Impaired secretion of TNF-α by monocytes stimulated with EBV peptides associates with infectious complications following kidney transplantation

ABSTRACTBackgroundThe successful development of immunosuppressive agents has paradoxically led to an era in which adverse effects of immunosuppression, such as infections and cancer, are now a major concern in solid organ recipients. Nevertheless, the main focus of immune monitoring research remains the identification of rejection. There is currently no clinical tool to assess the net state of immunosuppression or to identify patients at increased risk of infectious complications.MethodsWe report a prospective, longitudinal study in which we conducted detailed phenotyping of over 300 peripheral blood mononuclear cell samples from 45 kidney recipients during the first 24 months posttransplant. Patients were classified as cases or controls according to the following events: an opportunistic infection, recurring bacterial infections, or de novo neoplasia.ResultsUsing a training cohort, an exploratory analysis revealed that the TNFα response to synthetic EBV peptides by CD14+CD16+ monocytes was lower in cases. A classifier rule based on ≥2 consecutive values below a threshold of 73% of TNFα-positive cells provided a sensitivity and specificity of 83%. In the validation cohort, the assay exhibited a sensitivity of 90% and a specificity of 63%. Analysis of IFNγ responses by T cells showed no correlation with the cases' phenotype. The association between over-immunosuppression status and the monocyte response was independent of age, renal function and immunosuppressive regimen.ConclusionsThese data suggest that patients with infectious complications posttransplantation have lower CD14+CD16+ monocyte responses to EBV peptides. This assay seems promising to help personalize the immunotherapy. Background The successful development of immunosuppressive agents has paradoxically led to an era in which adverse effects of immunosuppression, such as infections and cancer, are now a major concern in solid organ recipients. Nevertheless, the main focus of immune monitoring research remains the identification of rejection. There is currently no clinical tool to assess the net state of immunosuppression or to identify patients at increased risk of infectious complications. Methods We report a prospective, longitudinal study in which we conducted detailed phenotyping of over 300 peripheral blood mononuclear cell samples from 45 kidney recipients during the first 24 months posttransplant. Patients were classified as cases or controls according to the following events: an opportunistic infection, recurring bacterial infections, or de novo neoplasia. Results Using a training cohort, an exploratory analysis revealed that the TNFα response to synthetic EBV peptides by CD14+CD16+ monocytes was lower in cases. A classifier rule based on ≥2 consecutive values below a threshold of 73% of TNFα-positive cells provided a sensitivity and specificity of 83%. In the validation cohort, the assay exhibited a sensitivity of 90% and a specificity of 63%. Analysis of IFNγ responses by T cells showed no correlation with the cases' phenotype. The association between over-immunosuppression status and the monocyte response was independent of age, renal function and immunosuppressive regimen. Conclusions These data suggest that patients with infectious complications posttransplantation have lower CD14+CD16+ monocyte responses to EBV peptides. This assay seems promising to help personalize the immunotherapy. Correspondance information: Sacha A. De Serres, MD SM FRCPC, Transplantation Unit, Renal Division, Department of Medicine, University Health Center of Quebec, Faculty of Medicine, Laval University, 11 Côte du Palais, Quebec, QC, Canada G1R 2J6, Tel: 418-691-5464, Fax: 418-691-5757. sacha.deserres@crchuq.ulaval.ca AUTHORSHIP PAGE P.V. participated in research design, performance of the research, data analysis and writing of the paper. O.D. participated in the performance of the research, data analysis and writing of the paper. S.B. and F.B.B. participated in the performance of the research. I.H. participated in research design and in the writing of the paper. S.A.D.S. participated in research design, data analysis and writing of the paper. DISCLOSURE. The authors declare no conflicts of interest. FUNDING. S.A.D.S. was supported by a Kidney Research Scientist Core Education and National Training (KRESCENT) New Investigator Award from Canadian Institutes of Health Research (CIHR Grant KRI123890) and Kidney Foundation of the Canada (KFOC Operating Grants KFOC120027 and KFOC170009) and a scholarship from the Fonds the Recherche Quebec Sante (FRQS Grants 24676 and 26726). This work also received support from CIHR through the Operating Grant 201309 PCL-134068 and from Canada Found for Innovation Grant 31981 to S.A.D.S. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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