Development of an anti‐IL‐12 p40 auto‐vaccine: protection in experimental autoimmune encephalomyelitis at the expense of increased sensitivity to infection

Abstract

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 (αIL‐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‐γ 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 αIL‐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 αIL‐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 αIL‐12 vaccination at the expense of reduced, but not completely abrogated, cell‐mediated immunity.

Development of an anti‐IL‐17A auto‐vaccine that prevents experimental auto‐immune encephalomyelitis

“…Concentrations and isotypes of anti-PLP Ab measured in the serum after disease resolution were also unchanged. This result is in sharp contrast with observations we previously made in anti-IL-12-p40 vaccinated animals, where a clear Th2 shift was noted [19]. Our present findings support the idea that IL-17A inhibition does not change the Th1/Th2 balance of the response, confirming the results previously reported in MOG-induced EAE [5].…”

“…Protein-based vaccines have been obtained by cross-linking to OVA (IL-9 [18]) or immunogenic peptides (IL-12 [19], IL-1 [23], CD20 [24]) or by administration of OVA peptide containing fusion protein in the case of TNF-a [25]. DNA vaccines encoding a fusion protein (IL-5-p30 tetanus helper epitope [26]), altered IL-6 sequences [27] or even non-modified naked DNA, as reported for C-C chemokines [28] have also proven successful.…”

“…Immunization of mice with mouse IL-9 and IL-12 crosslinked to OVA induces strong neutralizing Ab responses against the corresponding cytokine [18,19] but for some cytokines like IL-6 or IL-4, Ab are induced that have little or no inhibitory activity (personal unpublished observation). To gain further information on the auto-vaccine process and possibly extend its application, IL-17A dimers were cross-linked with OVA at a 1/2 molar ratio by overnight reaction with glutaraldehyde.…”

Local immunostimulation leading to rejection of accepted male skin grafts by female mice as a model for cancer immunotherapy

“…IL-1α, GM-CSF, IL-2, IL-18, IFN-α, and gardiquimod were purchased (SI Materials and Methods). Recombinant murine IL-12 was produced as described (34).…”

Clinical evaluation of BCR-ABL peptide immunisation in chronic myeloid leukaemia: results of the EPIC study

“…9 In vitro, PADRE induces CD4 þ T cell responses in virtually all individuals. 8 It has been used as an adjuvant in vaccination studies in cervical carcinoma, 10 malaria, 11 CMV, 12 polio 13 and Alzheimers disease. 14 …”