Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes

Haller, Michael J.; Gitelman, Stephen E.; Gottlieb, Peter A.; Michels, Aaron; Rosenthal, Stephen M.; Shuster, Jonathan J.; Zou, Baiming; Brusko, Todd M.; Hulme, Maigan A.; Wasserfall, Clive; Mathews, Clayton E.; Atkinson, Mark A.; Schatz, Desmond

doi:10.1172/jci78492

Cited by 143 publications

(142 citation statements)

References 24 publications

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“…In sharp contrast to what we observed in T1DAL, antithymocyte globulin led to a significant decrease in Treg/Tem ratios. Interestingly, results from a recently reported pilot study (n = 25) of the combination of antithymocyte globulin and G-CSF in patients with established T1D suggested a treatment benefit and revealed the preservation of Tregs (35). These results suggest that higher Treg/Tem ratios may be an important biomarker of treatment benefit, a hypothesis that needs validation in larger trials and with other agents.…”

Section: Discussionmentioning

confidence: 97%

Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

Rigby

Harris²,

Pinckney³

et al. 2015

Journal of Clinical Investigation

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BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D.METHODS. In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses.RESULTS. A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent betweengroup difference in glycemic control or adverse events. Alefacept treatment depleted CD4 + and CD8 + central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1 + CD4+ Tem and Tcm (P < 0.01).CONCLUSIONS. In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy.TRIAL REGISTRATION. https://clinicaltrials.gov/ NCT00965458.FUNDING. NIH and Astellas.

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Section: Discussionmentioning

confidence: 97%

Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

Rigby

Harris²,

Pinckney³

et al. 2015

Journal of Clinical Investigation

Self Cite

256

210

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“…Promising findings were also noted in the TIDAL study, in which new onset T1D subjects treated with human leukocyte function antigen-3 (LFA-3)-Ig (Alefacept) exhibited depletion of T central and effector memory cells but preserved Tregs, with an increase in the Treg to Teff ratio, and with resultant preservation of beta cell function approximately 18 months after therapy was stopped [12]. Although anti-thymocyte globulin (ATG) alone was ineffective [48], lower dose ATG coupled with granulocyte colony stimulating factor (GCSF) appears promising in resetting the balance bewteen Tregs and Teffs in recent onset T1D, while preserving beta cell function [49].…”

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

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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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“…A combination therapy of G-CSF with ATG was also successful in reversing new-onset diabetes in NOD mice [13]. A recent clinical trial testing this combination therapy met the primary endpoint of preserved c-peptide at 12 months, suggesting that G-CSF, when combined with a T lymphocyte depleting therapy, can provide beneficial therapeutic effects in patients with T1D [64].…”

Section: Immunoregulatory Role Of G-csf In Autoimmune Diseasesmentioning

confidence: 99%