Experimental Allergic Encephalomyelitis In Guinea Pigs Research Articles

Low-molecular-weight enzyme inhibitors suppress the development of experimental allergic encephalomyelitis.

We tested the activity of low-molecular-weight enzyme inhibitors with immunomodifying actions on the suppression of experimental allergic encephalomyelitis (EAE). Of the agents tested the inhibitors of alkaline phosphatase, aminopeptidase B and esterase gave significant protection against the clinical expression of EAE in guinea pigs.

Suppression of experimental allergic encephalomyelitis (EAE) with liposome-encapsulated protease inhibitor: therapy through the blood-brain barrier.

Experimental allergic encephalomyelitis (EAE) is an experimentally induced autoallergic demyelinating disease which is caused by immunization with a particular neuroantigen, such as myelin basic protein (MBP). Results have suggested that protease inhibitors might be useful therapeutically. Leupeptin (acetyl-L-leucyl-L-leucyl-argininal), a protease inhibitor of tripeptide nature, was effective in suppressing EAE in guinea pigs, when administered in a form of liposomes consisting of egg lecithin, cholesterol and sulfatide. The drug seemed to be transported into the central nervous system (CNS) tissues across the blood-brain barrier with the aid of a particular type of liposomes as vehicle. Some outbred Hartley guinea pigs completely recovered from distinct symptoms of EAE, such as loss of weight, paralysis, incontinence and/or diarrhea, when treated i.p. every day with lecithin-cholesterol-sulfatide (molar ratio, 4:5:1) reverse-phase evaporation vesicles-encapsulated leupeptin (REV-Leu) from day 6 after sesitization with 30 micrograms of bovine MBP. Scarcely any typical histopathological changes of EAE were found in the CNS of most survivors treated with REV-Leu.

The development of periventricular lesions in chronic relapsing experimental allergic encephalomyelitis in guinea-pigs: a light and scanning electron microscopic study.

Periventricular lesions in the centrum semiovale are the most frequent changes in the brain in chronic relapsing experimental encephalomyelitis in guinea-pigs. They are generally distributed symmetrically at the lateral angle of the ventricular wall. The number of lesions and their size increases in anterior-posterior direction. Typically periventricular lesions in the later chronic stages are similar to those in multiple sclerosis. Earlier lesions generally originate in the depth of the white matter and secondarily, by extension, reach the ventricular surface. Lesions developing at later stages after sensitization may also originate from the ventricular wall and extent into the centrum semiovale. In these latter, severe structural changes in the ventricular ependyma may generally be found. Increased intracranial pressure in these animals may be one of the possible mechanisms leading to the peculiar topographical distribution of the periventriuclar lesions.

Immunosuppression of experimental allergic encephalomyelitis in guinea pigs by antibrain and antithymocyte heteroantisera

Experimental allergic encephalomyelitis (EAE), induced by central nervous system (CNS) myelin basic protein (MBP) in adjuvant, is considered a thymus dependent autoimmune disease. Brain contains the thymic antigen, thy 1. The possibility that brain associated anti thy 1 immunoglobulin may be provoked in certain pathologic conditions of the CNS suggested a comparative evaluation of brain and thymocyte antisera on the development of EAE. Antisera produced in rabbits against brain from guinea pigs, rats and mice or fetal guinea pig thymus were highly reactive against thy 1 containing cells when assessed by indirect immunofluorescent staining or complement-mediated cell lysis. Treatment of guinea pigs with heteroantisera to guinea pig and mouse, but not to rat brain, for 3 days around the time of MBP sensitization markedly reduced physical signs of disease, particularly paralysis, but had little effect on the development of inflammatory lesions in the CNS. Anti-guinea pig thymocyte sera eliminated all physical signs of EAE with only residual pathology. These results establish the relative immunosuppressive effect of brain and thymocyte antisera in EAE and corroborate the thymus-dependent nature of EAE in guinea pigs.

Experimental allergic encephalomyelitis in cobra venom factor-treated and C4-deficient guinea pigs.

Experimental allergic encephalomyelitis (EAE) was studied in guinea pigs with an inherited deficiency of the fourth component of complement (C4) and in guinea pigs injected with cobra venom factor to deplete the third component and late-acting components of complement. EAE was elicited by immunization with homologous spinal cord or purified basic protein. Administration of cobra factor after the injection of encephalitogenic emulsion delayed the onset and reduced the intensity of the clinical manifestations of EAE. In addition, cobra factor markedly reduced mortality during the sixty days of observation. However, pathological changes of perivascular infiltration and demyelination were similar in cobra factor-treated and untreated animals. Clinical signs of EAE an mortality in C4-deficient guinea pigs were no different from those in normocomplementemic controls. Thus, although activation of the classic complement pathway does not appear to be involved in the production of EAE in guinea pigs, our results suggest a possible role of the alternative complement pathway in the pathogenesis of EAE.

Suppression of experimental allergic encephalomyelitis by chemically modified encephalitogen

The results of enzymatic and chemical degradation studies of the basic myelin protein suggested that tryptophan is essential for encephalitogenic activity in the guinea pig. The object of the present investigation was to modify the protein through its tryptophan residue in such a way that it becomes non-encephalitogenic, yet suppresses experimental allergic encephalomyelitis (EAE). Accordingly, the single tryptophan residue of the protein was modified with specific reagents such as 2-hydroxy-5-nitrobenzylbromide (HNB-BR), 2-nitrophenylsulfenyl chloride (NPSCl) and performic acid. Injection of the modified proteins did not result in neurological disease, although some guinea pigs did exhibit histological changes in the brain. Starting 3 days after injection with the active inoculum, the treatment with the modified proteins was carried out for four weeks, using a total of 900 μg og the modified proteins. The guinea pigs treated with HNB and performic acid oxidized protein did not show neurological signs of the disease, but from the NPSCl group, two out of 10 developed EAE, although at a later data compared with those guinea pigs which were injected with the unmodified encephalitogen. The results not only confirm previous findings that intact tryptophan in the protein is a prime requirement for the production of EAE in guinea pigs, but also provide evidence that tryptophan is not essential for suppression of the disease. The conclusion we may draw from these studies is that the encephalitogenic basic myelin protein has two active sites: one which contains tryptophan required for the paralytic effect, the other without tryptophan which provides protection.

Antilymphocytic serum in experimental allergic encephalomyelitis.

Antilymphocytic and antithymic sera (raised in rabbits) are highly potent in preventing or alleviating experimental allergic encephalomyelitis in guinea-pigs. Good results are obtained when treatment is begun as late as 10 days after challenge. No protracted disease was seen from the use of antilymphocytic serum. Attempts to use this serum therapeutically once the disease was clinically established gave equivocal results. Antilymphocytic serum appears to have a non-specific stressor effect as well as its specific action, and possibly this adrenocorticotrophic-hormone (antiphlogistic) effect may ameliorate a developing encephalitis. The presence of an antimacrophagic factor in antilymphocytic serum may be important in increasing local reaction to injection of the serum and perhaps also in diminishing the appearance of haematogenous elements in the nervous lesions.

Encephalitogenic peptides from spinal cord.

IN a recent symposium on experimental allergic encephalomyelitis there was considerable discussion on the size of encephalitogenic factors from brain and spinal cord1–4. We have fractionated extracts from bovine spinal cord by gel-filtration with phenol–acetic acid–water. This solvent system was introduced by Synge and colleagues5–7 for the fractionation of peptides on ‘Sephadex G-75’. It is a strongly dissociating solvent which prevents adsorption of peptides on ‘Sephadex’, and gel-filtration in this solvent can be used to estimate the molecular size of peptides as there is an approximately linear relationship between the relative elution volume and the log of molecular weight8,9. This communication describes a typical fractionation of basic polypeptides which were found to produce experimental allergic encephalomyelitis in guinea-pigs.