Experimental Autoimmune Encephalomyelitis Paralysis Research Articles

Increased expression of neuronal nitric oxide synthase in astrocytes and macrophages in the spinal cord of Lewis rats with autoimmune encephalomyelitis

Neuronal nitric oxide synthase (nNOS) is constitutively expressed in neurons of the central nervous system, where it plays a physiological role in neurotransmission. In this study, we examined the functional role of nNOS in experimental autoimmune encephalomyelitis(EAE). The effects of the specific nNOS inhibitor 7-nitroindazole on normal and EAE rats were studied by immunohistochemistry and Western blot analysis. We found that nNOS is constitutively expressed in the spinal cords of normal rats, whilst in the spinal cords of EAE rats, nNOS expression slightly increased, concomitant with the infiltration of T cells and macrophages. Immunohistochemical studies showed that nNOS expression in macrophages and astrocytes increased at the peak stage of EAE and declined thereafter. Treatment with 7-nitroindazole (30 mg/kg) significantly delayed the onset of EAE paralysis, but had no effect on either the incidence or the severity of the paralysis. These findings suggest that nNOs inhibition has a limited role in the induction of rat EAE, and that constitutive nNOS in the spinal cord functions as a novel neurotransmitter, rather than a pro-inflammatory agent.

Aminoguanidine-Induced Amelioration of Autoimmune Encephalomyelitis is Mediated by Reduced Expression of Inducible Nitric Oxide Synthase in the Spinal Cord

ABSTRACT:To elucidate whether an inducible nitric oxide synthase (iNOS) inhibitor, aminoguanidine (AMG), affects the expression of iNOS in the spinal cords of rats with experimental autoimmune encephalomyelitis (EAE), we induced EAE in Lewis rats, and treated EAE rats with AMG. AMG (200mg/kg administered intraperitoneally from day 0 to day 7 post-immunization) significantly reduced the clinical severity of EAE paralysis. AMG, however did not prevent the occurrence of EAE. Western blot analysis showed that iNOS expression was significantly reduced in the spinal cords of rats with EAE treated with AMG compared with rats treated with the vehicle. This rinding supports the conclusion that the production of nitric oxide by iNOS plays an important role in the induction of EAE. The corollary is that the amelioration of EAE paralysis by the treatment with AMG is associated with the suppression of iNOS expression in the target organ i.e. the spinal cord.

Inhibition of relapsing experimental autoimmune encephalomyelitis in SJL mice by feeding the immunodominant PLP139-151 peptide

Peripheral antigen-specific tolerance can be induced by feeding protein antigens. The mechanism has been described as either clonal anergy/deletion or induction of antigen-specific regulatory cells that produce transforming growth factor-beta (TGF-beta). These two mechanisms have been linked to the magnitude and frequency of the dose of antigen fed; a single high dose induces anergy/deletion, whereas multiple low doses of antigen induce TGF-beta-secreting regulatory cells. In the present study, we investigated the mechanisms of feeding soluble peptides of proteolipid protein (PLP) for prevention of experimental autoimmune encephalomyelitis (EAE) induced by either intact PLP or the immunodominant PLP139-151 peptide. Feeding PLP139-151 prevented acute and relapsing EAE induced by either PLP139-151 or intact PLP. PLP139-151 feeding induced anergy in the T helper 1 (Th1) population as measured by an inhibition of both proliferation and interferon-gamma (IFN-gamma) production. Interleukin-4 (IL-4) production was increased, but increased TGF-beta production was not observed. Importantly, PLP139-151 feeding induced anergy in peripheral and central nervous system (CNS)-in-filtrating T cells. Feeding of the subdominant PLP epitope (PLP178-191) failed to inhibit EAE induced by PLP139-151; therefore, oral tolerance was not due to induction of bystander suppression. These results demonstrate that both acute and relapsing paralysis in EAE can be prevented by feeding the immunodominant peptide of PLP.

Induction of relapsing paralysis in experimental autoimmune encephalomyelitis by bacterial superantigen.

The role of infection in the pathogenesis of clinical relapses that occur in most autoimmune diseases, including multiple sclerosis, remains to be established. Experimental autoimmune encephalomyelitis (EAE) serves as a model for multiple sclerosis, with episodes of relapsing paralysis. In certain strains of mice, T-lymphocytes expressing the V beta 8 T-cell receptor (TCR) engage the amino-terminal epitope Ac1-11 of myelin basic protein, leading to EAE. The bacterial superantigen staphylococcal enterotoxin B (SEB) activates V beta 8-expressing T cells. Here we show that after immunization with Ac1-11, or after transfer of encephalitogenic T-cell lines or clones reactive to Ac1-11, SEB induces exacerbation or relapses of paralytic disease in mice that are in clinical remission following an initial episode of paralysis, and triggers paralysis in mice with subclinical disease. Tumour necrosis factor has a critical role in the mechanism underlying SEB-induced exacerbation of disease, because anti-tumour necrosis factor antibody given in vivo delays the onset of paralysis triggered by SEB. On reactivation of autoaggressive cells through their T-cell receptor, superantigens may induce clinical relapses of autoimmune disease.

The use of monoclonal antibodies for treatment of autoimmune disease

Over the past decade monoclonal antibodies have been successfully employed in a number of animal models of autoimmune disease. We have used antibodies to the class II gene products of the major histocompatibility complex, the CD4 molecule on helper T cells, and the T-cell receptor. Monoclonal anti-class II antibodies have been administered to treat paralytic disease in the animal model of multiple sclerosis--experimental allergic encephalomyelitis. These antibodies not only reverse acute paralytic disease but also decrease the number of relapses in a model of relapsing/remitting multiple sclerosis when given after the first attack. The advantage of this form of therapy is that it is haplotype specific. In other words, in a heterozygous individual it is possible to block the major histocompatibility gene associated with disease susceptibility while leaving other major histocompatibility gene products free for antigen presentation. Thus, animals given this form of immunotherapy are not significantly immunosuppressed. Antibodies to the CD4 molecule have been equally effective in treating animal models of autoimmunity. We and others have reversed ongoing paralysis in experimental autoimmune encephalomyelitis. Relapses have been diminished after the administration of anti-CD4. Antibodies to CD4 have been used successfully to treat animal models of systemic lupus erythematosus, rheumatoid arthritis and myasthenia gravis. Recent trials with anti-CD4 have been successful in the treatment of rheumatoid arthritis and cutaneous T-cell lymphoma. The latter trial employed a chimeric human/mouse antibody. Antibodies to the variable region of the T-cell receptor have been employed to treat experimental autoimmune encephalomyelitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of autoimmune disease and the generation of suppressor cells by spirogermanium: A biological profile similar to total lymphoid irradiation

Oral administration of spirogermanium (Sg), inhibits the development of immune-mediated hindpaw inflammation in the rat model of adjuvant arthritis (AA) and DTH responses to PPD (30 mg/kg/day). A similar dosing protocol inhibits hindleg paralysis in experimental autoimmune encephalomyelitis (EAE). The spleens of these animals and those of normal rats contain radiation resistant (2000 R) non-specific suppressor cells (SC) which bear some similarity to those generated following total lymphoid irradiation (TLI). These cells do not appear to be mature T cells, they are partially adherent to plastic, sephadex G10 and nylon wool, insensitive to indomethacin and are enriched in a 1.07 g/ml fraction of a Percoll density gradient.

Properties, structure and possible neuroreceptor role of the encephalitogenic protein of human brain.

The principal determinant region of the encephalitogenic protein, the amino-acids of which have been sequenced, is located round the sole tryptophan residue. The determinant may be the receptor site for 5-hydroxytryptamine in certain regions of the central nervous system, and the paralysis in experimental autoimmune encephalomyelitis may be caused by an immunopharmacological block of nervous transmission.