Early reduction in PD-L1 expression predicts faster treatment response in human cutaneous leishmaniasis.

Autor:	Dey NS; York Biomedical Research Institute, Hull York Medical School, University of York, York, United Kingdom., Senaratne S; Department of Parasitology, University of Sri Jayewardenepura, Nugegoda, Sri Lanka., Somaratne V; Dermatology Unit, District General Hospital Embilipitiya, Embilipitiya, Sri Lanka., Madarasinghe NP; Dermatology Unit, Teaching Hospital Anuradhapura, Anuradhapura, Sri Lanka., Seneviratne B; Deparment of Pathology, University of Sri Jayewardenepura, Nugegoda, Sri Lanka., Forrester S; York Biomedical Research Institute, Hull York Medical School, University of York, York, United Kingdom., Montes de Oca M; York Biomedical Research Institute, Hull York Medical School, University of York, York, United Kingdom., Reis LC; Instituto de Medicina Tropical de São Paulo, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil., Moulik S; Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, India., Walrad PB; York Biomedical Research Institute, Department of Biology, University of York, York, United Kingdom., Chatterjee M; Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, India., Goto H; Instituto de Medicina Tropical de São Paulo, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil.; Departamento de Medicina Preventiva, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil., Wickremasinghe R; Department of Parasitology, University of Sri Jayewardenepura, Nugegoda, Sri Lanka., Lagos D; York Biomedical Research Institute, Hull York Medical School, University of York, York, United Kingdom., Kaye PM; York Biomedical Research Institute, Hull York Medical School, University of York, York, United Kingdom., Ranasinghe S; Department of Parasitology, University of Sri Jayewardenepura, Nugegoda, Sri Lanka.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2021 Nov 15; Vol. 131 (22).
DOI:	10.1172/JCI142765
Abstrakt:	Cutaneous leishmaniasis (CL) is caused by Leishmania donovani in Sri Lanka. Pentavalent antimonials (e.g., sodium stibogluconate [SSG]) remain first-line drugs for CL with no new effective treatments emerging. We studied whole blood and lesion transcriptomes from Sri Lankan patients with CL at presentation and during SSG treatment. From lesions but not whole blood, we identified differential expression of immune-related genes, including immune checkpoint molecules, after onset of treatment. Using spatial profiling and RNA-FISH, we confirmed reduced expression of programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) proteins on treatment in lesions of a second validation cohort and further demonstrated significantly higher expression of these checkpoint molecules on parasite-infected compared with noninfected lesional CD68+ monocytes and macrophages. Crucially, early reduction in PD-L1 but not IDO1 expression was predictive of rate of clinical cure (HR = 4.88) and occurred in parallel with reduction in parasite load. Our data support a model whereby the initial anti-leishmanial activity of antimonial drugs alleviates checkpoint inhibition on T cells, facilitating immune-drug synergism and clinical cure. Our findings demonstrate that PD-L1 expression can be used as a predictor of rapidity of clinical response to SSG treatment in Sri Lanka and support further evaluation of PD-L1 as a host-directed therapeutic in leishmaniasis.
Databáze:	MEDLINE
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