RELATIONSHIP OF CYTOKINES AND CYTOKINE SIGNALING TO IMMUNODEFICIENCY DISORDERS IN THE MOUSE

The contributions of cytokines to the development and progression of d isease in a mouse model of retrovirus-induced immunodeficiency (MAIDS) are controversial. Some studies have indicated an etiologic role for type 2 cytokines, while others have emphasized the importance of type 1 cytokines. We have used mice deficient in expression of IL-4, IL-10, IL-4 and IL-10, IFN-gamma, or ICSBP - a transcriptional protein invol ved in IFN signaling - to examine their contributions to this disorder . Our results demonstrate that expression of type 2 cytokines is an ep iphenomenon of infection and that IFN-gamma is a driving force in dise ase progression. In addition, exogenously administered IL-12 prevents many manifestations of disease while blocking retrovirus expression. I nterruption of the IFN signaling pathways in ICSBP-/- mice blocks indu ction of MAIDS. Predictably, ICSBP-deficient mice exhibit impaired res ponses to challenge with several other viruses, This immunodeficiency is associated with impaired production of IFN-gamma and IL-12, Unexpec tedly, however, the ICSBP-/- mice also develop a syndrome with many si milarities to chronic myelogenous leukemia in humans. The chronic phas e of this disease is followed by a fatal blast crisis characterized by clonal expansions of undifferentiated cells, ICSBP is thus an importa nt determinant of hematopoietic growth and differentiation as well as a prominent signaling molecule for IFNs.