Immunoenhancement combined with amphotericin B as treatment for experimental visceral leishmaniasis.
To determine if stimulation of Th1-cell-associated immune responses, mediated by interleukin 12 (IL-12) and gamma interferon (IFN-gamma), enhance the antileishmanial effect of amphotericin B (AMB), Leishmania donovani-infected BALB/c mice were first treated with (i) exogenous IL-12 to induce IFN-gamma, (ii) agonist anti-CD40 monoclonal antibody (MAb) to maintain IL-12 and induce IFN-gamma, or (iii) anti-IL-10 receptor (IL-10R) MAb to blockade suppression of IL-12 and IFN-gamma. In animals with established visceral infection, low-dose AMB alone (two injections of 1 mg/kg of body weight; total dose, 2 mg/kg) killed 15 to 29% of liver parasites; by themselves, the immunointerventions induced 16 to 33% killing. When the interventions were combined, the leishmanicidal activities increased 3.4-fold (anti-CD40), 6.3-fold (anti-IL-10R), and 9-fold (IL-12) compared with the activities of AMB plus the control preparations; and overall killing (76 to 84%) approximated the 84 to 92% killing effect of 7.5-fold more AMB alone (three injections of 5 mg/kg; total dose, 15 mg/kg). These results suggest that strengthening the host Th1-cell response may be a strategy for the development of AMB-sparing regimens in visceral leishmaniasis.
Murray
Henry W
HW
Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA. hwmurray@med.cornell.edu
Brooks
Elaine B
EB
DeVecchio
Jennifer L
JL
Heinzel
Frederick P
FP
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000666:Amphotericin B / Q000627:therapeutic use*; D000818:Animals; D000981:Antiprotozoal Agents / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000097:blood; D006224:Cricetinae; D016207:Cytokines / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000235:genetics; D018664:Interleukin-12 / Q000097:blood; D015847:Interleukin-4 / Q000037:antagonists & inhibitors; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D018418:Th2 Cells / Q000276:immunology
D000276:Adjuvants, Immunologic; D000981:Antiprotozoal Agents; D019013:CD40 Antigens; D016207:Cytokines; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D000666:Amphotericin B