Allergic Encephalomyelitis In Guinea Pigs Research Articles

Polymeric drugs as immunomodulatory vaccines against multiple sclerosis

AbstractCOP‐1, a synthetic basic random amino acid copolymer, is effective in suppression of experimental allergic encephalomyelitis in guinea pigs, rabbits, mice, rhesus monkeys and baboons, and of the exacerbating‐remitting type of multiple sclerosis in humans. COP‐1 is cross‐reactive at the monoclonal antibody level with the basic protein of the myelin sheath of the brain (BP), and the suppressive effect may be related to this immunological cross‐reaction. Indeed, competition for the major histocompatibility complex (MHC) class II antigen, between BP and COP‐1, may be one explanation for its beneficial effect in the disease. This polymeric drug, COP‐1, may, therefore, be considered also an immunomodulatory vaccine, and may serve as a prototype to vaccines against autoimmune diseases.

Abrogation of induced resistance to experimental allergic encephalomyelitis in guinea pigs by host-versus-graft reaction

Experimental allergic encephalomyelitis (EAE) effector cells known to exist in guinea pigs with myelin basic protein-incomplete Freund's adjuvant (MBP-IFA)-induced resistance to EAE could be activated in vivo by means of allogeneic confrontation (local host-versus-graft reaction (HVGR)). The abrogation of the resistance was observed only when HVGR was combined with encephalitogenic challenge (myelin basic protein-complete Freund's adjuvant (MBP-CFA)) in a certain order and at certain time intervals. The injection of 20 × 10 7 γ-irradiated allogeneic lymphoid cells 7 or 4 days prior to or along with MBP-CFA treatment resulted in development of EAE with delayed onset and protracted course. The effect was most prominent when HVGR was induced on day −4. Histological examination revealed inflammatory lymphoid cell infiltrations in spinal cord. Serum level of total and anaphylactic anti-MBP antibodies correlated with the clinical picture.

Experimental allergic encephalomyelitis in guinea pig: variability of response to intradermal emulsion injection.

Different forms of experimental allergic encephalomyelitis were obtained in 4 groups of guinea pigs: 7 adult Hartley guinea pigs (Group I), 12 adults of the same strain (Group II), 6 juvenile strain 2 guinea pigs (Group III) and 6 juvenile strain 13 animals (Group IV), by the injection of emulsions. Groups I and II received emulsions containing 250 mg and 500 mg respectively of fresh isologous spinal cord tissue, complete Freund adjuvant (CFA) and saline solution while Groups III and IV received an emulsion containing 120 mg of isologous spinal cord, CFA, saline solution and 15 mg of Mycobacterium tuberculosis. The increased antigen load induced a disease with delayed onset and prolonged progressive course (C-P-EAE) in Groups I and II, although 8 animals showed no symptoms of illness. The findings in C-P-EAE were large demyelinated plaques, perivenous fibrosis and large areas of infiltration. Demyelinated areas occurred within the spinal cord white matter only in two asymptomatic animals. C-P-EAE was obtained in 4 of the Strain 2 animals. In conclusion, the increased antigen load induced a range of lesions in Hartley guinea pigs, although not all animals were affected. C-P-EAE was induced also in strains of guinea pig other than the Heartley strain. These different reactions may have been the outcome of partial or complete inactivation of the cell-mediated response to the inoculated antigens.

Effect of thymostimulin in models of cell-mediated and humoral autoreactivity and on T-dependent suppression

To explore the therapeutic potential of the thymic hormone preparation thymostimulin (TS) in animal models of cell-mediated and humoral autoimmunity, its effects were investigated on experimental allergic encephalomyelitis in guinea pigs and on anti-erythrocytic autoantibody production in C57B1/6 mice. In both autoimmunity models, TS produced significant therapeutic effects in terms of proportion of diseased animals, disease severity and/or disease duration; however, both the TS dose and the time of treatment start relative to the disease-inducing stimulus critically influenced results. TS effects on the generation and expression of suppressive activity induced in C57B1/6 mice by a supraoptimal immunization with 10 10 SRBC were also examined. TS given after 10 10 SRBC did not influence the level of suppression, and the activity of effectors of suppression was not modified by this agent. Conversely, using a treatment protocol analogous to that effective in reducing murine autoantibody production, TS administration prior to 10 10 SRBC was associated with a significant increase in the subsequent generation of T-dependent, antigen-specific suppressive activity. These findings suggest that effects of TS on the development of suppressor cells may be involved in the activity of this agent in animal models of autoaggression.

Allergic encephalomyelitis in guinea pigs after intradermal and subcutaneous injection of fragment 114?122 of human basic myelin protein

In guinea pigs EAE can be induced [I, 3, 9-15] by injection of a fragment of basic myelin protein containing tryptophan. The presence and position of tryptophan in the amino acid chain are:decisive for induction of EAR. The important role of glutathione and lysine also is emphasized, although the latter can be replaced by arginine [15]. The view has been expressed [ii] that other amino acid residues of synthetic peptides play an exclusive role, for replacement of any of them leads to loss of the encephalitogenic properties.

Suppression of experimental allergic encephalomyelitis in guinea pigs by spergualin and 15-deoxyspergualin.

Suppression of experimental allergic encephalomyelitis in guinea pigs by spergualin and 15-deoxyspergualin.

Evolutionary Divergence in the Structure of Myelin Basic Protein: Comparison of Chondrichthye Basic Proteins with Those from Higher Vertebrates

A basic protein has been purified from the CNS myelin of the gummy shark (Mustelus antarticus). Electroblotting was used to examine the capacity of rabbit antisera raised against this electrophoretically pure protein to recognize myelin basic protein from higher vertebrates. The antisera bound to two shark proteins including the original polypeptide antigen and to chicken, bovine, and human myelin basic proteins. Thus, the shark protein appeared to possess antigenic determinants that have been retained through evolutionary divergence of these proteins. Whereas bovine basic protein caused experimental allergic encephalomyelitis in guinea pigs, animals that received injections of the shark protein showed neither clinical nor histological signs of this disease. However, tests for delayed-type hypersensitivity and for Arthus reaction following injection with the shark protein revealed a T-cell-mediated response to this antigen and substantial cross-reactivity with higher vertebrate basic proteins. Analysis of the amino acid composition of the shark protein, and comparison of its tryptic peptide map with that of the bovine protein, revealed substantial changes in the amino acid sequence. Although the shark protein has some antigenic determinants in common with the proteins from higher vertebrates, it appears that much of the structure differs.

Chronic experimental allergic encephalomyelitis in guinea pigs induced by proteolipid protein

A chronic experimental allergic encephalomyelitis (EAE) was produced in Hartley guinea pigs with bovine white matter proteolipid protein (PLP), in which the levels of myelin basic protein (MBP) and galactocerebroside (GC) were less than 0.014% and 0.13%, respectively, by our method of purification. Cells of an MBP-specific T-cell line did not proliferate in the presence of 100 μg of PLP and antigen-presenting cells. Eleven animals were sensitized with 250 μg of PLP in Freund's complete adjuvant. Three guinea pigs developed paraplegia about 45 days after sensitization. Histological examination of the three animals revealed marked demyelinating lesions in the spinal cord, particularly in the dorsal columns and subpial regions of the lateral and anterior columns. Another guinea pig without apparent clinical symptoms had demyelinating plaques in the dorsal columns of the spinal cord and periventricular white matter of the brain. Antibodies to PLP were highly elevated in the animals with demyelinating plaques but antibodies to MBP and GC were not elevated in the serum samples. Skin response to PLP was positive in sensitized animals, but was not related to the clinical state. Since none of four strain 13 guinea pigs developed chronic EAE, it seems to be strain specific. These results suggest that PLP is encephalitogenic and produces demyelination in the central nervous system without contamination by MBP or GC in Hartley guinea pigs.

Thymectomy and chronic relapsing experimental allergic encephalomyelitis in guinea pigs.

Chronic relapsing experimental allergic encephalomyelitis (EAE) was induced in young Dunkin Hartley guinea pigs by a single sensitization with guinea pig spinal cord homogenate. The effect of either newborn thymectomy or young adult thymectomy on the clinical course of chronic and relapsing EAE was studied and evaluated statistically by Student's t test. All the animals that underwent thymectomy showed a significant delay in the onset of the disease compared with control groups. In addition, in the young adult guinea pigs in which thymectomy was done, the incidence of clinical disease was decreased. No substantial differences, however, were observed in the severity of the disease and number of remissions or relapses between guinea pigs in which thymectomy was done and in which clinical symptoms developed and controls.

Protective action of antioxidants on development of experimental allergic encephalomyelitis in guinea pigs

Protective action of antioxidants on development of experimental allergic encephalomyelitis in guinea pigs

Chronic experimental allergic encephalomyelitis in guinea pigs: Immunologic studies on the two major myelin proteins

Humoral and cell-mediated immunity to the two major myelin proteins, basic protein (MBP) and proteolipid protein, have been investigated during the course of chronic experimental allergic encephalomyelitis (EAE) induced in guinea pigs with whole neural tissue. A positive proliferative response to MBP was observed at 10 and 13 days postimmunization, but was not detectable at subsequent stages. Serum antibodies to MBP first appeared during the chronic stages of the disease. A proliferative response to proteolipid apoprotein was not detected during any stage of chronic EAE. Guinea pigs immunized with proteolipid alone, however, showed a proliferative response. The data suggest that MBP is one of the antigens involved in the induction of the acute episode of chronic EAE, but its role in later stages and that of proteolipid protein remain unknown.

Prevention of experimental allergic encephalomyelitis by ganglioside G M4

Guinea pigs inoculated with a mixture of myelin basic protein and the myelin-specific ganglioside, sialosylgalactosylceramide (G M4), do not develop the signs or neuropathology of experimental allergic encephalomyelitis. The results indicate that G M4 cloaks the basic protein molecule so that it is no longer immunopathogenic in these animals. The interaction of basic protein with G M4, previously shown in vitro, appears to be relevant to the pathogenesis of experimental allergic encephalomyelitis in guinea pigs.

Experimental allergic encephalomyelitis in guinea pigs: Influence of thymosin fraction V on the disease

Experimental allergic encephalomyelitis (EAE) was induced in strain 13 guinea pigs by sensitization with 10 micrograms of myelin basic protein (BP) in complete Freund's adjuvant (CFA). These animals were treated with saline or with thymosin factor V in 3 different doses in 3 separate experiments. Thymosin had no suppressive effect on the incidence and severity of EAE.

Further studies on bacterial lipopolysaccharide-induced protection against experimental allergic encephalomyelitis in guinea pigs: Effects of chemical modifications

Bacterial lipopolysaccharide (LPS)-induced protection against experimental allergic encephalomyelitis (EAE) was studied in guinea pigs using chemically modified derivatives. Hydroxylaminolysis or alkaline hydrolysis of LPS, by which ester-linked fatty acids are removed from LPS, resulted in total loss of its mitogenic activity for B lymphocytes, and EAE-suppressive activity was simultaneously reduced. Similar diminished activity was observed in delayed-type skin reactions to myelin basic protein (BP) and anti-BP antibody production detected by passive hemagglutination and enzyme-linked immunosorbent assay (ELISA). These results indicate that the active site of LPS in suppressing EAE is in the lipid portion and that there exists a good correlation between the capacity of LPS to suppress EAE and its mitogenic activity.

Demonstration of serum IgG antibodies against myelin during the course of relapsing experimental allergic encephalomyelitis in guinea pigs

Chronic relapsing allergic encephalomyelitis (r-EAE) was induced in a local strain of guinea pigs. By the use of isoelectric focusing (IF) followed by antigen immunofixation and autoradiography, antibodies directed against central nervous system (CNS) myelin were detected in 21 of 23 sera sampled during the course of r-EAE. Previous absorption of the sera with CNS myelin reduced or abolished antibody activity on autoradiograms. One r-EAE guinea pig developed definite oligoclonal IgG bands in serum while in 7 r-EAE animals faint oligoclonal IgG bands were present. The mobility of oligoclonal IgG bands differed from the mobility of antimyelin antibody bands on autoradiograms. The significance of these findings has not been definitely elucidated but the antimyelin antibodies may possibly be involved in the pathogenesis of the disease while oligoclonal IgG bands may represent an epiphenomenon not pathogenetically related to r-EAE.

Suppression of acute experimental allergic encephalomyelitis in guinea pigs by prior transfer of suboptimal numbers of EAE-effector cells: induction of chronic EAE in whole tissue-sensitized guinea pigs.

Experimental allergic encephalomyelitis (EAE) in strain 13 guinea pigs is an acute monophasic disease induced with myelin basic protein (BP) in complete Freund's adjuvant (CFA). We report here that EAE can be effectively suppressed by transfer of a limited number of EAE-effector cells. Lymph node cells (LNC) from donors sensitized with BP/CFA are activated in vitro by incubation with BP and strain 2 peritoneal exudate cells (PEC). 5 X 10(7) of these cells are capable of inducing lethal EAE in recipients; 0.5 to 1 X 10(7) cells (a suboptimal transfer) effectively suppress EAE induction in animals subsequently sensitized with BP/CFA. Suppressed recipients develop an early mild disease from which they recover completely. In contrast, suboptimal transfer of BP-sensitized cells does not protect recipients against sensitization with whole central nervous system (CNS) tissue/CFA. About 50% of these recipients succumb to acute EAE; the survivors develop chronic EAE of varying intensity: a mild chronic form with recovery, a severe chronic form that is eventually fatal, and a chronic relapsing form that results in permanent neurologic deficit. Preliminary attempts at detecting suppressor cells in the suppressed animals were unsuccessful. Instead, PEC of all recipients of suboptimal transfers were capable of transferring EAE to naive animals.

Lipophilin-induced experimental allergic encephalomyelitis in guinea pigs.

Clinical signs of EAE were infrequently observed (1/20) in adult Hartley guinea pigs challenged with isolated human myelin lipophilin in complete Freund's adjuvant. However, CNS vasculitis and parenchymal infiltration by inflammatory cells were found in 10 of 20 inoculated animals. Localized, nonconfluent, small demyelinated lesions were detected in the brain and spinal cord of 5/20 Hartley guinea pigs during an observation period of 120 days. The frequency of both inflammatory and demyelinated lesions in Hartley animals appeared to be dose-dependent, but extensive demyelinated lesions were not induced. Persistent residual inoculation mixture at the site of injection was found in animals showing CNS inflammatory and/or demyelinated lesions. In contrast to the Hartley strain, young strain 13 guinea pigs were clinically and pathologically unresponsive to challenge with lipophilin and mycobacteria in water-in-oil emulsion.

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.

Prevention of experimental allergic encephalomyelitis in guinea pigs by the use of magnetophores

Subcutaneous application of magnetophores with a field intensity of 210 ersted prevented the development of experimental allergic encephalomyelitis (EAE) in guinea-pigs. The magnetophores appeared efficacious both at the beginning of the induction period and in the second half of the latent period, i.e. within the first two weeks after injection of encephalitogenic suspension. Application of magnetophores after the appearance of the neurological signs of EAE was ineffective. Magnetophores did not affect cellular or humoral response in animals. It may be assumed that the effect of magnetophores is related to the increased resistance of nerve cells to the immunopathological action of the immune response factors, a topic for further studies.

Optimum conditions for inducing chronic relapsing experimental allergic encephalomyelitis in guinea pigs

The aim of this study was to investigate some of the conditions required for the consistent production of chronic relapsing experimental allergic encephalomyelitis (EAE). The concentration of mycobacterium/antigen was found to be a critical factor in producing relapses. Of the 3 antigens used to produce EAE — myelin, myelin basic protein (MBP) and whole spinal cord — only the latter produced a relapsing-remitting EAE. F1 crosses between female Hartley and male Strain 13 guinea pigs displayed an identical relapsing pattern to that of juvenile Strain 13 animals. The frequency of relapses was increased in Hartley guinea pigs when injected over the nuchal region.