Effect of an Immunosuppressive Agent, Cyclophosphamide, on Chronic Lactic Dehydrogenase Virus Viremia of Mice

Abstract

The immunosuppressive drug cyclophosphamide was used to study the effect of immunosuppression on the degree of chronic lactic dehydrogenase virus (LDV) viremia in mice. Weekly injections of cyclophosphamide caused an increase of LDV viremia of ca. 2.5 logio 50% infectious doses per ml as compared to the viremia in the nontreated mice. This increase occurred at about the same time that the formation of antibody with a neutralization index of 2 to 3 logio per ml could be demonstrated in the serum of control mice, whereas both neutralizing antibody and sensitized (antibody-bound but infectious) virus were absent in the immunosuppressed mice. In one experiment, antibody did not reappear 28 weeks after a 24-week course of cyclophosphamide treatment. In another experiment in which the drug was given for 12 weeks, antibody appeared again in the treated mice 14 weeks after cessation of drug administration and was accompanied by a decrease in viremia. The normal decrease of early viremia during the first 2 weeks of infection in immunosuppressed mice suggests that the immune response is not the cause of this initial decrease in LDV viremia but that interferon and perhaps other nonimmune factors may be involved here. The increased viremia in the immunosuppressed mice during the later stages of infection indicates that the immune response plays an important role in partial control of chronic viremia. The quantitative correlation between the decrease in neutralizing antibody and the increase in viremia in immunosuppressed mice suggests that antibody rather than cellular immunity may be the more important immune factor in the control of chronic viremia.Mice infected with lactic dehydrogenase virus (LDV; reference 17) present a useful model for a study of the role of immune and nonimmune factors in controlling viremia in a chronic viral infection. The viremia in LDV-infected mice lasts for the lifetime of the mice without any overt pathology (14). Serum interferon can be detected during the first few days of infection (3, 7, 10), and neutralizing antibody can be detected after a few weeks (15, 19); however, the relative roles of interferon and antibody, as well as that of cellular immunity, in determining the level of viremia in this infection remain unclear.In an attempt to clarify the importance of immune processes in this chronic infection, we have studied the effect of a potent immunosuppressive agent, cyclophosphamide, on viremia and on the formation of neutralizing antibody and sensitized virus in LDV-infected mice. MATERIALS AND METHODSAnimals. Random bred Swiss albino (15 to 20 g, female) mice were supplied by the animal production section of the National Institutes of Health.Virus. The strain of LDV used was isolated from a naturally infected Ehrlich ascites carcinoma carried in CDF, mice (7). Stock LDV was obtained from LDVfree Ehrlich ascites tumor-bearing mice, which were infected intraperitoneally with 107°50.% infectious doses (ID50) per mouse 6 to 8 days after tumor implantation. Twenty-four hours after infection...

Effect of Immunosuppression on Chronic LCM Virus Infection of Mice

“…Effects of cyclophosphamide on various chronic viral infections have been investigated with different results. In chronic LDV infection of mice, Dubey et al (16) observed increased virus titers in plasma after 2 mo of weekly cyclophosphamide administration, although the mice underwent no obvious ill effects. Cheema et al (17) noted a log increase in virus titer of mink infected with Aleutian disease and treated with cyclophosphamide; glomerular immune complex deposition which occurs in unmanipulated mink infected with Aleutian disease virus was prevented.…”

Role of Interferon in Murine Lactic Dehydrogenase Virus Infection, In Vivo and In Vitro

“…1) to participate in the early decline of' virus titers to the lower levels which persist thereafter. It is not known how the virus level is maintained below its peak between the 72nd hour, when circulating IF is no longer demonstrable, and the 2nd week, when the neutralizing antibody response further reduces the virus level (7). It is possible that the LDV-producing macrophages in the chronically infected mouse begin to limit the amount of' LDV produced, since LDV superinf'ection of' such macrophages in vitro resulted in decreased levels of' LDV multiplication as compared with macrophages from uninfected mice (Table 4).…”

“…The interferon was induced by NDV in C243 cells, a cloned mouse cell line (18). The interferon was harvested after 24 h, treated at pH 2 for 5 days, and then readjusted to pH 7 Macrophages. Unstimulated m were obtained from female Swis injecting, after decapitation, 3 to medium i.p., massaging gently, fluid through a ventral incision v pette.…”

Effect of a potent interferon inducer on acute and chronic lactic dehydrogenase virus viremia

“…A few weeks after infection, neutralizing antibody (10,16,24) and infectious antigen antibody complexes (10,16) can be detected in the plasma. These complexes are deposited in the kidneys and a mild glomerulonephritis can be detected (19,21).…”