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.
Department of Medicine, Weill Medical College of Cornell University, Box 136, 1300 York Ave., New York, New York 10021, USA. hwmurray@med.cornell.edu
Henry W
HW
Murray
Kathleen C
KC
Flanders
Debra D
DD
Donaldson
Joseph P
JP
Sypek
Philip J
PJ
Gotwals
Jianguo
J
Liu
Xiaojing
X
Ma
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