Azathioprine therapy induces selective NK cell depletion and IFN-? deficiency predisposing to herpesvirus reactivation
Por:
Ingelfinger F., Sparano C., Bamert D., Reyes-Leiva D., Sethi A., Rindlisbacher L., Zwicky P., Kreutmair S., Widmer C.C., Mundt S., Cortés-Vicente E., Tugues S., Becher B., Schreiner B.
Publicada:
1 ene 2022
Ahead of Print:
1 ene 2023
Resumen:
Background: Azathioprine is a widely prescribed drug for patients with chronic inflammatory diseases such as myasthenia gravis or organ transplant recipients. Azathioprine exerts immunosuppressive effects by inhibiting intracellular purine synthesis and reducing the numbers of circulating B and T lymphocytes. Case reports indicate increased risk for serious infections that can occur despite regular measurements of lymphocyte counts during azathioprine therapy. Objective: We sought to comprehensively investigate therapy-associated patient risks and the underlying immune dysfunction of azathioprine use. Methods: Peripheral blood leukocytes were analyzed using single-cell mass and spectral flow cytometry to detect specific effects of azathioprine use on the systemic immune signature. Therapy-associated clinical features were analyzed in 2 independent cohorts of myasthenia gravis patients. Results: Azathioprine therapy selectively induced pronounced CD56dimCD16+ natural killer cell depletion and concomitant IFN-? deficiency. Cytokine profiling revealed a specific contraction of classical TH1 cells during azathioprine treatment. We further observed an increased occurrence of reactivation of endogenous latent herpesviruses in the azathioprine-treated group versus in patients with myasthenia gravis who were not receiving immunomodulatory treatment; this increased occurrence was validated in an independent cohort. Conclusion: Our study highlights the risk of development of adverse events during azathioprine therapy and suggests that natural killer cell monitoring could be valuable in clinical practice. © 2022 The Authors
Filiaciones:
Ingelfinger F.:
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
Department of Neurology, University Hospital Zurich, Zurich, Switzerland
Sparano C.:
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
Bamert D.:
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
Reyes-Leiva D.:
Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Department of Medicine, Universitat Autònoma de Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
Sethi A.:
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
Rindlisbacher L.:
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
Zwicky P.:
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
Kreutmair S.:
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
Widmer C.C.:
Department of Medical Oncology and Hematology, University Hospital Zurich and the University of Zurich, Zurich, Switzerland
Mundt S.:
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
Cortés-Vicente E.:
Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Department of Medicine, Universitat Autònoma de Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
Tugues S.:
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
Becher B.:
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
Schreiner B.:
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
Department of Neurology, University Hospital Zurich, Zurich, Switzerland
Green Published, All Open Access; Green Open Access
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