CD4+ T-Lymphocytes prevent reactivation of toxoplasmic encephalitis (TE) in the SCID mouse

Abstract

TE is common life-threatening opportunistic infection in patients with AIDS. We have recently developed a model of TE reactivation using the SCID mouse (Clin Res 1992:40;I75A). The objective of the current study was to use this model to determine the mechanisms of resistance to reactivation of TE. Immune Balb/c spleen cells were treated with monoclonal antibodies (MAb) and complement in vitro to deplete specific lymphocyte subsets prior to transfer lo SCID mice chronically infected with T.gondii. Mice then received MAb in vivo to maintain lymphocyte subset depletion. Cells depleted of both CD4+ and CD8+ cells resulted in a significant increase in mortality over controls (p = 001). Severe necrotising encephalitis associated with many T.gondii organisms were seen in CD4+/CD8+ depleted mice whereas control animals only had mild meningeal and perivascular inflammation. CD4+ or CD8+ depleted animals did not die, however whereas CD4+ depleted animals developed necrotic brain lesions associated with T.gondii., CD8+ depleted micc only developed mild meningeal and perivascular inflammation which were similar to lesions seen in controls. Depletion of CD4+ cells resulted in markedly reduced serum levels of interferon-γ (IFN-γ) and interleukin-6 (IL-6) as well as markedly impaired production of IFN-γ, IL-6, IL-4 and IL-10 (by ELISA) in splenic cultures stimulated with concanavalin A or toxoplasma lysale antigen. We conclude that in this model of TE: (I) Resistance from reactivation of TE is mediated by lymphocytes. (2) CD4+ cells appear to be more important than CD8+ cells in mediating such resistance. (3) Impairment of cytokine production due to CD4 depletion appears to play a role in reactivation of TE. (4) These results should assist in our understanding the Immunopathogenesis of TE in AIDS patients. TE is common life-threatening opportunistic infection in patients with AIDS. We have recently developed a model of TE reactivation using the SCID mouse (Clin Res 1992:40;I75A). The objective of the current study was to use this model to determine the mechanisms of resistance to reactivation of TE. Immune Balb/c spleen cells were treated with monoclonal antibodies (MAb) and complement in vitro to deplete specific lymphocyte subsets prior to transfer lo SCID mice chronically infected with T.gondii. Mice then received MAb in vivo to maintain lymphocyte subset depletion. Cells depleted of both CD4+ and CD8+ cells resulted in a significant increase in mortality over controls (p = 001). Severe necrotising encephalitis associated with many T.gondii organisms were seen in CD4+/CD8+ depleted mice whereas control animals only had mild meningeal and perivascular inflammation. CD4+ or CD8+ depleted animals did not die, however whereas CD4+ depleted animals developed necrotic brain lesions associated with T.gondii., CD8+ depleted micc only developed mild meningeal and perivascular inflammation which were similar to lesions seen in controls. Depletion of CD4+ cells resulted in markedly reduced serum levels of interferon-γ (IFN-γ) and interleukin-6 (IL-6) as well as markedly impaired production of IFN-γ, IL-6, IL-4 and IL-10 (by ELISA) in splenic cultures stimulated with concanavalin A or toxoplasma lysale antigen. We conclude that in this model of TE: (I) Resistance from reactivation of TE is mediated by lymphocytes. (2) CD4+ cells appear to be more important than CD8+ cells in mediating such resistance. (3) Impairment of cytokine production due to CD4 depletion appears to play a role in reactivation of TE. (4) These results should assist in our understanding the Immunopathogenesis of TE in AIDS patients.