Cytokine production in vitro and the lymphoproliferative defect of natural measles virus infection

In natural measles virus infection, evidence of intense immune system activation is present simultaneously with clinically relevant immune suppression. While evidence of activation is most prominent early in the disease, skin test responses and in vitro lymphoproliferation are depressed for weeks after the onset of the rash. It is not known whether the prolonged period of reduced immune responsiveness results from a single defect or a succession of different abnormalities. To gain further insight into measles-induced immune suppression we studied the production of soluble IL-2 receptor (sIL-2R), interferon-γ (IFN-γ), IL-1β, and tumor necrosis factor (TNFα) by peripheral blood mononuclear cells (PBMC) isolated from measles patients at various times after the onset of the rash. Studies included addition of supplemental recombinant IL-1β (rIL-1β) or recombinant IL-2 (rIL-2) or suppression of prostaglandin synthesis by indomethacin (IM). Proliferation in response to phytohemagglutin (PHA) was abnormal at all stages of disease. During the acute phase (first week after the onset of the rash) spontaneous production of sIL-2R was increased (76±54 vs. controls 4±4;P<0.03), suggesting in vivo T cell activation while PHA-induced sIL-2R was decreased (228±43 vs. control 582 ±127; P<0.002), suggesting that the capacity to produce IL-2 in response to mitogen was limited. Supplementation of PHA-stimulated cultures with rIL-2 improved but did not normalize both proliferation (58,600±4900 to 70,700±4400 vs. control 97,700±15,500; P<0.03) and sIL-2R levels (114±58 to 309±87 vs. control 582±127; P<0.003). Both spontaneous (25±18 vs. control 237±92; P<0.002) and PHA-induced (20 ±20 vs. control 604±129; P<0.004) TNFα levels were subnormal and were not improved with rIL-2, rIL-1β, or IM, suggesting a block in monocyte TNFα production. Spontaneous and PHA-induced IFN-γ and IL-1β levels were normal. During the convalescent phase (>2 weeks after the onset of the rash), spontaneous levels of sIL-2R were normal and PHA-induced levels were completely normalized with supplemental rIL-2 but proliferation remained below normal. Spontaneous TNFα was low but increased normally in response to PHA. Both spontaneous (808±345 vs. control 152±78; P<0.02) and PHA-induced (1448±339 vs. control 475±88; P<0.01) levels of IL-1β were increased, suggesting in vivo activation of monocytes. Spontaneous and PHA-induced IFN-γ production was normal but the addition of either rIL-2 (63±32 to 174±74, P<0.01) or IM (124±46, P<0.002) increased levels three-to sixfold over control values (39±12). These findings suggest that the in vitro lymphoproliferative defect associated with measles, particularly early in the infection, is caused, in part, by inadequate IL-2 production. During the acute phase, TNFα production is also reduced while during convalescence IL-1β production is increased. These data suggest an evolution of immunologic abnormalities affecting both lymphocytes and monocytes over the course of this illness.