Effects of irradiation on development of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease in genetically resistant mice.

Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a model for multiple sclerosis, is a chronic T cell-mediated disease. Development of clinical symptoms in susceptible mouse strains generally correlates with TMEV-specific delayed-type hypersensitivity (DTH) responses. These responses, minimal or absent in resistant mouse strains, have been proposed as the pathogenic basis for the central nervous system inflammation and demyelination characterizing the disease. We demonstrate here that normally resistant (C57BL/6 x DBA/2)F1 hybrid mice develop clinical symptoms and DTH responses against TMEV after low doses of gamma-irradiation. Parental C57BL/6 animals remain resistant after similar pretreatment. Thus low-dose irradiation elicits a "latent" susceptibility to TMEV-IDD in some, but not all, resistant mice. Adoptively transferred spleen cells from syngeneic, unirradiated donors reconfer resistance on irradiated, infected B6D2F1 hybrids and reduce DTH responsiveness against TMEV, suggesting a protective role for a radiation-sensitive splenic population(s). The closely related C57BL/6 and C57BL/10 strains differ with respect to intrinsic and latent susceptibility.

Induction of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease in genetically resistant mice.

Theiler's murine encephalomyelitis virus-induced demyelinating disease, a murine model for multiple sclerosis, is the result of persistent infection which leads to a T cell-mediated immunopathology. Susceptible strains develop virus-specific DTH responses while resistant strains do not, and this response has been proposed as the basis for inflammation and demyelination. (C57BL/6 x DBA/2)F1 hybrid animals, normally resistant to TMEV-induced demyelinating disease, become susceptible when treated in vivo prior to infection with low dose cyclophosphamide. Comparable pretreatment of other resistant animals, C57BL/6 and CB6 (BALB/c x C57BL/6) F1 hybrids, does not render them susceptible (despite the H-2 identity of CB6F1 and B6D2F1 hybrids). Thus the "latent" susceptibility in B6D2F1 hybrids must be attributed to non-H-2 genes from the susceptible D2 parent. Resistance can be restored to CY-treated B6D2F1 animals by the adoptive transfer of splenic cells (including T cell enriched populations) from non-CY-treated donors. Resistance to TMEV-IDD in these animals, therefore, may involve active inhibition of a "latent" disease susceptibility.

Analysis of contractile properties of muscles from rats immunized with purified acetylcholine receptor.

Experimental autoimmune myasthenia gravis (EAMG) was induced in rats by injection of purified acetylcholine receptor (AChR). In addition to detecting elevated serum titers of anti-AChR antibodies, we observed decreased twitch-tension at submaximal stimulation voltages and increased curare sensitivity by muscles obtained from immunized rats when compared to muscles obtained from nonimmune control rats. Furthermore, antibody-induced neuromuscular impairment was expressed to differing extents dependent on whether the diaphragm, soleus, or extensor digitorum longus muscle was examined. Thus, we conclude that potential antibody perturbation of AChR function will depend not only on the nature of the antibody, but also on the complex structure-function relationships that exist in individual muscles. This may partially explain the variable impairment of different muscle groups in patients with myasthenia.

Selective in vitro inhibition of an antibody response to purified acetylcholine receptor by using antigen-ricin A chain immunotoxin.

Purified acetylcholine receptor (AChR) covalently coupled to the catalytically toxic A chain of ricin has been used to selectively eliminate rat lymph node cells involved in in vitro anti-AChR antibody responses. The resulting inhibition was specific in view of the lack of such inhibition of anti-Keyhole limpet hemocyanin antibody responses. Furthermore, when fractionated B cell or T cell populations were treated with AChR-A chain, both populations were found to be sensitive to the specific cytotoxicity. However, T cell cytotoxicity required higher concentrations of the immunotoxin. Furthermore, when AChR-immune lymphocytes were treated with AChR-A chain in vitro, they became unable to mediate secondary adoptive transfer responses in vivo. The abrogation of the anti-AChR adoptive response correlated with the lack of muscle weakness characteristic of experimental autoimmune myasthenia gravis. Thus, it is possible, in principle, to eliminate clones of antigen-reactive lymphocytes with antigen-ricin A chain immunotoxins. This lets open the possibility of using such agents in immunotherapeutic approaches to autoimmune disease.