title: Lethal NK-mediated inflammation induced by IL-12 in the absence of polymorphic and nonpolymorphic MHC class I molecules.
abstract: Interleukin-12 is a potent activator and initiator of type-1 T cell development, and can be used as an adjuvant to bias for the development of vaccine-induced Th1 immune responses. During vaccination of MHC class I deficient beta-2 microglobulin knockout mice (β2M(-/-)) with an IL-12/αIL-4 Th1 biasing procedure, all of the mice died. None of the IL-12/αIL-4 treated wild type mice developed any noticeable complications. We hypothesized that NK cells may be activated by IL-12 treatment in these β2M(-/-) mice, leading to necrosis and eventual death. IL-12/αIL-4 treatment of β2M(-/-) mice resulted in increased NK cell numbers and activation status (IFN-γ(+), CD69(+)). Finally, in vivo depletion of NK cells reversed the pathology induced by IL-12/αIL-4 treatment in β2M deficient mice. These results indicate that IL-12 combined with αIL-4 irreversibly activates NK cells leading to a disseminated inflammatory pathology and death in β2M(-/-) mice.
authors.affiliation: Department of Internal Medicine, Saint Louis University, Saint Louis, MO 63104, United States.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Eickhoff
authors.forename: Anita R
authors.initials: AR
authors.lastname: Schnapp
authors.forename: John E
authors.initials: JE
authors.lastname: Sagartz
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hoft
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D049109:Cell Proliferation; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000008:administration & dosage / Q000009:adverse effects*; D053662:Interleukin-4 Receptor alpha Subunit / Q000276:immunology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018417:Th1 Cells / Q000276:immunology; D001613:beta 2-Microglobulin / Q000235:genetics / Q000276:immunology*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma; D018664:Interleukin-12; D053662:Interleukin-4 Receptor alpha Subunit; D037181:Lectins, C-Type; D001613:beta 2-Microglobulin; D000099192:CD69 Antigens
keywords: Beta-2 microglobulin (β(2)M); IL-12; Inflammation; Interleukin 12; Interleukin 12 (IL-12); Intraperitoneal; NK; Natural killer cells (NK); Polymorphic and nonpolymorphic MHC; Subcutaneous; beta-2 microglobulin; i.p.; natural killer cells; s.c.; β(2)M
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