Modulation of ex Vivo Cytokine Production by Splenocytes Using in Vitro Combined Therapeutics in Murine Retroviral Model

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Abstract
Altered levels of Type 1 and Type 2 cytokines are important in retrovirus-induced immunosuppression. The combination of immunostimulatory agents with antiviral drugs alters the course of murine retroviral infections. Previously, it was demonstrated that in vitro treatment of noninfected splenocytes and in vivo treatment of Friend leukemia virus (FLV)-infected mice with the combination of azidothymidine (AZT) and methionine enkephalin (MENK) significantly increases Type 1 cytokine levels and decreases Type 2 cytokines compared with treatment with only AZT. In order to study the effect of the time of initiation of immunomodulation on the course of retroviral infections, we examined the kinetics of cytokine production by isolated splenocytes from infected mice. BALB/c mice were infected with FLV, and spleen cells were removed at specified times postinfection (days 1, 3, 7, 10, and 14). Interleukin (IL)-2, interferon (IFN-gamma, IL-4, and IL-10 production by unstimulated or ConA-stimulated splenocytes treated in vitro with AZT, MENK, or AZT + MENK was determined after 48 h. The capacity of the isolated splenocytes to produce the Type 1 cytokines IL-2 and IFN-gamma in response to stimulation with ConA and combination therapy decreased over the course of infection. These results suggest that MENK treatment initiated later in the course of infection is unable to modulate the cytokine profile and would likely be ineffective in altering the course of FLV induced-disease. The results indicate the necessity to initiate antiretroviral therapy early in infection. Such information may be applicable in designing future regimens for HIV-1 infections in humans.

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