Antagonizing deactivating cytokines to enhance host defense and chemotherapy in experimental visceral leishmaniasis.
In experimental visceral leishmaniasis, inhibition of interleukin 10 (IL-10) signaling enhances Th1-cell-associated responses, promoting gamma interferon (IFN-gamma) secretion, granuloma assembly, macrophage activation with substantial liver parasite killing, and synergy with pentavalent antimony (Sb) chemotherapy. To determine if inhibiting other suppressive cytokines has similar therapeutic potential, Leishmania donovani-infected BALB/c mice were injected with anti-IL-4 monoclonal antibody or receptor fusion antagonists of IL-13 or transforming growth factor beta (TGF-beta). Targeting IL-13 or TGF-beta enabled inhibition of L. donovani replication but little parasite killing; anti-IL-4 had no effect. None of the three antagonists promoted IFN-gamma production, granuloma maturation, or Sb efficacy. Excess IL-13 and TGF-beta exacerbated liver infection; however, effects were transient. Among IL-10, IL-4, IL-13, and TGF-beta, cytokines capable of disabling Th1-cell mechanisms (including those which support chemotherapy), IL-10 appears to be the appropriate target for therapeutic inhibition in visceral L. donovani infection.
Murray
Henry W
HW
Department of Medicine, Weill Medical College of Cornell University, Box 136, 1300 York Ave., New York, New York 10021, USA. hwmurray@med.cornell.edu
Flanders
Kathleen C
KC
Donaldson
Debra D
DD
Sypek
Joseph P
JP
Gotwals
Philip J
PJ
Liu
Jianguo
J
Ma
Xiaojing
X
D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors*; D005260:Female; D018793:Interleukin-13 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors; D053701:Receptors, Interleukin-10; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics
D016207:Cytokines; D018793:Interleukin-13; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D016212:Transforming Growth Factor beta; D015847:Interleukin-4