The Critical Role of IL‐12p40 in Initiating, Enhancing, and Perpetuating Pathogenic Events in Murine Experimental Autoimmune Neuritis

Interleukin 12 (IL‐12) is a proinflammatory cytokine with important immunoregulatory activities and is critical in determining the differentiation and generation of Th1 cells. For the present study, we investigated the role of endogenous IL‐12 in the pathogenesis of experimental autoimmune neuritis (EAN), which is a CD4 + T‐cell mediated autoimmune inflammatory disease of the peripheral nervous system. EAN is used as an animal model for Guillain‐Barré syndrome of humans. Here, EAN was established in IL‐12 p40 deficient mutant (IL‐12 ‐/‐ ) C57BL/6 mice by immunization with P0 peptide 180–199, a purified component of peripheral nerve myelin, and Freund's complete adjuvant. In these IL‐12 ‐/‐ mice the onset of clinical disease was delayed, and the incidence and severity of EAN were significantly reduced compared to that in wild‐type mice. The former group's clinical manifestations were associated with less P0‐peptide 180–199 induced secretion of interferon‐γ (IFN‐γ) by splenocytes in vitro and low production of anti‐P0‐peptide 180–199 IgG2b antibodies in serum. Fewer IFN‐γ and TNF‐α producing cells, but more cells secreting IL‐4, were found in sciatic nerve sections from IL‐12 ‐/‐ mice, consistent with impaired Th1 functions and response. However, the IL‐12 deficiency appeared not to affect P0 peptide 180–199‐specific T‐cell proliferation. These results indicate that IL‐12 has a major role in the initiation, enhancement and perpetuation of pathogenic events in EAN by promoting a Th1 cell‐mediated immune response and suppressing the Th2 response. This information augments consideration of IL‐12 as a therapeutic target in Guillain‐Barré syndrome and other T‐cell‐mediated autoimmune diseases.