INFECTION AND IMMUNITY, Dec. 1991, p. 4710-4714
Vol. 59, No. 12
0019-9567/91/124710-05$02.00/0 Copyright X) 1991, American Society for Microbiology
Cytokine Regulation of Murine Leishmaniasis: Interleukin 4 Is Not Sufficient To Mediate Progressive Disease in Resistant C57BL/6 Mice MICHAEL D. SADICK,1t NANCY STREET,2t TIMOTHY R. MOSMANN,2§ AND RICHARD M. LOCKSLEY1* Department of Medicine, Division of Infectious Diseases, University of California, San Francisco Medical Center, San Francisco, California 94143,1 and DNAX Research Institute, Palo Alto, California 943042 Received 24 June 1991/Accepted 3 October 1991
Neutralization of interleukin 4 (IL-4) at the time of infection with Leishmania major allowed susceptible BALB/c mice to heal. Recombinant IL-4, however, had little effect on the course of L. major infection in resistant C57BL/6 mice, nor did coinfection with Nippostrongylus brasiliensis, despite marked elevation of endogenous IL-4 levels.
Infection of BALB/c mice with Leishmania major leads to dissemination of the parasite and death over 3 to 4 months. Disease is associated with the expansion of CD4+ T cells that contain high levels of interleukin 4 (IL-4) mRNA in the draining lymph nodes and spleen (11) and with elevated levels of immunoglobulin E, an IL-4-dependent immunoglobulin isotype (10). Previous results demonstrated that neutralization of IL-4 by 6 weekly doses of monoclonal antibody llBl (18) beginning at the time of infection
=,
a
allowed these mice to heal and develop effective immunity
(24).
To assess at what time neutralization of IL-4 was most
critical, individual groups of four mice were infected in the footpads with L. major WHOM/IR/-/173 as described previously (24) and given either no therapy, 1 mg of anti-IL-4 antibody intraperitoneally in a single dose, or 1 mg of anti-IL-4 antibody weekly beginning either at the time of infection or 1, 2, or 4 weeks later. Although animals that
8.00 7.00 6.00E400
0o ULL
1
2
3
4 5 6 Weeks Post-infection
7
8
FIG. 1. Effect of anti-IL-4 treatment of infected BALB/c mice. Groups of four BALB/c mice were inoculated in the hind footpads with 106 stationary-phase promastigotes. Groups were either untreated (l) or treated weekly with 1 mg of anti-IL-4 antibody intraperitoneally starting either at the time of infection (@) or 1 (A), 2 (*), or 4 (*) weeks after infection or were treated with a single dose of 1 mg of anti-IL-4 antibody at the time of infection (0). Footpad swelling was measured in a metric caliper; bars represent standard errors of the mean. Results are from one of three comparable experiments. 2
x
* Corresponding author. t Present address: Genentech, Inc., 460 Point San Bruno Blvd, South San Francisco, CA 94080. t Present address: Cancer Immunobiology Center, University of Texas SW Medical Center, Dallas, TX 75235. § Present address: Department of Immunology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
4710
NOTES
VOL. 59, 1991
4711
5.00
*
Vol. 59, No. 12
0019-9567/91/124710-05$02.00/0 Copyright X) 1991, American Society for Microbiology
Cytokine Regulation of Murine Leishmaniasis: Interleukin 4 Is Not Sufficient To Mediate Progressive Disease in Resistant C57BL/6 Mice MICHAEL D. SADICK,1t NANCY STREET,2t TIMOTHY R. MOSMANN,2§ AND RICHARD M. LOCKSLEY1* Department of Medicine, Division of Infectious Diseases, University of California, San Francisco Medical Center, San Francisco, California 94143,1 and DNAX Research Institute, Palo Alto, California 943042 Received 24 June 1991/Accepted 3 October 1991
Neutralization of interleukin 4 (IL-4) at the time of infection with Leishmania major allowed susceptible BALB/c mice to heal. Recombinant IL-4, however, had little effect on the course of L. major infection in resistant C57BL/6 mice, nor did coinfection with Nippostrongylus brasiliensis, despite marked elevation of endogenous IL-4 levels.
Infection of BALB/c mice with Leishmania major leads to dissemination of the parasite and death over 3 to 4 months. Disease is associated with the expansion of CD4+ T cells that contain high levels of interleukin 4 (IL-4) mRNA in the draining lymph nodes and spleen (11) and with elevated levels of immunoglobulin E, an IL-4-dependent immunoglobulin isotype (10). Previous results demonstrated that neutralization of IL-4 by 6 weekly doses of monoclonal antibody llBl (18) beginning at the time of infection
=,
a
allowed these mice to heal and develop effective immunity
(24).
To assess at what time neutralization of IL-4 was most
critical, individual groups of four mice were infected in the footpads with L. major WHOM/IR/-/173 as described previously (24) and given either no therapy, 1 mg of anti-IL-4 antibody intraperitoneally in a single dose, or 1 mg of anti-IL-4 antibody weekly beginning either at the time of infection or 1, 2, or 4 weeks later. Although animals that
8.00 7.00 6.00E400
0o ULL
1
2
3
4 5 6 Weeks Post-infection
7
8
FIG. 1. Effect of anti-IL-4 treatment of infected BALB/c mice. Groups of four BALB/c mice were inoculated in the hind footpads with 106 stationary-phase promastigotes. Groups were either untreated (l) or treated weekly with 1 mg of anti-IL-4 antibody intraperitoneally starting either at the time of infection (@) or 1 (A), 2 (*), or 4 (*) weeks after infection or were treated with a single dose of 1 mg of anti-IL-4 antibody at the time of infection (0). Footpad swelling was measured in a metric caliper; bars represent standard errors of the mean. Results are from one of three comparable experiments. 2
x
* Corresponding author. t Present address: Genentech, Inc., 460 Point San Bruno Blvd, South San Francisco, CA 94080. t Present address: Cancer Immunobiology Center, University of Texas SW Medical Center, Dallas, TX 75235. § Present address: Department of Immunology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
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NOTES
VOL. 59, 1991
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*
