Combination Therapy Using IL-2/IL-2 Monoclonal Antibody Complexes, Rapamycin, and Islet Autoantigen Peptides Increases Regulatory T Cell Frequency and Protects against Spontaneous and Induced Type 1 Diabetes in Nonobese Diabetic Mice

Manirarora, Jean N.; Wei, Cheng‐Hong

doi:10.4049/jimmunol.1402540

Cited by 36 publications

(34 citation statements)

References 52 publications

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“…A combinational therapy has also been assessed with the use of IL-2/anti-IL-2 Ab complexes in combination with rapamycin and islet antigen peptide treatment. T reg expansion was observed and mice protected from diabetes development in both spontaneous and induced models of diabetes (43). …”

Section: Boosting Tregs In Mice and Humansmentioning

confidence: 99%

Are Regulatory T Cells Defective in Type 1 Diabetes and Can We Fix Them?

Visperas

Vignali

2016

The Journal of Immunology

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Regulatory T cells (Tregs) are critical regulators of peripheral immune tolerance. Treg insufficiency can lead to autoimmune disorders, including Type 1 Diabetes (T1D). Increasing evidence in mouse models of T1D, as well as other autoimmune disorders, suggest that there are defects in Treg-mediated suppression. Indeed, while Treg frequency in the peripheral blood of T1D patients is unaltered, their suppressive abilities are diminished compared to Tregs in healthy controls. Although expression of the transcription factor Foxp3 is a prerequisite for Treg development and function, there are many additional factors that can alter their stability, survival and function. Much has been learned in other model systems, such as tumors, about the mechanism and pathways that control Treg stability and function. This review poses the question: can we use these findings to develop new therapeutic approaches that might boost Treg stability, survival and/or function in T1D, and possibly other autoimmune disorders?

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Section: Boosting Tregs In Mice and Humansmentioning

confidence: 99%

Are Regulatory T Cells Defective in Type 1 Diabetes and Can We Fix Them?

Visperas

Vignali

2016

The Journal of Immunology

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“…Besides, studies have also shown that Tregs in subjects with T1D has defects in their immunosuppressive function . Tregs, especially beta cell‐specific Tregs have been shown to preserve the beta cell mass, delay progression of diabetes and have been explored during the past few years for cellular therapy of T1D . To the best of our knowledge, this is first report that shows the characteristics of islet‐associated (PI‐specific) Tregs in human subjects with T1D.…”

Section: Discussionmentioning

confidence: 88%

“…12,42 Tregs, especially beta cell-specific Tregs have been shown to preserve the beta cell mass, delay progression of diabetes and have been explored during the past few years for cellular therapy of T1D. [43][44][45][46][47] To the best of our knowledge, this is first report that shows the characteristics of islet-associated (PI-specific) Tregs in human subjects with T1D. In this study, we first observed a higher frequency of polyclonal Tregs in AOT1D subjects with better preservation of beta cell mass that had a positive correlation with age.…”

Section: Discussionmentioning

confidence: 99%

Characterization of proinsulin‐specific regulatory T cells in type 1 diabetes at different ages of onset

et al. 2019

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Background and Objectives Regulatory T cells (Tregs) play an important role in maintaining tolerance to self‐antigens. Defects in the frequency and function of polyclonal Tregs have been reported in type 1 diabetes (T1D). However, characteristics of proinsulin (PI)‐specific Tregs in human T1D have not yet been explored. Therefore, we aimed to characterize PI‐specific Tregs in two distinct pathophysiological subtypes of T1D, juvenile‐onset T1D (JOT1D) and adult‐onset T1D (AOT1D), distinguished by the age of onset. Methods Peripheral blood mononuclear cells of the recruited subjects were stimulated in vitro with PI‐derived peptides. PI‐specific Tregs were characterized by flow cytometry using the combination of markers CD25, CD137, FOXP3 and CD45RA. Results Firstly, we observed similar frequencies of polyclonal Tregs in the T1D (n = 25) and healthy control (HC) (n = 20) subjects (P = 0.96), with a positive correlation between age and frequency of polyclonal Tregs (r = +0.35, P = 0.04). While the frequency of polyclonal Tregs was higher in AOT1D group (P = 0.02), both JOT1D (n = 14) and AOT1D groups (n = 11) had a comparable frequency of PI‐specific Tregs in their peripheral blood. The frequency of PI‐specific memory Tregs was significantly high in both the JOT1D (P = 0.02) and AOT1D (P = 0.009) groups compared to their respective HC groups (n = 10). Finally, we observed no significant difference in the expression of FOXP3 and IL‐2 receptor in PI‐specific Tregs in all the groups. Conclusions Unlike polyclonal Tregs, both T1D subtypes harbor comparable frequencies of PI‐specific Tregs. Chronic antigen presentation results in a distinct memory‐like phenotype of PI‐specific Tregs in these subjects irrespective of the age of disease onset.

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“…A phase I trial focused on use of rapamycin and IL-2 in an effort to boost Treg function in recent-onset T1D, and the use of this combination was based on strong preclinical data suggesting modulation of multiple aspects of T1D pathogenesis in mouse studies (73, 74). Rapamycin is routinely used during organ transplantation and blocks the mammalian target of rapamycin complex 1 (mTORc1), which is an important regulator of cell cycle progression (75).…”

Section: Combination Immunotherapiesmentioning

confidence: 99%

Combination Immunotherapy for Type 1 Diabetes

Bone

Evans‐Molina

2017

Curr Diab Rep

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Purpose of Review Type 1 Diabetes (T1D) is an autoimmune disease marked by β-cell destruction. Immunotherapies for T1D have been investigated since the 1980s and have focused on restoration of tolerance, T-cell or B-cell inhibition, regulatory T-cell (Treg) induction, suppression of innate immunity and inflammation, immune system reset, and islet transplantation. The purpose of this review is to provide an overview and lessons learned from single immunotherapy trials, describe recent and ongoing combination immunotherapy trials, and provide perspectives on strategies for future combination clinical interventions aimed at preserving insulin secretion in T1D. Recent Findings Combination immunotherapies have had mixed results in improving short-term glycemic control and insulin secretion in recent-onset T1D. Summary A handful of studies have successfully reached their primary end-point of improved insulin secretion in recent-onset T1D. However, long-term improvements glycemic control and the restoration of insulin independence remain elusive. Future interventions should focus on strategies that combine immunomodulation with efforts to alleviate β-cell stress and address the formation of antigens that activate autoimmunity.

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Combination Therapy Using IL-2/IL-2 Monoclonal Antibody Complexes, Rapamycin, and Islet Autoantigen Peptides Increases Regulatory T Cell Frequency and Protects against Spontaneous and Induced Type 1 Diabetes in Nonobese Diabetic Mice

Cited by 36 publications

References 52 publications

Are Regulatory T Cells Defective in Type 1 Diabetes and Can We Fix Them?

Are Regulatory T Cells Defective in Type 1 Diabetes and Can We Fix Them?

Characterization of proinsulin‐specific regulatory T cells in type 1 diabetes at different ages of onset

Combination Immunotherapy for Type 1 Diabetes

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