T cells in the control of organ-specific autoimmunity

Bluestone, Jeffrey A.; Bour-Jordan, Hélène; Cheng, Mickie; Anderson, Mark S.

doi:10.1172/jci78089

Cited by 133 publications

(97 citation statements)

References 202 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We evaluated T-cell receptor (TCR) b-chain diversity prior to and after expansion, and found that polyclonality was maintained, without preferential expansion of a limited cell clonotypes, suggesting the expansion of a highly diverse Treg cell population. We noted that the expanded Tregs up-regulated several functional cell surface markers, including CCR7, CD38, CD25, CTLA-4, and LAP, which suggested enhanced activity of the expanded cells [16,17].…”

Section: Treg Manufacture For Clinical Usementioning

confidence: 85%

“…To control autoimmunity, a number of suppressor cell populations have been defined in rodents and man, including regulatory B cells, dendritic cells and macrophages. However, regulatory T cells (Tregs) have emerged as the major cell subset maintaining tolerance, with the ability to potently suppress the activation and effector function of other immune cells, including CD4 and CD8 T cells, B cells, NK cells, macrophages, and dendritic cells [15,16]. Tregs encompass various subsets of CD4 þ and CD8 þ cells and may develop centrally in the thymus (tTregs) or in the periphery from conventional T cells (pTregs) in response to activation signals and exposure to cytokines such as TGFb and retinoic acid (Fig.…”

Section: Treg Overview and Role In Dmmentioning

confidence: 99%

See 1 more Smart Citation

Regulatory T cell therapy for type 1 diabetes: May the force be with you

Gitelman

Bluestone

2016

Journal of Autoimmunity

Self Cite

View full text Add to dashboard Cite

a b s t r a c tType 1 diabetes mellitus (T1DM) results from autoimmune destruction of insulin producing beta cells. Regulatory T cells (Tregs) have been shown to be defective in this setting. Immuno-therapies targeting T cells, and resetting the balance between T effectors and Tregs, have had some initial success in preserving beta cell function. With a goal to use Tregs themselves as a novel therapeutic, we developed a technique to isolate and expand Tregs from patients with T1DM. These ex vivo expanded CD4 þ CD127 lo/À CD25 þ cells exhibit improved function and retain their T cell receptor diversity. These cells have subsequently been used in phase I clinical trials in patients with recent onset T1DM. The infusions were well tolerated, with no safety concerns. The studies are too small to assess efficacy definitively, although some individuals exhibit stable beta cell function over intervals as long as 2 years. These efforts set the stage for a larger phase II effort in new onset T1DM, and combination studies with other drugs, as well as efforts in other autoimmune diseases.

show abstract

Section: Treg Manufacture For Clinical Usementioning

confidence: 85%

Section: Treg Overview and Role In Dmmentioning

confidence: 99%

Regulatory T cell therapy for type 1 diabetes: May the force be with you

Gitelman

Bluestone

2016

Journal of Autoimmunity

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although Treg-based therapies hold great promise for treatment of autoimmunity, it is unclear whether a general expansion of the Treg population in patients with autoimmunity is an efficient or effective approach. It is more likely that therapies focused on tissue antigen-specific Tregs would be more efficacious, as the cells could home to the appropriate tissue site and exert local, robust suppression (42,43). Unfortunately, isolation of sufficient numbers of human antigen-specific Tregs is a challenging prospect; therefore, the use of alternative markers associated with functional self-reactive Tregs should be explored.…”

Section: Among the 1328 Genetic Transcripts Increased In Cd5mentioning

confidence: 99%

High self-reactivity drives T-bet and potentiates Treg function in tissue-specific autoimmunity

Sprouse

Scavuzzo²,

Blum

et al. 2018

JCI Insight

View full text Add to dashboard Cite

“…Jeffrey Bluestone and colleagues discuss how CD4 + Tregs control the outgrowth of potentially pathogenic self-reactive cells (10). In…”

Section: Discussionmentioning

confidence: 99%

Putting together the autoimmunity puzzle

Cava¹

2015

J. Clin. Invest.

View full text Add to dashboard Cite

R e v i e w S e R i e S : A u t o i m m u n i t y2highlighting the evidence for a key role of these suppressor cells in the prevention and suppression of autoimmunity, these authors review the experimental support for the existence of functionally and phenotypically distinct suppressor cell subsets and their complementary role in regulating immune responses. By including considerations of Treg stability under changing environments and the recent immunotherapeutic approaches for the restoration of peripheral immune tolerance, these authors ponder the current challenges in achieving remission of autoimmunity without continuous immune suppression (i.e., by maintaining uncompromised overall immune responses). The restoration of immune homeostasis might be accomplished by enhancing suppressive immune responses, to limit the damage caused by T cells or B cells (or by the cytokines that they produce). George Tsokos and colleagues analyze the central role of T cells in orchestrating autoimmune responses and the characteristics of these cells in a prototypical systemic autoimmune disease (11), while Betty Diamond and Jolien Suurmond address the importance of the mechanisms that drive autoantibody pathogenicity and the mechanisms by which autoantibody production is initiated (12). Autoantibodies appear long before clinical symptoms of autoimmunity, thus representing a marker for potential disease development (13). Their predictive value is also reflected by the finding that there is an approximately six-to eight-fold increase in the risk of developing an autoimmune disease when only one autoantibody is present compared with three autoantibodies present (14).Autoantibodies develop because of inefficient removal of autoreactive B cells, which in healthy individuals are eliminated both at central and peripheral levels. In untreated patients with active autoimmune disease, both central and peripheral B cell tolerance checkpoints can be defective (15). Fritz Melchers describes three checkpoints of central tolerance for B cells in the bone marrow and discusses the importance of the microenvironment in the effective removal of the vast majority of B cell clones that express polyreactive antibodies (16). He then discusses the mechanisms of peripheral B cell tolerance, namely checkpoint 4, which removes peripheral autoreactive new emigrant B cells before they enter the mature naive B cell pool (17), and checkpoint 5, which eliminates accidental products of hypermutation that are created during antibody affinity maturation (18). ConclusionsIn summary, this Review series surveys the complex mechanisms of autoimmunity and the potential new therapies that might target critical disease pathways, cells, and molecules. Much has been learned about the pathogenesis of autoimmune disease since the original formulation of the concept of horror autotoxicus that was forged by Paul Ehrlich during his study of the development of hemolytic antibodies in animals injected with blood of unrelated species (19)(20)(21)(22)(23)(24). The failure to deve...

show abstract

T cells in the control of organ-specific autoimmunity

Abstract: R e v i e w S e R i e S : A u t o i m m u n i t y2 2 5 1

Cited by 133 publications

References 202 publications

Regulatory T cell therapy for type 1 diabetes: May the force be with you

Regulatory T cell therapy for type 1 diabetes: May the force be with you

High self-reactivity drives T-bet and potentiates Treg function in tissue-specific autoimmunity

Putting together the autoimmunity puzzle

Contact Info

Product

Resources

About