IL-4 depletion enhances host resistance and passive IgA protection against tuberculosis infection in BALB/c mice.
The influence of Th2 cytokines in tuberculosis has been a matter of dispute. Here we report that IL-4 has a profound regulatory effect on the infection of BALB/c mice with Mycobacterium tuberculosis. Depletion of IL-4 with a neutralizing mAb caused only evanescent reduction of lung infection, but when combined with i.n. inoculations of IgA anti-mycobacterial alpha-crystallin mAb and mouse rIFN-gamma, we observed a 40-fold reduction of the bacterial counts in the lungs at 3 wks following i.n. infection (p<0.001). In genetically deficient IL-4-/- BALB/c mice, infection in both lung and spleen was substantially reduced for up to 8 wks without further treatment. Reconstitution of IL-4-/- mice with rIL-4 increased bacterial counts to wild-type levels and made the mice refractory to protection by IgA/IFN-gamma. Analysis of the lungs showed increased granulomatous infiltration and proinflammatory mediators in anti-IL-4/IgA/IFN-gamma-treated and infected mice. We conclude that the action of IL-4 in tuberculosis is targeted at macrophages and that it may include an antagonistic effect on their IgA/IFN-gamma-induced activation and nitric oxide production. The described novel immunotherapy, combining treatments with anti-IL-4, IgA antibody and IFN-gamma, has potential for translation toward the passive immunoprophylaxis of tuberculosis.
Buccheri
Simona
S
Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Italy.
Reljic
Rajko
R
Caccamo
Nadia
N
Ivanyi
Juraj
J
Singh
Mahavir
M
Salerno
Alfredo
A
Dieli
Francesco
F
D000818:Animals; D007113:Immunity, Innate; D007116:Immunization, Passive; D007070:Immunoglobulin A / Q000502:physiology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000502:physiology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control
D007070:Immunoglobulin A; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma