Modulation of T-cell costimulation as immunotherapy or immunochemotherapy in experimental visceral leishmaniasis.
CD40 ligand (CD40L)-deficient C57BL/6 mice failed to control intracellular Leishmania donovani visceral infection, indicating that acquired resistance involves CD40-CD40L signaling and costimulation. Conversely, in wild-type C57BL/6 and BALB/c mice with established visceral infection, injection of agonist anti-CD40 monoclonal antibody (MAb) induced killing of approximately 60% of parasites within liver macrophages, stimulated gamma interferon (IFN-gamma) secretion, and enhanced mononuclear cell recruitment and tissue granuloma formation. Comparable parasite killing was also induced by MAb blockade (inhibition) of cytotoxic T lymphocyte antigen-4 (CTLA-4) which downregulates separate CD28-B7 T-cell costimulation. Optimal killing triggered by both anti-CD40 and anti-CTLA-4 required endogenous IFN-gamma and involved interleukin 12. CD40L(-/-) mice also failed to respond to antileishmanial chemotherapy (antimony), while in normal animals, anti-CD40 and anti-CTLA-4 synergistically enhanced antimony-associated killing. CD40L-CD40 signaling regulates outcome and response to treatment of experimental visceral leishmaniasis, and MAb targeting of T-cell costimulatory pathways (CD40L-CD40 and CD28-B7) yields macrophage activation and immunotherapeutic and immunochemotherapeutic activity.
Department of Medicine, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, New York 10021, USA. hwmurray@med.cornell.edu
Henry W
HW
Murray
Cristina M
CM
Lu
Elaine B
EB
Brooks
Richard E
RE
Fichtl
Jennifer L
JL
DeVecchio
Frederick P
FP
Heinzel
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology; D019013:CD40 Antigens / Q000502:physiology; D023201:CD40 Ligand / Q000502:physiology; D060908:CTLA-4 Antigen; D005260:Female; D007167:Immunotherapy; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000097:blood; D053762:Interleukin-12 Subunit p40; D007898:Leishmaniasis, Visceral / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D021122:Protein Subunits / Q000097:blood; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma