Stimulation with lysates of Aspergillus terreus, Candida krusei and Rhizopus oryzae maximizes cross-reactivity of anti-fungal T cells

Deo, Shivashni; Virassamy, Balaji; Halliday, Catriona; Clancy, Leighton; Chen, Sharon; Meyer, Wieland; Sorrell, Tania C.; Gottlieb, David

doi:10.1016/j.jcyt.2015.09.013

Cited by 19 publications

(14 citation statements)

References 32 publications

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“…In striking contrast, lysate stimulation in our Asp-STs predominantly induced Th1 cells and barely regulatory cells, demonstrating higher hyphal damage over unmanipulated DLIs. Such Th1 cell prevalence ensures that Asp-STs are amenable to activation and capable of mounting protective responses against Aspergillus [33][34][35][36][37].…”

Section: Discussionmentioning

confidence: 99%

Clinical-scale production of Aspergillus-specific T cells for the treatment of invasive aspergillosis in the immunocompromised host

Παπαδοπούλου

Alvanou

Koukoulias

et al. 2019

Bone Marrow Transplant

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Invasive aspergillosis (IA) represents a leading cause of mortality in immunocompromised patients. Although adoptive immunotherapy with Aspergillus-specific T cells (Asp-STs) represents a promising therapeutic approach against IA, the complex and costly production limits its broader application. We generated Asp-STs from a single blood draw of healthy individuals or IA patients in only 10 days, by either Aspergillus fumigatus (AF) lysate or peptide stimulation of mononuclear cells. The cells were phenotypically and functionally characterized, and safety was assessed in xenografts. Healthy donorderived and lysate-or peptide-pulsed Asp-STs presented comparable fold expansion, immunophenotype, and Th1 responses. Upon cross-stimulation, only the lysate-pulsed Asp-STs were empowered to respond to peptide stimulation, although both cell products induced hyphal damage. Importantly, Asp-STs cross-reacted with other fungal species and did not induce alloreactivity in vivo. IA patient-derived T cells displayed an anergic phenotype that prohibited sufficient expansion and yield of meaningful doses of Asp-STs for autologous immunotherapy. Using a rapid and simple process, we generated, from healthy donors but not IA patients, functionally active Asp-STs of broad specificity and at clinically relevant numbers. Such an approach may form the basis for the effective management of IA in the context of allogeneic hematopoietic cell transplantation.

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Section: Discussionmentioning

confidence: 99%

Clinical-scale production of Aspergillus-specific T cells for the treatment of invasive aspergillosis in the immunocompromised host

Παπαδοπούλου

Alvanou

Koukoulias

et al. 2019

Bone Marrow Transplant

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“…Fungal antigen specificity was assessed by intracellular cytokine flow cytometry as previously described. 36 T cells and MoDCs were mixed at a 5:1 ratio and cultured in the presence of antibodies to CD28 and CD49d (BD Biosciences). Extracellular release of cytokines was blocked with 1 mg/mL brefeldin A and 2 mg/mL monensin (BD Biosciences).…”

Section: Flow Cytometrymentioning

confidence: 99%

Rapidly expanded partially HLA DRB1–matched fungus-specific T cells mediate in vitro and in vivo antifungal activity

et al. 2020

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Invasive fungal infections are a major cause of disease and death in immunocompromised hosts, including patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Recovery of adaptive immunity after HSCT correlates strongly with recovery from fungal infection. Using initial selection of lymphocytes expressing the activation marker CD137 after fungal stimulation, we rapidly expanded a population of mainly CD4+ T cells with potent antifungal characteristics, including production of tumor necrosis factor α, interferon γ, interleukin-17, and granulocyte-macrophage colony stimulating factor. Cells were manufactured using a fully good manufacturing practice–compliant process. In vitro, the T cells responded to fungal antigens presented on fully and partially HLA-DRB1 antigen–matched presenting cells, including when the single common DRB1 antigen was allelically mismatched. Administration of antifungal T cells lead to reduction in the severity of pulmonary and cerebral infection in an experimental mouse model of Aspergillus. These data support the establishment of a bank of cryopreserved fungus-specific T cells using normal donors with common HLA DRB1 molecules and testing of partially HLA-matched third-party donor fungus-specific T cells as a potential therapeutic in patients with invasive fungal infection after HSCT.

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“…indicated by the correlation of the presence of Aspergillus-specific T cells with a T-helper (Th) 1 phenotype with the clearance of the Aspergillus infection in patients after allogeneic stem cell transplantation [23]. As a result, transfer of specific T cells has been suggested as a therapeutic or prophylactic treatment option [24][25][26][27][28][29][30][31][32]. T cells are also important in the even higher number of immunocompetent patients, in particular, those with impaired lung function that are affected by noninvasive Aspergillus-related clinical complications.…”

Section: The Adaptive Immune System and Aspergillus Infectionsmentioning

confidence: 99%

Immunoproteomics of Aspergillus for the development of biomarkers and immunotherapies

Kniemeyer

Ebel²,

Krüger

et al. 2016

Proteomics Clinical Apps

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Filamentous fungi of the genus Aspergillus play significant roles as pathogens causing superficial and invasive infections as well as allergic reactions in humans. Particularly invasive mycoses caused by Aspergillus species are characterized by high mortality rates due to difficult diagnosis and insufficient antifungal therapy. The application of immunoproteomic approaches has a great potential to identify new targets for the diagnosis, therapy, and vaccine development of diseases caused by Aspergillus species. Serological proteome analyses (SERPA) that combine 2D electrophoresis with Western blotting are still one of the most popular techniques for the identification of antigenic proteins. However, recently a growing number of approaches have been developed to identify proteins, which either provoke an antibody response or which represent targets of T-cell immunity in patients with allergy or fungal infections. Here, we review advances in the studies of immune responses against pathogenic Aspergilli as well as the current status of diagnosis and immunotherapy of Aspergillus infections.

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Stimulation with lysates of Aspergillus terreus, Candida krusei and Rhizopus oryzae maximizes cross-reactivity of anti-fungal T cells

Cited by 19 publications

References 32 publications

Clinical-scale production of Aspergillus-specific T cells for the treatment of invasive aspergillosis in the immunocompromised host

Clinical-scale production of Aspergillus-specific T cells for the treatment of invasive aspergillosis in the immunocompromised host

Rapidly expanded partially HLA DRB1–matched fungus-specific T cells mediate in vitro and in vivo antifungal activity

Immunoproteomics of Aspergillus for the development of biomarkers and immunotherapies

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