Rapamycin/IL-2 Combination Therapy in Patients With Type 1 Diabetes Augments Tregs yet Transiently Impairs β-Cell Function

Long, S. Alice; Rieck, Mary; Sanda, Srinath; Bollyky, Jennifer; Samuels, Peter L.; Goland, Robin; Ahmann, Andrew; Rabinovitch, Alex; Aggarwal, Sudeepta; Phippard, Deborah; Turka, Laurence A.; Ehlers, Mario R.; Bianchine, Peter J.; Boyle, Karen D.; Adah, Steven A.; Bluestone, Jeffrey A.; Buckner, Jane H.; Greenbaum, Carla J.

doi:10.2337/db12-0049

Cited by 286 publications

(256 citation statements)

References 43 publications

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“…Downstream of the cytokine receptors, small molecule inhibitors of JAKs have proven to be successful as potent immunosuppressants, but their ability to target specific T helper cell activities is limited because several cytokine receptors use each kinase 34 . Blockade of mTOR activity with rapamycin in type 1 diabetes is already under investigation in combination with IL-2 to promote T Reg cell function 177 . However, enhanced T Reg cell frequencies with rapamycin and IL-2 is transient because, as discussed, it seems that inhibition further up the signalling cascade at AKT is most important for the promotion of T Reg cell stability and function 79,80 .…”

Section: Bet Inhibitorsmentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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| CD4 + T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4 + T cell plasticity by examining the molecular mechanisms that regulate it -from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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Section: Bet Inhibitorsmentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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“…Individuals carrying the rs12722495 susceptibility gene, which encodes an IL-2RA haplotype, exhibit reduced proliferative responses to IL-2 and decreased suppressive function of Tregs in vitro, which presumably indicates impaired Treg function in these patients [40,41]. Notably, in response to IL-2, this defect appears to be reversible: in a previously conducted clinical trial of exogenous IL-2, the impaired STAT5 phosphorylation was improved [39,42].…”

Section: Treg Overview and Role In Dmmentioning

confidence: 99%

“…This transcription factor is essential for Treg expansion and survival. A prior clinical trial with IL-2 and rapamycin showed that this signaling pathway improved in the Tregs from the T1D patients at least one year post treatment [42]. We addressed whether the in vitro-expanded Tregs would have similar improvement following culture with exogenous IL-2.…”

Section: Treg Manufacture For Clinical Usementioning

confidence: 99%

“…Early clinical studies with low dose IL-2 have resulted in selective Treg increases with salutary clinical responses in alopecia areata, HCV-induced vasculitis, and graft versus host disease [63e65]. A clinical trial with IL-2 plus rapamycin showed transient worsening in beta cell function [42], likely due to either the relatively higher dose of IL-2 employed and/or the rapamycin, with a dramatic increase in natural killer cells and eosinophils. However, early T1D studies with lower IL-2 doses have shown no acute worsening in b-cell function [66,67], and several studies are underway now to further assess safety and efficacy.…”

Section: Combination Therapymentioning

confidence: 99%

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

Gitelman

Bluestone

2016

Journal of Autoimmunity

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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.

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“…146 Although this combination therapy increased Treg numbers in the first month, it also transiently impaired β-cell function.…”

Section: Disclosure Of Potential Conflicts Of Interestmentioning

confidence: 99%