Immunotherapy with OX40L-Fc or anti-CTLA-4 enhances local tissue responses and killing of Leishmania donovani.
Enhancing granuloma development and effector function, but without inducing the pathology associated with excess granulomatous inflammation, poses a major challenge for immunotherapeutic intervention against diseases such as visceral leishmaniasis (VL). Here, we demonstrate that a chimeric fusion protein (OX40L-Fc) which stimulates T cells through OX40 and a monoclonal antibody which blocks CTLA-4, an inhibitory receptor on T cells, both enhanced the rate of granuloma maturation, CD4(+) T cell proliferation, and killing of Leishmania. Costimulation-based therapy induced no adverse fibrotic or necrotic reactions, and had no significant effect on the levels of endogenous anti-inflammatory cytokines (IL-10 and TGF-beta). Furthermore, both OX40L-Fc and anti-CTLA4 could be co-administered with conventional anti-leishmanial drugs. Until now, enhancing T cell immunity by the manipulation of costimulatory pathways has only received serious attention for cancer immunotherapy, but our data provide a compelling argument for the evaluation of this approach in human VL and other infectious diseases.
Zubairi
Soombul
S
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, GB.
Sanos
Stephanie L
SL
Hill
Sue
S
Kaye
Paul M
PM
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000502:physiology; D006099:Granuloma / Q000378:metabolism; D007107:Immune System / Q000187:drug effects*; D007167:Immunotherapy; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007893:Leishmania donovani / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D053278:OX40 Ligand; D048069:Tumor Necrosis Factors
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors; D018664:Interleukin-12; D007371:Interferon-gamma