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Relevance of different CD4+ T-cell subsets for antifungal defense. What is aberrant in immunocompromised patients?

Applicant Khanna Nina
Number 142403
Funding scheme Ambizione
Research institution Abteilung für Infektiologie + Spitalhygiene Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.01.2013 - 31.12.2015
Approved amount 625'890.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Medical Microbiology

Keywords (6)

Innate immune cells; Invasive pulmonale Aspergillose; Antifungal immunity; Cross-talk; Candida esophagitis; T Helper subsets

Lay Summary (German)

Lead
Verbessertes Verständnis opportunistischer Infektionen bei immunsupprimierten Patienten
Lay summary
Während des Ambizione erarbeite meine Forschungsgruppe und ich die Pathogenese verschiedener Pilzinfektionen. Wir untersuchten die Wechselwirkung von Wirt und Erreger  mit dem Ziel zentrale Mechanismen des Abwehrsystems und Lücken besser zu verstehen. Wir erhoffen damit neue, personalisierte, infektiologische Therapien zu ermöglichen.

Zum Beispiel können invasive Pilzinfektionen oder aber auch Virusinfektionen bei Patienten mit Leukämien, nach Transplantation sowie fortgeschrittener HIV-Infektion schwerste Komplikationen verursachen. Unser Ziel ist es, Risikopatienten für diese Infektionen frühzeitig zu identifizieren, z.B. gelang es uns Unterschiede in der zellulären Infektabwehr zu finden und dann das Abwehrsystem mit Zelltherapien zu verbessern. Seit 2014 haben wir eine T-Zelltherapie zur Behandlung von schwierig zu behandelnden Virusinfektionen (Zytomegalovirus, Epstein Barr virus und Adenovirus) nach allogener Stammzelltransplantation etabliert und bereits 3 Patienten behandelt. Diese Therapie ist bisher einzigartig in der Schweiz. Gerne würden wir diese Therapien zur Verbesserung der Pilzimmunität anwenden.

Direct link to Lay Summary Last update: 08.11.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Immune recovery in HIV-infected patients after Candida esophagitis is impaired despite long-term antiretroviral therapy
Stuehler Claudia, Bernardini Claudia, Elzi Luigia, Stoeckle Marcel, Zimmerli Stefan, Furrer Hansjakob, Gunthard Huldrych F., Leibundgut-Landmann Salome, Battegay Manuel, Khanna Nina (2016), Immune recovery in HIV-infected patients after Candida esophagitis is impaired despite long-term antiretroviral therapy, in AIDS, 30(12), 1923-1933.
Immune reconstitution after allogeneic hematopoietic stem cell transplantation and association with occurrence and outcome of invasive aspergillosis.
Stuehler Claudia, Kuenli Esther, Jaeger Veronika, Baettig Veronika, Ferracin Fabrizia, Rajacic Zarko, Kaiser Deborah, Bernardini Claudia, Forrer Pascal, Weisser Maja, Elzi Luigia, Battegay Manuel, Halter Jörg, Passweg Jakob, Khanna Nina (2015), Immune reconstitution after allogeneic hematopoietic stem cell transplantation and association with occurrence and outcome of invasive aspergillosis., in Journal of Infectious Diseases, 959.
T cells specific for different latent and lytic viral proteins efficiently control Epstein-Barr virus-transformed B cells
Nowakowska Justyna, Stuehler Claudia, Egli Adrian, Battegay Manuel, Rauser Georg, Bantung Glenn, Brander Christian, Hess Christoph, Khanna Nina (2015), T cells specific for different latent and lytic viral proteins efficiently control Epstein-Barr virus-transformed B cells, in Cytotherapy, 17(9), 1280-1291.
Multi-specific Aspergillus T cells selected by CD137 or CD154 induce protective immune responses against the most relevant mold infections.
Stuehler Claudia, Nowakowska Justyna, Bernardini Claudia, Topp Max S, Battegay Manuel, Passweg Jakob, Khanna Nina, Multi-specific Aspergillus T cells selected by CD137 or CD154 induce protective immune responses against the most relevant mold infections., in The Journal of infectious diseases.

Collaboration

Group / person Country
Types of collaboration
Prof. Christoph Hess/Departement Biomedizin Universität Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Jakob Passweg/Hämatologie Universitätsspital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
PD Dr. Luigia Elzi/Infektiologie Universitätsspital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Giulio Spagnoli/Departement Biomedizin Universität Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Hans H. Hirsch/Departement Biomedizin Universität Basel Switzerland (Europe)
- Research Infrastructure
Prof. Salomé Leibundgut-Landmann/ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Marten Trendelenburg/Departement Biomedizin Universität Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Daniel Goldenberger PhD/Diagnostic Microbiology, University Hospital of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Associated projects

Number Title Start Funding scheme
163648 Relevance of different CD4+ T-cell subsets for antifungal defense. What is aberrant in immunocompromised patients? 01.01.2016 Ambizione
148522 Swiss HIV Cohort Study (SHCS) 01.01.2014 Cohort Studies Large

Abstract

The incidence of opportunistic fungal infections caused in particular by Aspergillus fumigatus and Candida species has increased over the last decades. These infections have earlier been a leading cause of morbidity and mortality in patients with HIV/AIDS and have now become most prevalent in patients suffering from leukemia and in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), solid organ transplantation (SOT) or immunosuppressive treatment. Despite antifungal prophylaxis or treatment, the therapeutic efficacy is often limited due to impaired host immunity, difficulties encountered in rapid and accurate diagnosis, emergence of uncommon or resistant pathogens, drug interactions and toxicity. Hence, specific immunological markers that predict development and outcome as well as alternative treatment approaches that could restore or boost fungus-specific immunity would be desirable for these patients. Adoptive T-cell therapy for fungal infections is promising but little is known regarding the protective immune response in humans. In mice, distinct CD4+ T-helper (TH) subsets are important for host responses against fungi. Coordinated activation of TH1 immunity, regulatory T cells and probably TH17 cells seems to be necessary for pathogen control by enhancing the innate immune cells, whereas activation of TH2 cells often exacerbates disease. Therefore, understanding the mechanisms enhancing protective and/or dampening counteractive TH subsets may help to prevent or treat local and disseminated fungal infections in humans, which is particularly important in the development of immunotherapeutic approaches such as adoptive T-cell therapy or when identifying immunomodulatory compounds. Although the time course of recovery of normal numbers of immune cells is well known for HSCT recipients or HIV-infected patients receiving antiretroviral therapy, only little is known regarding possible qualitative impairments and the kinetics of recovery of the different fungus-specific TH subsets as well as the interaction of fungus-specific adaptive immunity with the cells of the innate immune system. As we have previously identified a T-cell epitope stimulating cross-reactive T cells that recognize A. fumigatus as well as C. albicans, we are able by using a MHC class II tetramer to directly monitor and track the recovery of these epitope-specific T cells in patients suffering from A. fumigatus or C. albicans infections and correlate it with clinical outcome. AimsWe aim to identify parameters of the antifungal immune response that correlate with the risk for developing invasive fungal infections (IFI) and/or the outcome of these infections. Further, we aim to increase and/or regulate antifungal T-cell immunity in immunocompromised patients either by adoptive transfer of fungus-specific T cells or by immunomodulatory compounds such as antifungal drugs, statins or vitamin D. Therefore, we need to characterise the different TH subsets involved in antifungal defence as well as their interaction with innate immunity in patients with disease compared to unaffected patients and healthy donors.Aim 1To characterize the different TH subsets specific for A. fumigatus and C. albicans in healthy donors, their interplay with each other and with cells of the innate immune system as well as their ability to be modulated by different compounds.Aim 2To identify qualitative and quantitative impairments of different TH subsets and/or innate immunity in HSCT recipients with IA in a nested unmatched case-control study. Aim 3To assess qualitative and quantitative impairments of different TH subsets in HIV-infected patients with Candida esophagitis in a CD4+ T-cell matched nested case-control study. RelevanceThe current antifungal treatments are associated with high costs and yet with unsatisfactory outcome. Therefore, specific immunological parameters that influence outcome or correlate with the risk for developing IFI are of great interest to optimize treatment duration or to identify the need for prophylaxis. The development of anti-infective immunotherapeutic strategies is still at a very early stage and we hope and are confidential to make a valuable contribution in the understanding of the plasticity as well as cross-talk between different antigen-specific immune cells that have to be taken into consideration for successful intervention. The results of this study should provide the rational for immunomodulatory and immunotherapeutic strategies in patients at risk for IFI, which could complement or replace conventional antifungal therapy.
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