Nitric oxide and the immunomodulation of experimental allergic encephalomyelitis

Abstract

Previous studies examining the effect of nitric oxide synthase (NOS) inhibition on the course of experimental allergic encephalomyelitis (EAE) have yielded conflicting results. This may relate to the use of nonspecific inhibitors and to differences between active and adoptive EAE. We examined the effect of treatment with L-N-(1-iminoethyl)lysine (L-NIL), a selective inhibitor of the cytokine-inducible isoform of NOS, on the clinical course of active and adoptive EAE in Lewis rats. We find that while L-NIL treatment of recipients is protective in adoptive EAE, treatment of active EAE with L-NIL leads to a marked accentuation of disease expression. In L-NIL-treated animals treated with myelin basic protein/complete Freund's adjuvant (MBP/CFA), disease onset is accelerated and clinical symptoms are more severe. Accentuation of integrated disease scores is seen even if L-NIL treatment is started 5 days following immunization. The histological findings in involved spinal cords from L-NIL-treated animals with active EAE are similar to those from untreated animals with similar clinical scores. L-NIL treatment of MBP/CFA-immunized animals does not prevent recovery from clinical symptoms, nor does it allow for reinduction of disease in animals previously immunized with MBP/CFA. Treatment of F344 rats, a strain which is relatively nonsusceptible for EAE, with L-NIL results in consistent evidence of EAE following immunization with MBP/CFA. These findings, together with our previous work on interstitial nephritis, support a role for endogenously generated NO in immunoregulation of T cell responses following immunization with antigen in CFA, and suggest that inducibility of NOS expression may be an important susceptibility factor for autoimmunity.

Inhibition of Nitric Oxide Synthase Initiates Relapsing Remitting Experimental Autoimmune Encephalomyelitis in Rats, Yet Nitric Oxide Appears to be Essential for Clinical Expression of Disease

“…Its inhibition leads to a more severe disease in a primary course of EAE (17,18,32,33), and as we have now shown, its inhibition can initiate a second episode of inflammatory cell accumulation in the CNS. In contrast, it appears as if the production of NO in the CNS, in excess of normal levels, is required for clinical expression of disease.…”

“…The difference between their findings and ours could of course be due to the fact that L-NIL is more specific for iNOS than is L-NMA; the latter also inhibits the endothelial (eNOS) and neuronal (nNOS) enzymes. Dose and timing of treatment could also account for the different results, and most importantly, based on the findings presented in this work, we would now suggest that unless Gold et al (32) had ceased L-NIL treatment before termination of the experiment, clinical disease would not have been seen. We have shown in this work the necessity for cessation of inhibitor treatment in order for clinical disease to occur (Fig.…”

“…Gold et al (32) described the enhancement of EAE in Lewis rats treated with another NOS inhibitor, L-N-iminoethyl lysine (L-NIL). However, they were unable to induce disease recurrence using this agent.…”

Superoxide Prevents Nitric Oxide-Mediated Suppression of Helper T Lymphocytes: Decreased Autoimmune Encephalomyelitis in Nicotinamide Adenine Dinucleotide Phosphate Oxidase Knockout Mice

“…Despite extensive knowledge about NO regulation, the role of NO in tissue inflammation is controversial, as illustrated by studies involving the animal model for multiple sclerosis, experimental allergic encephalomyelitis (EAE). Some investigators concluded that NO is involved in the pathogenesis of EAE (4 -12), while others reported protective effects of NO (13)(14)(15)(16).…”

Regulation of Experimental Autoimmune Encephalomyelitis in the C57BL/6J Mouse by NK1.1+, DX5+, αβ+ T Cells

“…Although epitope spreading is hypothesized to be responsible for relapses (3)(4)(5)(6), the factors involved in recovery from the disease phases have been difficult to define. Mechanisms thought to play a role in recovery include apoptosis of effector T cells in the CNS, suppressive cytokines, immune deviation, and NK cells (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”