title: Combined Immune Therapy for the Treatment of Visceral Leishmaniasis.
abstract: Chronic disease caused by infections, cancer or autoimmunity can result in profound immune suppression. Immunoregulatory networks are established to prevent tissue damage caused by inflammation. Although these immune checkpoints preserve tissue function, they allow pathogens and tumors to persist, and even expand. Immune checkpoint blockade has recently been successfully employed to treat cancer. This strategy modulates immunoregulatory mechanisms to allow host immune cells to kill or control tumors. However, the utility of this approach for controlling established infections has not been extensively investigated. Here, we examined the potential of modulating glucocorticoid-induced TNF receptor-related protein (GITR) on T cells to improve anti-parasitic immunity in blood and spleen tissue from visceral leishmaniasis (VL) patients infected with Leishmania donovani. We found little effect on parasite growth or parasite-specific IFNγ production. However, this treatment reversed the improved anti-parasitic immunity achieved by IL-10 signaling blockade. Further investigations using an experimental VL model caused by infection of C57BL/6 mice with L. donovani revealed that this negative effect was prominent in the liver, dependent on parasite burden and associated with an accumulation of Th1 cells expressing high levels of KLRG-1. Nevertheless, combined anti-IL-10 and anti-GITR mAb treatment could improve anti-parasitic immunity when used with sub-optimal doses of anti-parasitic drug. However, additional studies with VL patient samples indicated that targeting GITR had no overall benefit over IL-10 signaling blockade alone at improving anti-parasitic immune responses, even with drug treatment cover. These findings identify several important factors that influence the effectiveness of immune modulation, including parasite burden, target tissue and the use of anti-parasitic drug. Critically, these results also highlight potential negative effects of combining different immune modulation strategies.
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.|Queensland University of Technology, Institute of Health and Biomedical Innovation, Brisbane, Australia.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Faleiro
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.|Netaji Subhas Institute of Technology, New Delhi, India.|Banaras Hindu University Institute of Medical Sciences, Varanasi, Uttar Pradesh, India.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.|Griffith University, Institute of Glycomics, Gold Coast, Australia.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Bunn
authors.affiliation: Banaras Hindu University Institute of Medical Sciences, Varanasi, Uttar Pradesh, India.
authors.forename: Neetu
authors.initials: N
authors.lastname: Singh
authors.affiliation: Banaras Hindu University Institute of Medical Sciences, Varanasi, Uttar Pradesh, India.
authors.forename: Shashi Bhushan
authors.initials: SB
authors.lastname: Chauhan
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Meru
authors.initials: M
authors.lastname: Sheel
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Amante
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.|University of Queensland, School of Medicine, Brisbane, Australia.
authors.forename: Marcela
authors.initials: M
authors.lastname: Montes de Oca
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.|University of Queensland, School of Medicine, Brisbane, Australia.
authors.forename: Chelsea L
authors.initials: CL
authors.lastname: Edwards
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.|Griffith University, School of Natural Sciences, Nathan, Australia.
authors.forename: Susanna S
authors.initials: SS
authors.lastname: Ng
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Best
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Ashraful
authors.initials: A
authors.lastname: Haque
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Lynette
authors.initials: L
authors.lastname: Beattie
authors.affiliation: Queensland University of Technology, Institute of Health and Biomedical Innovation, Brisbane, Australia.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Hafner
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: Sacks
authors.affiliation: Karolinska Institute, Stockholm, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Nylen
authors.affiliation: Banaras Hindu University Institute of Medical Sciences, Varanasi, Uttar Pradesh, India.
authors.forename: Shyam
authors.initials: S
authors.lastname: Sundar
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Engwerda
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D007167:Immunotherapy; D016753:Interleukin-10 / Q000276:immunology; D007893:Leishmania donovani / Q000502:physiology*; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000469:parasitology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000276:immunology / Q000469:parasitology; D018417:Th1 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; D016753:Interleukin-10