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-gamma (IFN-gamma), IL-1 beta, and tumor necrosis factor (TNF alpha) 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-1 beta (rIL-1 beta) 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 less than 0.03), suggesting in vivo T cell activation while PHA-induced sIL-2R was decreased (228 +/- 43 vs. control 582 +/- 127; P less than 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 less than 0.03) and sIL-2R levels (114 +/- 58 to 309 +/- 87 vs. control 582 +/- 127; P less than 0.003). Both spontaneous (25 +/- 18 vs. control 237 +/- 92; P less than 0.002) and PHA-induced (20 +/- 20 vs. control 604 +/- 129; P less than 0.004) TNF alpha levels were subnormal and were not improved with rIL-2, rIL-1 beta, or IM, suggesting a block in monocyte TNF alpha production. Spontaneous and PHA-induced IFN-gamma and IL-1 beta levels were normal. During the convalescent phase (greater than 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.(ABSTRACT TRUNCATED AT 400 WORDS)
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
B J
BJ
Ward
R T
RT
Johnson
A
A
Vaisberg
E
E
Jauregui
D E
DE
Griffin
D016516:CD4-CD8 Ratio; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008213:Lymphocyte Activation; D008457:Measles / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016207:Cytokines; D007375:Interleukin-1; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma