Susceptibility or resistance to Leishmania infection is dictated by the macrophages evolved under the influence of IL-3 or GM-CSF.
Although enhanced monocytopoiesis is a hallmark of leishmaniasis, its significance in determining the course of the disease has not been addressed. While the number of granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting cells increases in the draining lymph nodes in a resistant mouse strain (C57BL/6) during disease, in a susceptible strain (BALB/c) the number of interleukin-3 (IL-3)-secreting cells increases. Treatment of BALB/c mice with anti-IL-3 antibody significantly reduces the disease score. Bone marrow macrophages derived under stimulation with IL-3 (IL-3-Mphi) or GM-CSF (GM-Mphi) differ functionally. GM-Mphi are significantly more responsive to IFN-gamma-induced augmentation and more refractory to IL-4-mediated suppression of anti-leishmanial activity than IL-3-Mphi. LPS-induced IL-12 and TNF-alpha secretion by both the susceptible and resistant strain-derived macrophage subsets are down-regulated. Despite down-regulation of IL-12 secretion, GM-Mphi favor expansion of IFN-gamma-secreting cells and IL-3-Mphi favor IL-6-dependent expansion of the IL-4-secreting Th subset. Adoptive transfer of leishmanial antigen-pulsed IL-3-Mphi and GM-Mphi prior to infection either aggravated or reduced the disease score, respectively, in BALB/c mice. Anti-IL-6 treatment reverted the Th subset profile not only in vitro but also in vivo, resulting in a reduced disease score in both infected BALB/c mice and IL-3-Mphi recipients. The disease score in IL-3-Mphi recipients is also reduced significantly after anti-IL-4 treatment.
Saha
B
B
Immune Cell Biology Program, Naval Medical Research Institute, Bethesda, USA. infonccs@giaspn01.vsnl.net.in
Saini
A
A
Germond
R
R
Perrin
P J
PJ
Harlan
D M
DM
Davis
T A
TA
D019264:Adoptive Transfer; D000818:Animals; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D007114:Immunization; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D007377:Interleukin-3 / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D015850:Interleukin-6 / Q000096:biosynthesis; D018320:Leishmania major / Q000276:immunology* / Q000302:isolation & purification / Q000472:pathogenicity; D016773:Leishmaniasis, Cutaneous / Q000209:etiology / Q000276:immunology / Q000469:parasitology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D007377:Interleukin-3; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor