Treg cell therapy: How cell heterogeneity can make the difference

Giganti, Giulio; Atif, Muhammad; Mohseni, Yasmin R.; Mastronicola, Daniela; Grageda, Nathali; Povoleri, Giovanni A M; Miyara, Makoto; Scottà, Cristiano

doi:10.1002/eji.201948131

Cited by 59 publications

(51 citation statements)

References 130 publications

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“…Regulatory T cell therapies are remarkably promising in transplantation and have been reviewed recently (11,12,(72)(73)(74)(75)(76)(77)(78). To avoid broad immunosuppression and the risk of infection with polyclonal Tregs, one strategy is to focus on antigen-specific Treg cells, which induced tolerance in animal models and can also be expanded from patients (64).…”

Section: Targeting Enclysis In Transplantationmentioning

confidence: 99%

Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer

et al. 2021

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Persistent liver inflammation can lead to cirrhosis, which associates with significant morbidity and mortality worldwide. There are no curative treatments beyond transplantation, followed by long-term immunosuppression. The global burden of end stage liver disease has been increasing and there is a shortage of donor organs, therefore new therapies are desperately needed. Harnessing the power of the immune system has shown promise in certain autoimmunity and cancer settings. In the context of the liver, regulatory T cell (Treg) therapies are in development. The hypothesis is that these specialized lymphocytes that dampen inflammation may reduce liver injury in patients with chronic, progressive diseases, and promote transplant tolerance. Various strategies including intrinsic and extracorporeal expansion of Treg cells, aim to increase their abundance to suppress immune responses. We recently discovered that hepatocytes engulf and delete Treg cells by enclysis. Herein, we propose that inhibition of enclysis may potentiate existing regulatory T cell therapeutic approaches in patients with autoimmune liver diseases and in patients receiving a transplant. Moreover, in settings where the abundance of Treg cells could hinder beneficial immunity, such us in chronic viral infection or liver cancer, enhancement of enclysis could result in transient, localized reduction of Treg cell numbers and tip the balance towards antiviral and anti-tumor immunity. We describe enclysis as is a natural process of liver immune regulation that lends itself to therapeutic targeting, particularly in combination with current Treg cell approaches.

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Section: Targeting Enclysis In Transplantationmentioning

confidence: 99%

Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer

et al. 2021

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“…In this work, we have taken a cellular approachFc.IL-2 mutein-mediated Treg enrichmentto enforce tolerogenic responses to ASI. Treg employ multiple adaptive suppressive pathways to restrain different types of inflammation, increasing the likelihood that Treg enrichment will reliably control responses to ASI in different diseases and patient populations (6). For our experimental system, we used mice that had received OT-II TCR transgenic T cells, which contain a low proportion of OVA-responsive Treg.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Expansion of Antigen-Specific Regulatory T Cells through Staggered Fc.IL-2 Mutein Dosing and Antigen-Specific Immunotherapy

et al. 2021

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In mice, Ag administration in the absence of adjuvant typically elicits tolerogenic immune responses through the deletion or inactivation of conventional CD4 T cells and the formation or expansion of regulatory CD4 T cells (Treg). Although these Ag-specific immunotherapy (ASI) approaches are currently under clinical development to treat autoinflammatory conditions, efficacy and safety may be variable and unpredictable because of the diverse activation states of immune cells in subjects with autoimmune and allergic diseases. To reliably induce Ag-specific tolerance in patients, novel methods to control T cell responses during ASI are needed, and strategies that permanently increase Treg frequencies among Ag-specific CD4 T cells may provide long-lasting immunosuppression between treatments. In this study, we present an approach to durably increase the frequency of Ag-specific Treg in mice by administering ASI when Treg numbers are transiently increased with individual doses of a half-life-extended Treg-selective IL-2 mutein. Repeated weekly cycles of IL-2 mutein doses (day 0) followed by ASI (day 3) resulted in a 3-to 5-fold enrichment in Treg among Ag-responsive CD4 T cells. Expanded Ag-specific Treg persisted for more than 3 wk following treatment cessation, as well as through an inflammatory T cell response to an Ag-expressing virus. Combining Treg enrichment with ASI has the potential to durably treat autoimmune disease or allergy by increasing the Treg/conventional CD4 T cell ratio among autoantigen-or allergen-specific T cells. ImmunoHorizons, 2021, 5: 782-791.

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“…Normally, healthy hosts possess a wide range of regulatory mechanisms to control inflammatory responses. For example, during pathogen infection, Treg cell activity is increased, immunosuppressive cytokines are produced, and inflammatory responses are suppressed [ 44 , 45 , 46 ]. Meanwhile, regulatory B cells also play an immunomodulatory role in pathogen infection, with this type of cell inducing immunosuppression through the production of cytokines IL-10 and IL-35 [ 47 , 48 , 49 ].…”

Section: Pathophysiological Mechanisms Of Cytokine Stormsmentioning

confidence: 99%

Pathogenesis and Treatment of Cytokine Storm Induced by Infectious Diseases

Tang

Dong

et al. 2021

IJMS

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Cytokine storm is a phenomenon characterized by strong elevated circulating cytokines that most often occur after an overreactive immune system is activated by an acute systemic infection. A variety of cells participate in cytokine storm induction and progression, with profiles of cytokines released during cytokine storm varying from disease to disease. This review focuses on pathophysiological mechanisms underlying cytokine storm induction and progression induced by pathogenic invasive infectious diseases. Strategies for targeted treatment of various types of infection-induced cytokine storms are described from both host and pathogen perspectives. In summary, current studies indicate that cytokine storm-targeted therapies can effectively alleviate tissue damage while promoting the clearance of invading pathogens. Based on this premise, “multi-omics” immune system profiling should facilitate the development of more effective therapeutic strategies to alleviate cytokine storms caused by various diseases.

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Treg cell therapy: How cell heterogeneity can make the difference

Cited by 59 publications

References 130 publications

Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer

Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer

In Vivo Expansion of Antigen-Specific Regulatory T Cells through Staggered Fc.IL-2 Mutein Dosing and Antigen-Specific Immunotherapy

Pathogenesis and Treatment of Cytokine Storm Induced by Infectious Diseases

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