Interleukin-10 (IL-10) in experimental visceral leishmaniasis and IL-10 receptor blockade as immunotherapy.
Interleukin-10 (IL-10) is thought to promote intracellular infection, including human visceral leishmaniasis, by disabling Th1 cell-type responses and/or deactivating parasitized tissue macrophages. To develop a rationale for IL-10 inhibition as treatment in visceral infection, Th1 cytokine-driven responses were characterized in Leishmania donovani-infected BALB/c mice in which IL-10 was absent or overexpressed or its receptor (IL-10R) was blockaded. IL-10 knockout and normal mice treated prophylactically with anti-IL-10R demonstrated accelerated granuloma assembly and rapid parasite killing without untoward tissue inflammation; IL-12 and gamma interferon mRNA expression, inducible nitric oxide synthase reactivity, and responsiveness to antimony chemotherapy were also enhanced in knockout mice. In IL-10 transgenic mice, parasite replication was unrestrained, and except for antimony responsiveness, measured Th1 cell-dependent events were all initially impaired. Despite subsequent granuloma assembly, high-level infection persisted, and antimony-treated transgenic mice also relapsed. In normal mice with established infection, anti-IL-10R treatment was remarkably active, inducing near-cure by itself and synergism with antimony. IL-10's deactivating effects regulate outcome in experimental visceral leishmaniasis, and IL-10R blockade represents a potential immuno- and/or immunochemotherapeutic approach in this infection.
Murray
Henry W
HW
Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA. hwmurry@med.cornell.edu
Lu
Christina M
CM
Mauze
Smita
S
Freeman
Sherry
S
Moreira
Andre L
AL
Kaplan
Gilla
G
Coffman
Robert L
RL
D000818:Animals; D000965:Antimony / Q000627:therapeutic use; D006099:Granuloma / Q000473:pathology; D007167:Immunotherapy; D016753:Interleukin-10 / Q000502:physiology*; D018664:Interleukin-12 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000502:physiology; D007893:Leishmania donovani; D007898:Leishmaniasis, Visceral / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors*; D053701:Receptors, Interleukin-10; D012008:Recurrence
D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D000965:Antimony; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse