Development of an anti-IL-12 p40 auto-vaccine: protection in experimental autoimmune encephalomyelitis at the expense of increased sensitivity to infection.
IL-12 and IL-23, which share the IL-12 p40 subunit, have been ascribed central roles in many autoimmune disorders. We describe here an anti-IL-12 (alphaIL-12) auto-vaccine that potentially blocks both factors in vivo. Immunization of mice with mouse IL-12 coupled to OVA or Pan DR epitope (PADRE) peptide induced Ab directed against the IL-12 p40 subunit, which prevented IFN-gamma production in response to IL-12 administration in vivo. Experimental autoimmune encephalomyelitis, an IL-23-dependent disease model, induced in SJL mice with a proteolipid protein (PLP) peptide was almost undetectable after alphaIL-12 vaccination. Myelin oligodendrocyte glycoprotein (MOG)-induced disease in C57BL/6 mice was also significantly inhibited. This protection correlated with inhibited Th1 cytokine responses in vitro and with an increase in the IgG1/IgG2a anti-PLP Ab balance. Detrimental consequences of alphaIL-12 vaccination were evaluated in C57BL/6 mice infected with Leishmania major (L.m.). While delayed-type hypersensitivity (DTH) suppression and immunoglobulin as well as interleukin production patterns reflected a major shift toward a Th2-type response, L.m. growth was still significantly retarded as compared to that seen in susceptible BALB/c mice. However, vaccinated animals ultimately failed to control parasite expansion. These results suggest that some chronic autoimmune diseases may benefit from alphaIL-12 vaccination at the expense of reduced, but not completely abrogated, cell-mediated immunity.
Uyttenhove
Catherine
C
Ludwig Institute for Cancer Research, Brussels Branch, Brussels, Belgium. catherine.uytthenhove@bru.licr.org
Arendse
Berenice
B
Stroobant
Vincent
V
Brombacher
Frank
F
Van Snick
Jacques
J
D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000517:prevention & control; D018664:Interleukin-12 / Q000276:immunology*; D053762:Interleukin-12 Subunit p40; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D021122:Protein Subunits / Q000276:immunology*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D014611:Vaccination; D014612:Vaccines / Q000276:immunology*
D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D014612:Vaccines; D018664:Interleukin-12