IN-VIVO AUGMENTATION OF IFN-GAMMA WITH A RIL-12 HUMAN/MOUSE CHIMERA - PLEIOTROPIC EFFECTS AGAINST INFECTIOUS AGENTS IN MICE AND RATS

被引:11
作者
GLADUE, RP
LAQUERRE, AM
MAGNA, HA
CARROLL, LA
ODONNELL, M
CHANGELIAN, PS
FRANKE, AE
机构
[1] Central Research Division, Pfizer, Inc., Groton
关键词
IL-12; IFN-GAMMA; L-MONOCYTOGENES; ESCHERICHIA-COLI; VIRUS;
D O I
10.1016/1043-4666(94)90029-9
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A heterodimer containing the mouse 35 kDa and human 40 kDa subunit of IL-12 was expressed in COS cells (cIL-12). Administration of 25-200 U of the cIL-12-COS supernatant to mice twice daily for 2 days augmented spleen cell IFN-γ production in response to IL-2 and peritoneal macrophage activity (superoxide and nitrites) as compared to animals receiving mock transfected supernatants. cIL-12 also increased levels of IFN-γ in serum but most dramatically following an LPS injection (50-fold over controls). Animals pretreated with cIL-12 suffered enhanced mortality following challenge with the Gram negative organism E. coli but enhanced survival or clearance following infection with the Gram positive organisms L. monocytogenes and S. aureus. Although daily treatment of mice with cIL-12 following an intranasal influenza A infection elevated levels of IFN-γ in the bronchioalveolar lavage fluid three-fold over controls, neither prophylactic or therapeutic treatment with the same dose level decreased viral titres in the lung. In addition, no effect was observed in animals infected with encephalomyocarditis virus or respiratory syncytial virus. Therefore, cIL-12 is a potent in vivo augmentor of IFN-γ production. It has differential effects on infectious disease depending on the invading organism and time of administration; being efficacious for intracellular bacteria but ineffective at the same dose levels against viral diseases. © 1994.
引用
收藏
页码:318 / 328
页数:11
相关论文
共 49 条
  • [11] COLIGAN JE, 1991, CURRENT PROTOCOLS IM, pCH6
  • [12] MULTIPLE DEFECTS OF IMMUNE CELL-FUNCTION IN MICE WITH DISRUPTED INTERFERON-GAMMA GENES
    DALTON, DK
    PITTSMEEK, S
    KESHAV, S
    FIGARI, IS
    BRADLEY, A
    STEWART, TA
    [J]. SCIENCE, 1993, 259 (5102) : 1739 - 1742
  • [13] PRODUCTION OF NATURAL-KILLER-CELL STIMULATORY FACTOR (INTERLEUKIN-12) BY PERIPHERAL-BLOOD MONONUCLEAR-CELLS
    DANDREA, A
    RENGARAJU, M
    VALIANTE, NM
    CHEHIMI, J
    KUBIN, M
    ASTE, M
    CHAN, SH
    KOBAYASHI, M
    YOUNG, D
    NICKBARG, E
    CHIZZONITE, R
    WOLF, SF
    TRINCHIERI, G
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1992, 176 (05) : 1387 - 1398
  • [14] DOHERTY GM, 1992, J IMMUNOL, V149, P1666
  • [15] REDUCED MORTALITY IN MURINE CYTOMEGALO-VIRUS INFECTED MICE FOLLOWING PROPHYLACTIC MURINE INTERFERON-GAMMA TREATMENT
    FENNIE, EH
    LIE, YS
    LOW, MAL
    GRIBLING, P
    ANDERSON, KP
    [J]. ANTIVIRAL RESEARCH, 1988, 10 (1-3) : 27 - 39
  • [16] INVITRO COMBINED EFFECTS OF HUMAN INTERFERONS AND INTERLEUKIN-2 ON NATURAL CELL-MEDIATED CYTOTOXICITY
    FUGGETTA, MP
    AQUINO, A
    PEPPONI, R
    DATRI, S
    LANZILLI, G
    BONMASSAR, E
    GRAZIANI, G
    [J]. INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY, 1993, 15 (01): : 1 - 10
  • [17] GAJEWSKI TF, 1990, J IMMUNOL, V144, P548
  • [18] GALLIN JI, 1991, REV INFECT DIS, V13, P973
  • [19] REGULATION OF HUMAN CYTOLYTIC LYMPHOCYTE-RESPONSES BY INTERLEUKIN-12
    GATELY, MK
    WOLITZKY, AG
    QUINN, PM
    CHIZZONITE, R
    [J]. CELLULAR IMMUNOLOGY, 1992, 143 (01) : 127 - 142
  • [20] ENHANCED ANTIBACTERIAL RESISTANCE IN NEUTROPENIC MICE TREATED WITH HUMAN RECOMBINANT INTERLEUKIN-1-BETA
    GLADUE, R
    GIRARD, A
    NEWBORG, M
    [J]. AGENTS AND ACTIONS, 1988, 24 (1-2): : 130 - 136