Neutralization of IL-12 demonstrates the existence of discrete organ-specific phases in the control of Leishmania donovani.
IL-12 plays a key role in stimulating both innate and antigen-specific immune responses against a number of intracellular pathogens. A neutralizing anti-IL-12 monoclonal antibody (mAb) was used to define and compare the role of endogenous IL-12 in the liver and spleen of mice infected with Leishmania donovani. IL-12 neutralization both early and late in infection caused delayed resolution of parasite load, a transient decrease in IFN-gamma, IL-4, TNF-alpha and inducible nitric oxide synthase (NOS-2) production, and suppressed tissue granuloma formation in the liver of genetically susceptible BALB/c mice. In contrast to the liver of BALB/c mice, neutralization of IL-12 had no effect on parasite burden in the spleen over the first 28 days of infection. However, IL-12 appeared to be critical for the development of mechanisms which subsequently contain the growth of persistent parasites in this organ in that neutralization of IL-12 dramatically enhanced parasite growth after day 28 of infection. Following IL-12 neutralization, the later unchecked growth of parasites in the spleen was coincident with an extensive breakdown of the tissue microarchitecture. Immunohistochemical studies revealed that IL-12 was largely produced by uninfected cells in L. donovani-infected BALB/c mice. In contrast, the course of infection in the liver and spleen of genetically resistant CBA/n mice was unaffected by the administration of anti-IL-12 mAb. These results suggest that the liver and spleen in susceptible BALB/c mice have different temporal requirements for IL-12 in controlling L. donovani infection, whereas IL-12 plays little role in either organ in resistant CBA/n mice. In addition, IL-12 appears to be involved in the generation of both Th1 and Th2 responses during L. donovani infection in BALB/c mice.
Engwerda
C R
CR
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, GB. c.engwerda@lshtm.ac.uk
Murphy
M L
ML
Cotterell
S E
SE
Smelt
S C
SC
Kaye
P M
PM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D006224:Cricetinae; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005260:Female; D006790:Host-Parasite Interactions; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000276:immunology* / Q000502:physiology; D007893:Leishmania donovani / Q000254:growth & development / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D009928:Organ Specificity / Q000276:immunology; D013045:Species Specificity; D013154:Spleen / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016207:Cytokines; D018664:Interleukin-12