parasitic, and viral pathogens, and leads to tumor regression in animal models. For this reason, the use of IL-12 as a vaccine adjuvant and as a therapeutic agent for the treatment of cancer is being investigated. Unfortunately, the extreme toxicity of this molecule observed during clinical trials has limited its use. This toxicity correlates with increased IFN-gamma expression, decreased glucose levels, and altered histological responses in the spleen and duodenum. In this study, we show that intranasal (i.n.) delivery of IL-12 is a less toxic route of inoculation compared to the commonly employed subcutaneous route. When delivered i.n., IL-12 induces less systemic IFN-gamma production and fewer pathological tissue changes, yet is efficacious, as indicated by enhanced CD3(+) T cell activation and increased production of Th1-associated immunoglobulins (i.e., serum IgG2a). Thus, IL-12 can be delivered safely and effectively by the i.n. route, a finding which may allow IL-12 to fulfill its clinical potential.
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, 47 New Scotland Avenue, MC-151, Albany, NY 12208, USA.
authors.forename: Victor C
authors.initials: VC
authors.lastname: Huber
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Arulanandam
authors.forename: Paul M
authors.initials: PM
authors.lastname: Arnaboldi
authors.forename: Monica K
authors.initials: MK
authors.lastname: Elmore
authors.forename: Christine E
authors.initials: CE
authors.lastname: Sheehan
authors.forename: Bhaskar V S
authors.initials: BV
authors.lastname: Kallakury
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Metzger
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000633:toxicity*; D000281:Administration, Intranasal; D000818:Animals; D017252:CD3 Complex / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004386:Duodenum / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007074:Immunoglobulin G / Q000276:immunology; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000633:toxicity*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D017252:CD3 Complex; D016207:Cytokines; D007074:Immunoglobulin G; D018664:Interleukin-12; D007371:Interferon-gamma