Suppression of chronic allergic encephalomyelitis: relevance to multiple sclerosis.

The expression of chronic relapsing experimental allergic encephalomyelitis in strain 13 guinea pigs was suppressed with a single series of injections of myelin basic protein in incomplete Freund's adjuvant. The suppression appeared permanent, and subsequent rechallenge with central nervous system antigen failed to elicit exacerbations.

Adoptive autoimmune encephalomyelitis in inbred guinea pigs: immunological and histological aspects.

Major variables which determine the induction and severity of adoptive autoimmune encephalomyelitis are the age and strain of the animal, and the amount of killed mycobacteria in the adjuvant. Control of these factors results in consistent production of this disease in high incidence and in severe form. The pathologic changes in the central nervous system can be correlated with the clinical disease. Maturity of the target tissues in the central nervous system of the newborn appears to be an important factor which distinguishes the response of the guinea pig from that of other species.

Autoimmune chorioretinitis in rhesus monkeys.

Monkeys injected with monkey retinal tissue incorporated in Freunld's complete adjuvant developed ocular lesions characterized by choroiditic patches in the fundus periphery and sheathing of retinal vessels. Bovine retina, monkey choroid plexus, and guinea pig kidney were ineffective in this respect.

Autoimmune encephalomyelitis and ocular lesions in monkeys sensitized during the neonatal period.

The neonatal rhesus monkey is susceptible to the induction of autoimmune encephalomyelitis. The disease has been produced regularly by injection of neonatal animals with guinea pig spinal cord antigen in complete Freund's adjuvant. The onset of the disease, as compared with onset in adults, is delayed and is most often heralded by intrinsic eye lesions, notably widespread retinal hemorrhages.

Attempts to induce chronic experimental allergic neuritis in strain 13 and Hartley guinea pigs.

An attempt has been made to develop a model of chronic experimental allergic neuritis (EAN) using juvenile and adult inbred (Strain 13) and Hartley guinea pigs sensitized with peripheral nerve in complete Freund's adjuvant. Animals were followed clinically for periods ranging from 2 to 44 weeks postinoculation and then sacrificed for light and electron microscopy. Out of a total of 39 animals, 16 showed either clinical signs or had histopathologic changes. The remaining 23 guinea pigs were free of any disease. The animals' age at inoculation and strain did not seem to affect either the clinical course or ultimate histopathologic changes. The 7 animals that had clinical EAN displayed signs ranging from weight loss and soiling to quadriparesis (one animal). The histologic changes consisted of meningeal and perivascular inflammation as well as peripheral nervous system (PNS) and central nervous system demyelination and remyelination. An interesting abnormality seen the nerve roots of several animals was the proliferation of Schwann cells around remyelinated PNS fibers reminiscent of the "onion-bulb" formations seen in human hypertrophic neuropathies. Because of the lack of ongoing demyelination, onion-bulb formation appeared in this case to be a secondary proliferation of Schwann cells after a single primary episode of demyelination. It is concluded from the present study that despite some interesting histopathologic changes, the animals studied were largely resistant both to acute as well as chronic EAN.

Progressive demyelination and reparative phenomena in chronic experimental allergic encephalomyelitis.

Chronic experimental allergic encephalomyelitis (EAE), produced in inbred guinea pigs given a single inoculation during the juvenile period with isologous spinal cord in complete Freund's adjuvant, has been studied by light and electron microscopy. Most animals showed a delayed onset of nurologic signs from 12 to 68 weeks post-inoculation (PI), while several were asymptomatic up to 74 weeks PI. Two animals showed a relapsing clinical course. Examination of the spinal cords of all animals revealed chronic demyelination, remyelination, and recent demyelination. Marked perivascular inflammation, including plasma cells, was seen within demyelinated plaques. The usual type of central nervous system (CNS) remyelination was documented but in addition, remyelination of CNS axons by invading Schwann cells was noted. This Schwann cell invasion, not previously seen in EAE, was predominantly in the area of the root entry zone, and occasionally involved extensive areas of the dorsal or ventral horns. The extent of Schwann cell invasion, as well as the usual CNS-type remyelination, demonstrates the reparative capacity of the CNS. The recurrent clinical and morphologic changes in these long-term animals provides further evidence that this model of chronic EAE has many features reminiscent of multiple sclerosis. The underlying immunologic mechanisms responsible for the recurrent disease in these animals are unknown. The presence of plasma cells in the inflammatory exudates might suggest a role for B cells in these chronic animals. The possibility of an intermittent release of loculated adjuvant/antigen accounting for the recurrent disease was considered.

Chronic experimental allergic encephalomyelitis in strain 2 guinea pigs. Absence of resistance to nervous system changes and sex dependence of clinical disease.

Experimental autoimmune (allergic) encephalomyelitis (EAE) was induced in Strain 2 guinea pigs, a strain usually regarded as resistant to EAE. The development of disease in groups of juvenile male or female Strain 2/N guinea pigs was irregular with clinical EAE manifesting only in some groups of females. All animals examined morphologically (12 females and 9 males), between 3 and 18 months postinoculation, showed extensive changes in the central nervous system, although 12 of these had displayed no neurologic signs. This silent central nervous system disease, reminiscent of similar phenomena in man, indicates that Strain 2/N is fully competent immunologically at the level of the target organ.

Autoimmune encephalomyelitis and hemorrhagic retinal disease in neonatal, infant, juvenile, and adult monkeys.

Severe (24/24) and lethal (22/24) autoimmune encephalomyelitis was regularly induced in rhesus monkeys of all age groups from newborns to adults by a single injection of guinea pig spinal cord in complete Freund's adjuvant. Age dependency of the encephalomyelitis was manifested by a delayed onset and prolonged course in newborn monkeys. A hemorrhagic retinopathy usually accompanying the earliest CNS symptoms was observed in most of these monkeys. The most severe lesions were predominant in the cerebellum and brainstem of neonates, and in the cerebral hemispheres of older animals.

Congenital cataracts in strain 13 guinea pigs: an autosomal dominant human model.

A spontaneous nuclear cataract seen in strain 13 guinea pigs was inherited under circumstances compatible with it being due to an autosomal dominant gene. This animal model seems advantageous for studies in embryology, developmental neurology, and genetics.

Chronic relapsing experimental allergic encephalomyelitis. Correlation of circulating lymphocyte fluctuations with disease activity in suppressed and unsuppressed animals.

Groups of juvenile Strain 13 guinea pigs sensitized for chronic relapsing experimental allergic encephalomyelitis (EAE) with isogeneic central nervous system (CNS) tissue in complete Freund's adjuvant (CFA) were either left to develop late-onset chronic EAE (unsuppressed), or given a series of injections of bovine myelin basic protein (MBP) in incomplete Freund's adjuvant (IFA) to suppress the disease. All unsuppressed animals developed disease and all suppressed animals remained healthy over a 27-month period of study. some unsuppressed and suppressed animals were rechallenged with CNS tissue in CFA 12 or 26 months post-inoculation (PI). Unsuppressed animals all became sick 2-4 weeks after rechallenge, while rechallenged, suppressed animals were protected, indicating that the suppression was permanent. Pathologic findings in the CNS complemented the clinical changes. Circulating lymphocyte studies were performed on animals from all groups. Early (active, high-affinity rosetting) T cell levels in unsuppressed animals showed significant decreases during exacerbations (P less than 0.01) and normal values during remissions. After rechallenge, circulating early T cells decreased in unsuppressed animals with the development of signs. In suppressed animals, early T cells showed significant elevations during, and for a short time after, the period of suppressive injections, and normal values afterwards. These levels did not change significantly after rechallenge. Late (total, 24 hour rosetting) T cell and B cell values showed minor fluctuations only which did not correlate with disease activity. These results indicate that chronic relapsing EAE can be successfully suppressed with MBP in IFA, that this suppression is permanent and that the immunologic findings presented correlate well with the clinical and pathologic facets of the disease. the findings are presented in terms of their relevance to multiple sclerosis.

Experimental allergic encephalomyelitis--migration of early T cells from the circulation into the central nervous system.

Study of lymphocytes from the blood of guinea pigs with acute EAE induced by isologous spinal cord in adjuvant reconfirmed that in comparison to normals, the percentage of early (active or high affinity rosetting) T cells decreases dramatically and that these changes can be correlated with clinical signs. In addition, we have investigated matching samples of CNS infiltrating cells recovered by ultrasonication and have found that coinciding with the decrease in early T cells in the circulation, significantly higher levels (P less than 0.001) of these cells appear within the CNS compartment; It is concluded that the decrease of early T cells in the circulation is caused by their migration to the target organ, the CNS.

Chronic relapsing experimental autoimmune encephalomyelitis. treatment with combinations of myelin components promotes clinical and structural recovery.

Preliminary results are presented on the treatment of Strain 13 guinea pigs with chronic relapsing experimental autoimmune (allergic) encephalomyelitis (EAE) induced by a single sensitisation with whole spinal cord. Animals were treated at different stages of the disease with injection containing either myelin basic protein (MBP) alone in incomplete Freund's adjuvant (IFA), or MBP in combination with a lipid hapten of myelin, galactocerebroside (GC) in IFA. The rationale for this treatment stemmed from previous work which suggested that MBP was responsible for T cell sensitisation in EAE and that GC was important in producing demyelinating antibodies and that both myelin components were needed in the induction of disease. Although treatment with MBP alone caused some initial stabilisation of the disease process, subsequent relapses occurred in all animals. However, in animals given MBP and GC together, either early or late in the course of the disease, marked clinical improvement has been noted with little or no development of relapses over an observation period of more than one year post-treatment. In addition, evidence of extensive remyelination and oligodendroglial proliferation in CNS lesions has been found in MBP-GC-treated animals suggesting that this therapy might be beneficial for CNS repair and relevant to multiple sclerosis.

Dose-dependency of MBP-induced demyelination in the guinea pig.

The pathology of experimental allergic encephalomyelitis (EAE) induced by bovine myelin basic protein (MBP) has been examined in the guinea pig with a series of doses ranging from 37.5 micrograms to 600 micrograms. This was to investigate whether the previously demonstrated lack of demyelinative effect by MBP was dose-related. At all doses tested, MBP induced clinical disease. Inflammation was the major feature of lesions in all animals. However, no demyelination was seen when 75 micrograms MBP or less was given. At higher doses (150 micrograms upwards), MBP always induced intense inflammation but demyelination was encountered inconsistently. These observations support the contention that in addition to an immune response to MBP, other factors contribute to autoimmune demyelination.

Adoptive transfer of experimental allergic encephalomyelitis from immature guinea pig donors.

In immature Strain 13 guinea pigs sensitized to syngeneic spinal cord, a chronic allergic encephalomyelitis is elicited reminiscent of demyelinating diseases of man and which features relapses or progressive downhill course and extensive areas of demyelination in the central nervous system. However, juvenile recipients of syngeneic lymphocytes from similarly sensitized juveniles show only the acute form of experimental allergic encephalomyelitis. Neuropathologically, the CNS of affected animals displayed mild changes only and minimal demyelination. These observations indicate that the age-dependent differences seen between the acute disease of adults and the chronic disease of juveniles may be due to differences in availability of modulating or reparatory factors, rather than differences in the central nervous system organ or in the immune response itself.

Suppression of acute and chronic experimental allergic encephalomyelitis in Strain 13 guinea pigs. A clinical and pathological study.

Adult inbred Strain 13 guinea pigs develop an acute, fatal form of experimental allergic encephalomyelitis (EAE) about 2 weeks after a single injection of isologous spinal cord in complete Freund's adjuvant (CFA), but similarly injected juveniles develop a delayed, rarely fatal chronic form. Thirty-seven sensitised adult Strain 13 animals were separated into 2 groups. One group was permitted to develop acute EAE. The other group was injected intramuscularly with 1 mg of guinea pig or bovine myelin basic protein (MBP) in incomplete Freund's adjuvant (IFA) on day 2, 7 or 10 post-inoculation (PI) followed by 0.2 mg in IFA every third day for a total of 10 doses. Animals in the unsuppressed group succumbed to acute EAE 13-16 days post-sensitisation. No animal in the suppressed group died during this period. Animals treated with MBP beginning 2 days PI showed no clinical signs, but mild clinical manifestations occurred in animals suppressed from days 7 and 10 PI. These signs remitted by 21 days post-sensitisation. One suppressed animal (out of 21) died during the fourth week postsensitisation. The other 20 suppressed animals appeared clinically normal towards the end of the course of MBP injections and remained so for the 6 months of study. Morphological examination revealed that CNS lesions occurred in all animals. In animals suppressed with MBP beginning on day 2 PI, lesions consisted only of a few meningeal inflammatory cells. Animals given MBP beginning on day 7 or 10 PI and sampled 1-2 weeks later, had lesions which could not be distinguished from those occurring in the non-suppressed acute EAE group. In time, the suppressed animals developed lesions which were typical of chronic EAE with remyelination as a predominant feature. Preliminary experiments on the suppression of chronic EAE in 5 juvenile Strain 13 guinea pigs have revealed that 3 MBP-injected animals failed to develop clinical disease over a 28-week period of study although lesions typical of chronic EAE were present. Simultaneously, 2 non-suppressed juvenile animals developed clinical signs by 12 weeks. These were associated with both acute inflammation and demyelination superimposed upon regions of chronic demyelinative activity.

Zeta-crystallin, a novel lens protein from the guinea pig.

Lens proteins from the guinea pig (Cavia porcellus) were found to be similar to those of other mammals with the exception of the presence of a previously undescribed constituent comprising about 10% of the total soluble lens proteins. This oligomeric protein is composed of polypeptides with apparent molecular weight of 38,000 and elutes from gel exclusion chromatography columns in the beta H-crystallin fraction. Following purification by ion exchange chromatography an antibody was raised against the protein. Using that antibody and antibodies specific for other crystallins we could detect no cross-reactivity between the guinea pig protein and any other reported lens crystallin. This protein, which we have named zeta (zeta)-crystallin, is the first reported mammalian lens crystallin which is not part of the alpha- or beta-gamma families of crystallins. Unlike all other known mammalian crystallins, which have little or no alpha-helical structure, zeta-crystallin is estimated to be approximately 30-40% alpha-helix.

Autosomal dominant congenital nuclear cataracts in strain 13/N guinea pigs.

Bilateral cataracts observed in the eyes of a 13/N guinea pig and one of her two offspring led to studies to determine the nature of this cataract and its possible heritability. The cataract was determined to be of the nuclear type, was congenital, and apparently transmitted by a single autosomal dominant gene. The cataractous condition of the mother had no effect on the percentage of litters containing stillborns. The cataractous condition of the offspring had no effect on their viability in utero, i.e., there was no greater incidence of stillborns among cataractous than among non-cataractous offspring. The birthweights of the cataractous animals were lower, but not significantly, than those of their non-cataractous littermates; however, the survivability to weaning of the cataractous offspring was reduced significantly when compared to their non-cataractous siblings.

The unwanted pregnancy.

A questionnaire was submitted to the mothers of 200 consecutively delivered infants; 15% of mothers were unmarried. The results showed a high prevalence of unwanted pregnancy, most accounted for by well educated, married women having their first or second baby, and despite access to contraceptive agents. Most of the married women and over 50% of the unmarried who had not wanted to become pregnant wanted the baby after its birth.