The etiological agent of genetically restricted, age-dependent poioencephalomyelitis of mice (the ADPE agent) and several isolates of lactate dehydrogenaseelevating virus (LDV) were compared by biological, physical-chemical, and antigenic criteria. The data indicate that the ADPE agent is a strain of LDV. Like LDV, the ADPE agent induced a selective elevation of plasma enzymes and splenomegaly in mice. The enzyme-elevating activity and the paralytogenic activity of the ADPE agent preparations were shown to belong to the same virus. The ADPE agent demonstrated LDV-like replication kinetics in vivo and in vitro. Moreover, the ADPE agent required primary mouse macrophages for in vitro replication, as does LDV. In turn, the LDV isolates induced a paralytic disease with ADPE-like lesions in the spinal cords of immunosuppressed C58 mice. However, the LDV isolates showed a stronger dependence on strain and age of mouse for the induction of paralysis than did the ADPE agent. The LDV isolates and the ADPE agent exhibited indistinguishable morphologies, buoyant densities, structural protein patterns, and virion ribonucleic acid sedimentation rates. Furthermore, they displayed strong antigenic cross-reactivity, as determined by cross-protection in vivo and by radioimmunoassay.MATERLkIS AND METHODS Mice. C58/Wm mice (obtained from W. H. Murphy, The University of Michigan, Ann Arbor, Mich.) and AKR.M/nSn mice (obtained from the Jackson Laboratory, Bar Harbor, Maine) were maintained for Merck & Co. by Buckshire Corp., Perkasie, Pa. Swiss Albino mice were purchased from Lab Supply, Indianapolis, Ind. AKR/J, C3H/HeJ, CBA/J, and SJL/J mice were purchased from the Jackson Laboratory.
The etiology of immune polioencephalomyelitis (IPE) and the mechanisms of resistance to IPE induction were investigated in C58 mice. IPE was found to be induced by a lipid-solvent-sensitive, filterable replicating agent present in line Ib leukemic cell suspensions. IPE was serially transmitted in immunosuppressed mice with filtered extracts of spleens from diseased animals. The IPE-inducing activity of Ib cell extracts was abolished by chloroform or deoxycholate. Gel filtration of Ib cell extracts showed that the IPE agent has a molecular weight of at least 107. Electron microscopy of the active fractions from columns and of spinal cord extracts from mice with IPE revealed a virus-like particle, 40 nm in diameter, which is probably the IPE agent. Administration of cyclophosphamide at various times after challenge increased the incidence of IPE in mice, suggesting that IPE is not autoimmune mediated. Immunosuppression resulted in maintenance of high levels of IPE agent in the central nervous system tissue, while immunization resulted in low levels. Moreover, immunized mice produced neutralizing antibodies. These data suggest that antibodies help restrict the amount of IPE agent in the nervous tissue, and that this restriction is required for resistance to IPE induction in C58 mice.
Susceptibility to induction of immune polioencephalomyelitis (IPE) was found to be controlled by a gene that is closely linked to the H-2 complex. Whereas mice of the AKR (H-2k) strain were susceptible to IPE induction, H-2-congenic mice, AKR.H-2b (H-2b from C57BL/6) and AKR.M (H-2m), were resistant. However, susceptibility to IPE may be under additional control by a gene(s) outside of the H-2 region, since both C57BL/6 (H-2b) mice and congenic B6.H-2k mice (H-2k from AKR) were resistant to IPE induction. F1 hybrid mice derived from AKR (susceptible) and DBA/2 (resistant) mice were susceptible to IPE induction, indicating that susceptibility is dominant in at least one gene, but susceptibility developed at a later age in the hybrid mice than in AKR mice. B6.PL-Ly-2a Ly-3a/Cy, C57BR, C57L, PL, and RF strain mice were resistant to ipe induction. Thus, of the 12 inbred strains tested so far, only two (C58 and AKR) are susceptible to IPE.
We performed experiments with mice to determine the nature of the immune response(s) that prevents primary infections of the skin and the trigeminal ganglia with herpes simplex virus. Immunization with infectious herpes simplex virus, inactivated virus, or material enriched for viral glycoproteins protected hairless mice against primary facial and ganglionic infections. Live and inactivated vimses induced neutraliing antibodies, whereas glycoprotein material did not. Instead, glycoprotein material induced antibodies that were largely directed against two glycopolypeptides with molecular weights of 120,000 to 130,000. Hairless mice immunized with glycoprotein material responded faster than control mice in the synthesis of neutraliing antibodies after challenge with infectious virus. Congenital athymic BALB/c (nu/nu) mice were protected against primary facial infections after immunization with glycoprotein material, but glycoprotein-specific antibodies were not induced.
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