Next-generation regulatory T cell therapy

Ferreira, Leonardo M. R.; Müller, Yannick D.; Bluestone, Jeffrey A.; Tang, Qizhi

doi:10.1038/s41573-019-0041-4

Cited by 366 publications

(351 citation statements)

References 247 publications

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“…Tregs have been used to induce tolerance in multiple autoimmune and inflammatory diseases 355‐358 . Consequently, adoptive transfer of Tregs has become an active area of research and clinical trial development for autoimmune diseases 359 . CD4 + CD25 + T cells can prevent the development of AA in C3H/HeJ mice, indicating some potential for Treg therapy 258 .…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

“…CD4 + CD25 + T cells can prevent the development of AA in C3H/HeJ mice, indicating some potential for Treg therapy 258 . Once practical issues are addressed, 360 and the antigen epitopes targeted in AA are fully defined, 49,272,361 Treg cell therapy may be achievable for AA 359 . Similarly, NK cells with immunoregulatory properties, 277 and other immunoregulatory cell types, could be additional candidates for development into immunocell therapies.…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

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Hair follicle immune privilege and its collapse in alopecia areata

Bertolini

McElwee

Gilhar

et al. 2020

Experimental Dermatology

177

157

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Anagen stage hair follicles (HFs) exhibit “immune privilege (IP)” from the level of the bulge downwards to the bulb. Both passive and active IP mechanisms protect HFs from physiologically undesired immune responses and limit immune surveillance. IP is relative, not absolute, and is primarily based on absent, or greatly reduced, intra‐follicular antigen presentation via MHC class I and II molecules, along with prominent expression of “no danger” signals like CD200 and the creation of an immunoinhibitory signalling milieu generated by the secretory activities of HFs. Perifollicular mast cells, Tregs and other immunocytes may also contribute to HF IP maintenance in healthy human skin. Collapse of anagen hair bulb IP is an essential prerequisite for the development of alopecia areata (AA). In AA, lesional HFs are rapidly infiltrated by NKG2D + T cells and natural killer (NK) cells, while perifollicular mast cells acquire a profoundly pro‐inflammatory phenotype and interact with autoreactive CD8+ T cells. Using animal models, significant functional evidence has accumulated that demonstrates the dominance of the immune system in AA pathogenesis. Purified CD8+T‐cell and NK cell populations alone, which secrete fγ, suffice to induce the AA phenotype, while CD4+T‐cells aggravate it, and Tregs and iNKT cells may provide relative protection against AA development. While IP collapse may be induced by exogenous agents, inherent IP deficiencies might confer increased susceptibility to AA for some individuals. Thus, a key goal for effective AA management is the re‐establishment of a functional HF IP, which will also provide superior protection from disease relapse.

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Section: Therapeutic Perspectivesmentioning

confidence: 99%

Section: Therapeutic Perspectivesmentioning

confidence: 99%

Hair follicle immune privilege and its collapse in alopecia areata

Bertolini

McElwee

Gilhar

et al. 2020

Experimental Dermatology

177

157

View full text Add to dashboard Cite

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“…Future investigations should evaluate whether antigen-specific tolerogenic strategies with the potential to exert a more potent effect on the disease can be used for treatment, particularly since these would avoid some of the more damaging side effects of global immune suppression. For instance, given the marked loss of antigen-specific Tregs we observed in Copa E241K/+ mice, regulatory T cell based therapy may be an exciting area for future research once the critical autoantigens targeted in disease are defined (27,42), especially in light of recent evidence which shows an important role for Tregs in constraining lung fibrosis (43).…”

Section: Future Investigations Should Evaluate Whether Disturbances Imentioning

confidence: 99%

A defect in thymic tolerance causes T cell-mediated autoimmunity in a murine model of COPA syndrome

Deng

Law

et al. 2020

Preprint

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One Sentence Summary:A new mouse model of COPA syndrome develops lung pathology that recapitulates patients and reveals that T cells are important drivers of the disease. Abstract:COPA syndrome is a recently described Mendelian autoimmune disorder caused by missense mutations in the Coatomer protein complex subunit alpha (COPA) gene. Patients with COPA syndrome develop arthritis and lung disease that presents as pulmonary hemorrhage or 2 interstitial lung disease (ILD). Immunosuppressive medications can stabilize the disease, but many patients develop progressive pulmonary fibrosis that requires life-saving measures such as lung transplantation. Because very little is understood about the pathogenesis of COPA syndrome, it has been difficult to devise effective treatments for patients. To date, it remains unknown which cell types are critical for mediating the disease as well as the mechanisms that lead to autoimmunity. To explore these issues, we generated a Copa E241K/+ germline knock-in mouse bearing one of the same Copa missense mutations in patients. Mutant mice spontaneously developed ILD that mirrors lung pathology in patients, as well as elevations of activated cytokinesecreting T cells. Here we show that mutant Copa in epithelial cells of the thymus impairs the thymic selection of T cells and results in both an increase in autoreactive T cells and decrease in regulatory T cells in peripheral tissues. We demonstrate that T cells from Copa E241K/+ mice are pathogenic and cause ILD through adoptive transfer experiments. In conclusion, we establish a new mouse model of COPA syndrome to identify a previously unknown function for Copa in thymocyte selection and demonstrate that a defect in central tolerance is a putative mechanism by which COPA mutations lead to autoimmunity in patients.

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“…Regulatory T cells (Tregs) control immune homeostasis and their adoptive transfer is a promising therapeutic approach with multiple trials completed, on-going or planned to test their efficiency in autoimmunity, solid organ transplantation or hematopoietic stem cell transplantation (reviewed in (Ferreira et al, 2019)). As Tregs are relatively rare, the majority of cell therapy protocols involve in vitro stimulation and expansion, in some cases culturing cells for up to 36 days to achieve > 2,000 fold expansion (MacDonald et al, 2019b).…”

Section: Introductionmentioning

confidence: 99%

Repeated stimulation or tonic-signaling chimeric antigen receptors drive regulatory T cell exhaustion

Lamarche

Novakovsky

et al. 2020

Preprint

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Regulatory T cell (Treg) therapy is a promising approach to improve outcomes in transplantation and autoimmunity. In conventional T cell therapy, chronic stimulation can result in poor in vivo function, a phenomenon termed exhaustion. Whether or not Tregs are also susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. We studied how two methods which induce conventional T cell exhaustion -repetitive stimulation or expression of a tonic-signaling chimeric antigen receptor (CAR) -affect human Tregs. With each repetitive polyclonal stimulation Tregs progressively acquired an exhausted phenotype, and became less suppressive in vitro. Tregs expressing a tonic-signaling CAR rapidly acquired an exhausted phenotype and had major changes in their transcriptome and metabolism. Although tonicsignaling CAR-Tregs remained stable and suppressive in vitro, they lost in vivo function, as tested in a model of xenogeneic graft-versus-host disease. The finding that human Tregs are susceptible to exhaustion has important implications for the design of Treg adoptive immunotherapy strategies.

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Next-generation regulatory T cell therapy

Cited by 366 publications

References 247 publications

Hair follicle immune privilege and its collapse in alopecia areata

Hair follicle immune privilege and its collapse in alopecia areata

A defect in thymic tolerance causes T cell-mediated autoimmunity in a murine model of COPA syndrome

Repeated stimulation or tonic-signaling chimeric antigen receptors drive regulatory T cell exhaustion

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