Paradoxical effects of IL-12 in leishmaniasis in the presence and absence of vaccinating antigen.
Protective immunity against Leishmania major requires parasite-specific CD4+T helper cells, the development of which is promoted by interleukin 12 (IL-12). In this study we investigated the use of IL-12 DNA to enhance the protective immunity induced by prophylactic vaccination with the L. major Parasite Surface Antigen 2 (PSA-2) DNA. A plasmid was constructed in which the two murine IL-12 subunits p35 and p40 were secreted as a biologically active single chain cytokine. The immunomodulatory effects of this IL-12 DNA were examined by codelivery with PSA-2 DNA in susceptible BALB/c and resistant C3H/He mice and subsequent infection with L. major promastigotes. Surprisingly, administration of IL-12 DNA alone had a protective effect, while coadministration of IL-12 with PSA-2 DNA abrogated protection. This effect of IL-12 DNA was dose dependent and affected by the timing of administration in relation to PSA-2 DNA. The effect of IL-12 on protection was associated with a reduced number of INF-gamma-producing T cells early in infection. A further understanding of this paradoxical effect of IL-12 and possibly other cytokines on protective immunity may be important for their use as adjuvants for Leishmania DNA vaccines.
Noormohammadi
A H
AH
The Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia.
Hochrein
H
H
Curtis
J M
JM
Baldwin
T M
TM
Handman
E
E
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D000953:Antigens, Protozoan / Q000008:administration & dosage / Q000235:genetics; D000954:Antigens, Surface / Q000008:administration & dosage / Q000235:genetics; D001483:Base Sequence; D019556:COS Cells; D017931:DNA Primers / Q000235:genetics; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D018320:Leishmania major / Q000235:genetics / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D010957:Plasmids / Q000235:genetics; D015800:Protozoan Proteins; D016052:Protozoan Vaccines / Q000008:administration & dosage* / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics
D000276:Adjuvants, Immunologic; D000953:Antigens, Protozoan; D000954:Antigens, Surface; D017931:DNA Primers; D015800:Protozoan Proteins; D016052:Protozoan Vaccines; D019444:Vaccines, DNA; C072094:surface antigen P2, Leishmania; D018664:Interleukin-12; D007371:Interferon-gamma