Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency

Cepika, Alma-Martina; Sato, Yohei; Liu, Jeffrey Mao-Hwa; Uyeda, Molly Javier; Bacchetta, Rosa; Roncarolo, Maria Grazia

doi:10.1016/j.jaci.2018.10.026

Cited by 104 publications

(92 citation statements)

References 216 publications

(300 reference statements)

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“…An exciting alternative method to treat IPEX(-like) disorders is gene therapy 33 , and several approaches have been proposed, which entail ex vivo genetic manipulation of HSCs or conventional CD4 cells isolated from the patients, followed by transfer of the modified cells back into the patients [34][35][36] . Our study suggests a much simpler but powerful and perhaps safer approach that would bypass the ex vivo procedures.…”

Section: Discussionmentioning

confidence: 99%

“…Our study suggests a much simpler but powerful and perhaps safer approach that would bypass the ex vivo procedures. Specifically, in some IPEX (-like) patients, the Treg cells are dysfunctional but normal in numbers 33 . For such patients, viral vectors expressing gene editors might be systemically delivered, which would correct the Treg mutations and potentially convert them into SuperTreg cells.…”

Section: Discussionmentioning

confidence: 99%

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In situ conversion of defective Treg into SuperTreg cells to treat advanced IPEX-like disorders in mice

Chen

Mao

et al. 2020

Nat Commun

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Mutations disrupting regulatory T (Treg) cell function can cause IPEX and IPEX-related disorders, but whether established disease can be reversed by correcting these mutations is unclear. Treg-specific deletion of the chromatin remodeling factor Brg1 impairs Treg cell activation and causes fatal autoimmunity in mice. Here, we show with a reversible knockout model that re-expression of Brg1, in conjunction with the severe endogenous proinflammatory environment, can convert defective Treg cells into powerful, super-activated Treg cells (SuperTreg cells) that can resolve advanced autoimmunity, with Brg1 re-expression in a minor fraction of Treg cells sufficient for the resolution in some cases. SuperTreg cells have enhanced trafficking and regulatory capabilities, but become deactivated as the inflammation subsides, thus avoiding excessive immune suppression. We propose a simple, robust yet safe gene-editing-based therapy for IPEX and IPEX-related disorders that exploits the defective Treg cells and the inflammatory environment pre-existing in the patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

In situ conversion of defective Treg into SuperTreg cells to treat advanced IPEX-like disorders in mice

Chen

Mao

et al. 2020

Nat Commun

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“…Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is a recessive genetic disease that present in infancy with intractable enteropathy, erythroderma, and severe autoimmune manifestations, including type 1 diabetes mellitus, blood cytopenias, autoimmune hepatitis, nephropathy, and myopathy (154). IPEX is due to mutations in the FOXP3 gene, which encodes for the Forkhead box protein 3, that plays a crucial role in regulatory T (Treg) cell function and hence in immune tolerance.…”

Section: Hematopoietic Stem Cell Transplantation For Individual Primamentioning

confidence: 99%

Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Diseases: Current Status and Future Perspectives

et al. 2019

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Primary immunodeficiencies (PID) are disorders that for the most part result from mutations in genes involved in immune host defense and immunoregulation. These conditions are characterized by various combinations of recurrent infections, autoimmunity, lymphoproliferation, inflammatory manifestations, atopy, and malignancy. Most PID are due to genetic defects that are intrinsic to hematopoietic cells. Therefore, replacement of mutant cells by healthy donor hematopoietic stem cells (HSC) represents a rational therapeutic approach. Full or partial ablation of the recipient's marrow with chemotherapy is often used to allow stable engraftment of donor-derived HSCs, and serotherapy may be added to the conditioning regimen to reduce the risks of graft rejection and graft versus host disease (GVHD). Initially, hematopoietic stem cell transplantation (HSCT) was attempted in patients with severe combined immunodeficiency (SCID) as the only available curative treatment. It was a challenging procedure, associated with elevated rates of morbidity and mortality. Overtime, outcome of HSCT for PID has significantly improved due to availability of high-resolution HLA typing, increased use of alternative donors and new stem cell sources, development of less toxic, reduced-intensity conditioning (RIC) regimens, and cellular engineering techniques for graft manipulation. Early identification of infants affected by SCID, prior to infectious complication, through newborn screening (NBS) programs and prompt genetic diagnosis with Next Generation Sequencing (NGS) techniques, have also ameliorated the outcome of HSCT. In addition, HSCT has been applied to treat a broader range of PID, including disorders of immune dysregulation. Yet, the broad spectrum of clinical and immunological phenotypes associated with PID makes it difficult to define a universal transplant regimen. As such, integration of knowledge between immunologists and transplant specialists is necessary for the development of innovative transplant protocols and to monitor their results during follow-up. Despite the improved outcome observed after HSCT, patients with severe forms of PID still face significant challenges of short and long-term transplant-related complications. To address this issue, novel HSCT strategies are being implemented aiming to improve both survival and long-term quality of life. This article will discuss the current status and latest developments in HSCT for PID, and present data regarding approach and outcome of HSCT in recently described PID, including disorders associated with immune dysregulation.

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“…DC, dendritic cells; LT, lymphocyte T; LB, lymphocyte T; Mϕ, macrophage. may therefore be exploited for diseases in which dysfunction of the same host immune reactions is implicated in their pathogenesis, for instance the innate immune system in Sjögren's syndrome (42), adaptive immunity in Tregopathies (43) and autoimmune encephalomyelitis (44), and complement activation in local and/or systemic inflammation, tissue damage, and disease (45).…”

Section: Impact Of Tick Salivary Compounds On Host Immune Responsesmentioning

confidence: 99%

“…The complex mixture of tick salivary compounds specifically and selectively targets host immune reactions, subverting the rejection and death of the tick ( 24 ). This specificity and selectivity may therefore be exploited for diseases in which dysfunction of the same host immune reactions is implicated in their pathogenesis, for instance the innate immune system in Sjögren’s syndrome ( 42 ), adaptive immunity in Tregopathies ( 43 ) and autoimmune encephalomyelitis ( 44 ), and complement activation in local and/or systemic inflammation, tissue damage, and disease ( 45 ).…”

Section: Impact Of Tick Salivary Compounds On Host Immune Responsesmentioning

confidence: 99%

Tick Salivary Compounds for Targeted Immunomodulatory Therapy

et al. 2020

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Immunodeficiency disorders and autoimmune diseases are common, but a lack of effective targeted drugs and the side-effects of existing drugs have stimulated interest in finding therapeutic alternatives. Naturally derived substances are a recognized source of novel drugs, and tick saliva is increasingly recognized as a rich source of bioactive molecules with specific functions. Ticks use their saliva to overcome the innate and adaptive host immune systems. Their saliva is a rich cocktail of molecules including proteins, peptides, lipid derivatives, and recently discovered non-coding RNAs that inhibit or modulate vertebrate immune reactions. A number of tick saliva and/or salivary gland molecules have been characterized and shown to be promising candidates for drug development for vertebrate immune diseases. However, further validation of these molecules at the molecular, cellular, and organism levels is now required to progress lead candidates to clinical testing. In this paper, we review the data on the immunopharmacological aspects of tick salivary compounds characterized in vitro and/or in vivo and present recent findings on non-coding RNAs that might be exploitable as immunomodulatory therapies.

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Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency

Cited by 104 publications

References 216 publications

In situ conversion of defective Treg into SuperTreg cells to treat advanced IPEX-like disorders in mice

In situ conversion of defective Treg into SuperTreg cells to treat advanced IPEX-like disorders in mice

Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Diseases: Current Status and Future Perspectives

Tick Salivary Compounds for Targeted Immunomodulatory Therapy

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