Anti–PD-1 Antibody Treatment Promotes Clearance of Persistent Cryptococcal Lung Infection in Mice
Autor: | Seagal Teitz-Tennenbaum, Jonathan A. Roussey, John J. Osterholzer, Michal A. Olszewski, Steven P. Viglianti |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Programmed cell death Programmed Cell Death 1 Receptor Immunology Population Colony Count Microbial Inflammation Biology Article Mice 03 medical and health sciences 0302 clinical medicine Immune system Immunophenotyping Downregulation and upregulation medicine Animals Immunology and Allergy education Lung education.field_of_study Virulence Antibodies Monoclonal Cryptococcosis Th1 Cells Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Cryptococcus neoformans Cytokines Female Immunotherapy medicine.symptom Signal transduction Signal Transduction 030215 immunology |
Zdroj: | The Journal of Immunology. 199:3535-3546 |
ISSN: | 1550-6606 0022-1767 |
Popis: | Activation of immunomodulatory pathways in response to invasive fungi can impair clearance and promote persistent infections. The programmed cell death protein-1 (PD-1) signaling pathway inhibits immune effector responses against tumors, and immune checkpoint inhibitors that block this pathway are being increasingly used as cancer therapy. The objective of this study was to investigate whether this pathway contributes to persistent fungal infection and to determine whether anti–PD-1 Ab treatment improves fungal clearance. Studies were performed using C57BL/6 mice infected with a moderately virulent strain of Cryptococcus neoformans (52D), which resulted in prolonged elevations in fungal burden and histopathologic evidence of chronic lung inflammation. Persistent infection was associated with increased and sustained expression of PD-1 on lung lymphocytes, including a mixed population of CD4+ T cells. In parallel, expression of the PD-1 ligands, PD-1 ligands 1 and 2, was similarly upregulated on specific subsets of resident and recruited lung dendritic cells and macrophages. Treatment of persistently infected mice for 4 wk by repetitive administration of neutralizing anti–PD-1 Ab significantly improved pulmonary fungal clearance. Treatment was well tolerated without evidence of morbidity. Immunophenotyping revealed that anti–PD-1 Ab treatment did not alter immune effector cell numbers or myeloid cell activation. Treatment did reduce gene expression of IL-5 and IL-10 by lung leukocytes and promoted sustained upregulation of OX40 by Th1 and Th17 cells. Collectively, this study demonstrates that PD-1 signaling promotes persistent cryptococcal lung infection and identifies this pathway as a potential target for novel immune-based treatments of chronic fungal disease. |
Databáze: | OpenAIRE |
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