Relationship of cytokines and cytokine signaling to immunodeficiency disorders in the mouse.
The contributions of cytokines to the development and progression of disease in a mouse model of retrovirus-induced immunodeficiency (MAIDS) are controversial. Some studies have indicated at 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 involved in IFN signaling-to examine their contributions to this disorder. Our results demonstrate that expression of type 2 cytokines is an epiphenomenon of infection and that IFN-gamma is a driving force in disease progression. In addition, exogenously administered IL-12 prevents many manifestations of disease while blocking retrovirus expression. Interruption of the IFN signaling pathways in ICSBP-/- mice blocks induction of MAIDS. Predictably, ICSBP-deficient mice exhibit impaired responses to challenge with several other viruses. This immunodeficiency is associated with impaired production of IFN-gamma and IL-12. Unexpectedly, however, the ICSBP-/- mice also develop a syndrome with many similarities to chronic myelogenous leukemia in humans. The chronic phase of this disease is followed by a fatal blast crisis characterized by clonal expansions of undifferentiated cells. ICSBP is thus an important determinant of hematopoietic growth and differentiation as well as a prominent signaling molecule for IFNs.
Morawetz
R A
RA
Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Giese
N A
NA
Gabriele
L
L
Rothman
P
P
Horak
I
I
Ozato
K
K
Morse
H C
HC
D000818:Animals; D016207:Cytokines / Q000502:physiology*; D004195:Disease Models, Animal; D051379:Mice; D016183:Murine Acquired Immunodeficiency Syndrome / Q000276:immunology*; D018121:Receptors, Cytokine / Q000502:physiology*; D012192:Retroviridae Infections
D016207:Cytokines; D018121:Receptors, Cytokine