Determinants of response to interleukin-10 receptor blockade immunotherapy in experimental visceral leishmaniasis.
In established Leishmania donovani visceral infection in normal mice, anti-interleukin (IL)-10 receptor (IL-10R) monoclonal antibody (MAb) treatment induced intracellular parasite killing within liver macrophages. IL-10R blockade maintained IL-12 protein 40, markedly increased interferon (IFN)-gamma serum levels, and enhanced tissue inducible nitric oxide synthase (iNOS) expression and granuloma assembly. Optimal MAb-induced killing, including synergism with antimony chemotherapy, required endogenous IL-12 and/or IFN-gamma and at least one IFN-gamma-regulated macrophage mechanism-iNOS or phagocyte oxidase. However, in IFN-gamma knockout mice, anti-IL-10R also induced both granuloma formation and leishmanistatic activity. As judged by IL-10R blockade, endogenous IL-10 primarily regulates killing in L. donovani infection by suppressing production of and responses to the Th1 cell-type cytokines, IL-12, and IFN-gamma. However, because anti-IL-10R also released IFN-gamma-independent effects, IL-10 appears to act more broadly and suppresses multiple antileishmanial mechanisms.
Murray
Henry W
HW
Department of Medicine, Weill Medical College of Cornell University, New York, USA. hwmurray@med.cornell.edu.
Moreira
Andre L
AL
Lu
Cristina M
CM
DeVecchio
Jennifer L
JL
Matsuhashi
Maki
M
Ma
Xiaojing
X
Heinzel
Frederick P
FP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D006099:Granuloma / Q000469:parasitology / Q000473:pathology; D007371:Interferon-gamma / Q000097:blood / Q000172:deficiency / Q000235:genetics; D018664:Interleukin-12 / Q000097:blood / Q000172:deficiency / Q000235:genetics; D007893:Leishmania donovani; D007898:Leishmaniasis, Visceral / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008113:Liver Neoplasms / Q000469:parasitology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000172:deficiency / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D018123:Receptors, Interleukin / Q000276:immunology*; D053701:Receptors, Interleukin-10
D000911:Antibodies, Monoclonal; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse