Questionable role of mononuclear phagocytes in the elimination of lymphocytic choriomeningitis virus from spleens of acutely infected mice.
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Biomedical subjects
Publications and source records attributed to D Moskophidis.
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Adult mice were infected by i.v. inoculation with 10(3) mouse infectious doses of lymphocytic choriomeningitis virus (LCM virus). Despite widespread replication of the agent, overt illness did not develop; histopathologic alterations were moderate. High virus concentrations were attained in the spleen, which was chosen for further study. Cytotoxic spleen T cell responses were found to vary among inbred mouse strains, and as a rule, these were correlated with other virus-specific cell-mediated immune phenomena. However, high- and low-responder mice eliminated the virus equally fast and already at times when spleen cytotoxic T lymphocytes were just beginning to appear (and before delayed-type hypersensitivity could be demonstrated). Adoptive transfer experiments showed that very few immune T lymphocytes were capable of reducing virus replication in the recipients' spleens and, furthermore, that protection was rapidly induced; when low numbers of cells were transferred, the effect was apparent 8 hr later, and with higher numbers diminished virus replication was evident after an interval as short as 6 hr. In fact, the data suggest that virus was actually inactivated. In spite of this marked efficiency, morphologic alterations in spleens of adoptively immunized mice were absent. Attempts to reveal expansion of immune cells in the recipients have failed, and the observation that adoptive transfer was as efficient in nude mice as in their furred counterparts makes it unlikely that the recipients' T lymphocytes participated to any extent. The low number of T lymphocytes causing reduction of virus, the short interval after which the effect became measurable, and the lack of histopathologic alterations has led to a working hypothesis in which it is assumed that immunologically activated T lymphocytes secrete lymphokines that directly interfere with virus replication in neighboring cells.
The solid-phase immunoenzymatic technique for the enumeration of single rat cells producing antibodies against ovalbumin has been adapted to mouse cells producing antibodies against lymphocytic choriomeningitis (LCM) virus. After intravenous (i.v.) infection with 10(3) infectious units, IgM- and IgG-producing cells appeared on days 4 and 5, respectively. They rose to high numbers on days 7, 8, and 9 and were still detectable on day 38. After a second i.v. inoculation of 10(7) infectious units, antibody-producing cells (APC), most of which made IgG, appeared faster and reached much higher numbers. Mutatis mutandis, very similar results were obtained with mice inoculated with vesicular stomatitis virus. Antibodies were specific as to virus, but probably corresponded to more than one viral antigen. Relatively low numbers of APC were also detected in the spleens of NMRI strain carrier mice, which develop severe immune complex disease in later life, but not in spleens of persistently infected young mice of strains that remain free of late immune complex disease, namely CBA/J, C3H/HeJ, and gray house mice; APC were detected in spleens of aging CBA/J but not gray house mice.
By use of an accurate procedure for the measurement of relative numbers of murine cytotoxic T lymphocytes (CTL) marked differences of lymphocytic choriomeningitis virus-specific CTL in spleens were found among mouse strains that ranged from low over intermediate and high to very high, suggesting a gradient of responses rather than distinct classes. Differences were also found between mice sharing the major histocompatibility complex.