Underproduction of interleukin-12 in susceptible mice during progressive leishmaniasis is due to decreased CD40 activity.
Interleukin-12 promotes Th1 lymphocyte responses necessary for the cure of murine Leishmania major infection. We found that IL-12 p40 mRNA expression peaked at 4 weeks of infection in resistant C57BL/6 mice at levels threefold greater than in BALB/c mice. Peak IL-12 p40 expression in both strains was reduced threefold following treatment with neutralizing anti-CD40 ligand antibody and disease worsened in C57BL/6 mice. Direct activation of cultured lymph node cells by anti-CD40 MAb or soluble CD40 ligand failed to restore deficient IL-12 production by infected BALB/c mice unless recombinant IFN-beta was added to culture. Infected BALB/c lymph nodes also contained two- to threefold fewer low-density CD40+ accessory cells compared to that in C57BL/6 mice. We conclude that CD40-dependent responses are continually required for healing of leishmaniasis and that progressive disease is associated with decreased CD40-stimulated IL-12 synthesis as a consequence of either altered cytokine environment or inadequate accessory cell number.
Heinzel
F P
FP
Division of Geographic Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Rerko
R M
RM
Hujer
A M
AM
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001483:Base Sequence; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D023201:CD40 Ligand; D017931:DNA Primers / Q000235:genetics; D005260:Female; D007371:Interferon-gamma / Q000235:genetics / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D013045:Species Specificity; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D019013:CD40 Antigens; D017931:DNA Primers; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma