T reg  cell-based therapies: challenges and perspectives

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Cellular therapies using regulatory T (T _reg) cells are currently undergoing clinical trials for the treatment of autoimmune diseases, transplant rejection and graft-versus-host disease. In this Review, we discuss the biology of T _reg cells and describe new efforts in T _reg cell engineering to enhance specificity, stability, functional activity and delivery. Finally, we envision that the success of T _reg cell therapy in autoimmunity and transplantation will encourage the clinical use of adoptive T _reg cell therapy for non-immune diseases, such as neurological disorders and tissue repair.

Related collections

Most cited references 136

Record: found
Abstract: found
Article: not found

CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL

Terry Fry, Nirali Shah, Rimas Orentas … (2017)

Chimeric antigen receptor (CAR) T-cells targeting CD19 mediate potent effects in relapsed/refractory pre-B cell acute lymphoblastic leukemia (B-ALL) but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed on most B-ALL and usually retained following CD19 loss. We report results from a phase I trial testing a novel CD22-CAR in twenty-one children and adults, including 17 previously treated with CD19-directed immunotherapy. Dose dependent anti-leukemic activity was observed with complete remission in 73% (11/15) of patients receiving ≥ 1 × 106 CD22-CART cells/kg, including 5/5 patients with CD19dim/neg B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted escape from killing by CD22-CART cells. These results are the first to eastablish the clinical activity of a CD22-CAR in pre-B cell ALL, including in leukemia resistant to anti-CD19 immunotherapy, demonstrating comparable potency to CD19-CART at biologically active doses in B-ALL. They also highlight the critical role played by antigen density in regulating CAR function. (Funded by NCI Intramural Research Program)

0 comments Cited 579 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Foxp3 instability leads to the generation of pathogenic memory T cells in vivo

Xuyu Zhou, Samantha Bailey-Bucktrout, Lukas T. Jeker … (2009)

Regulatory T (Treg) cells play a central role in maintaining immune homeostasis. However, little is known about the stability of Treg cells in vivo. In this study, we demonstrate that a significant percentage of cells exhibited transient or unstable Foxp3 expression. These exFoxp3+ T cells express an activated-memory T cell phenotype, and produced inflammatory cytokines. Moreover, exFoxp3 cell numbers increased in inflamed tissues under autoimmune conditions. Adoptive transfer of autoreactive exFoxp3 cells led to the rapid-onset of diabetes. Finally, T cell receptor repertoire analyses suggested that exFoxp3 cells develop from both natural and adaptive Treg cells. Thus, the generation of potentially autoreactive effector T cells as a consequence of Foxp3 instability has important implications for understanding autoimmune disease pathogenesis.

0 comments Cited 387 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Interleukin-2 and regulatory T cells in graft-versus-host disease.

John Koreth, Ken-ichi Matsuoka, Haesook T. Kim … (2011)

Dysfunction of regulatory T (Treg) cells has been detected in diverse inflammatory disorders, including chronic graft-versus-host disease (GVHD). Interleukin-2 is critical for Treg cell growth, survival, and activity. We hypothesized that low-dose interleukin-2 could preferentially enhance Treg cells in vivo and suppress clinical manifestations of chronic GVHD. In this observational cohort study, patients with chronic GVHD that was refractory to glucocorticoid therapy received daily low-dose subcutaneous interleukin-2 (0.3×10(6), 1×10(6), or 3×10(6) IU per square meter of body-surface area) for 8 weeks. The end points were safety and clinical and immunologic response. After a 4-week hiatus, patients with a response could receive interleukin-2 for an extended period. A total of 29 patients were enrolled. None had progression of chronic GVHD or relapse of a hematologic cancer. The maximum tolerated dose of interleukin-2 was 1×10(6) IU per square meter. The highest dose level induced unacceptable constitutional symptoms. Of the 23 patients who could be evaluated for response, 12 had major responses involving multiple sites. The numbers of CD4+ Treg cells were preferentially increased in all patients, with a peak median value, at 4 weeks, that was more than eight times the baseline value (P<0.001), without affecting CD4+ conventional T (Tcon) cells. The Treg:Tcon ratio increased to a median of more than five times the baseline value (P<0.001). The Treg cell count and Treg:Tcon ratio remained elevated at 8 weeks (P<0.001 for both comparisons with baseline values), then declined when the patients were not receiving interleukin-2. The increased numbers of Treg cells expressed the transcription factor forkhead box P3 (FOXP3) and could inhibit autologous Tcon cells. Immunologic and clinical responses were sustained in patients who received interleukin-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60% (range, 25 to 100). Daily low-dose interleukin-2 was safely administered in patients with active chronic GVHD that was refractory to glucocorticoid therapy. Administration was associated with preferential, sustained Treg cell expansion in vivo and amelioration of the manifestations of chronic GVHD in a substantial proportion of patients. (Funded by a Dana-Farber Dunkin' Donuts Rising Star award and others; ClinicalTrials.gov number, NCT00529035.).

0 comments Cited 370 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-journal-id): 101124169

Journal ID (pubmed-jr-id): 27017

Journal ID (nlm-ta): Nat Rev Immunol

Journal ID (iso-abbrev): Nat Rev Immunol

Title: Nature reviews. Immunology

ISSN (Print): 1474-1733

ISSN (Electronic): 1474-1741

Publication date Nihms-submitted: 12 January 2021

Publication date (Electronic): 06 December 2019

Publication date (Print): March 2020

Publication date PMC-release: 19 January 2021

Volume: 20

Issue: 3

Pages: 158-172

Affiliations

[1 ]Sean N. Parker Autoimmune Research Laboratory, Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.

[2 ]These authors should be considered joint first authors: Caroline Raffin, Linda T. Vo.

Author notes

Author contributions

The authors contributed equally to all aspects of the article.

[* ] Jeff.bluestone@ 123456ucsf.edu

Author information

Jeffrey A. Bluestone http://orcid.org/0000-0001-8793-7848

Article

Accession ID: PMC7814338 Pmcid ID: PMC7814338 Pmc-uid ID: 7814338 Manuscript ID: nihpa1632373

DOI: 10.1038/s41577-019-0232-6

PMC ID: 7814338

PubMed ID: 31811270

SO-VID: bf8a3cce-9ceb-4f06-a195-06b33f45a50a

History

Comments

Comment on this article

scite_

Cited by 233

See all cited by

Most referenced authors 4,422

See all reference authors

- Version 1

T _reg cell-based therapies: challenges and perspectives

Read this article at

Abstract

Related collections

Gamma Delta T cells

Most cited references 136

CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL

Foxp3 instability leads to the generation of pathogenic memory T cells in vivo

Interleukin-2 and regulatory T cells in graft-versus-host disease.

Author and article information

Journal

Affiliations

Author notes

Author information

Article

History

Categories

Comments

Comment on this article

Similar content 692

Cited by 233

Most referenced authors 4,422