CD4+CD25+CD127hi cell frequency predicts disease progression in type 1 diabetes.

Aditi Narsale,Rosa Moya,Irene Gotuzzo,Martin J Hessner,Kerry Buchanan,Benedetta Pessina,Joanna D Davies,Elisavet Serti,Alessandra Mandelli,Mark Harris,Ranjeny Thomas,Anne-Sophie Bergot,Breanna Lam,Tingting Lu,Rhonda Geoffrey,Manuela Battaglia,Gianmaria Giamporcaro

doi:10.1172/jci.insight.136114

Abstract

Transient partial remission, a period of low insulin requirement experienced by most patients soon after diagnosis, has been associated with mechanisms of immune regulation. A better understanding of such natural mechanisms of immune regulation might identify new targets for immunotherapies that reverse type 1 diabetes (T1D). In this study, using Cox model multivariate analysis, we validated our previous findings that patients with the highest frequency of CD4+CD25+CD127hi (127-hi) cells at diagnosis experience the longest partial remission, and we showed that the 127-hi cell population is a mix of Th1- and Th2-type cells, with a significant bias toward antiinflammatory Th2-type cells. In addition, we extended these findings to show that patients with the highest frequency of 127-hi cells at diagnosis were significantly more likely to maintain β cell function. Moreover, in patients treated with alefacept in the T1DAL clinical trial, the probability of responding favorably to the antiinflammatory drug was significantly higher in those with a higher frequency of 127-hi cells at diagnosis than those with a lower 127-hi cell frequency. These data are consistent with the hypothesis that 127-hi cells maintain an antiinflammatory environment that is permissive for partial remission, β cell survival, and response to antiinflammatory immunotherapy.

Highlights

Type 1 diabetes (T1D) is a progressive heterogeneous autoimmune disease resulting in the destruction of insulin-secreting β cells by T cells [1]
This study validates our previously published finding that the probability of remaining in remission for patients newly diagnosed with T1D is significantly greater for the patients who have the highest relative frequency of 127-hi cells at diagnosis [19]. We extend these findings to show that patients with the highest frequency of 127-hi cells have the greatest probability of preserving β cell function
As β cell function declines over time after diagnosis, 127-hi cell frequency is reduced, again associating with disease progression

Summary

Introduction

Type 1 diabetes (T1D) is a progressive heterogeneous autoimmune disease resulting in the destruction of insulin-secreting β cells by T cells [1]. There is still no therapy to stop and reverse the disease. There are sufficient examples of immunotherapies that transiently preserve β cell function in subpopulations of patients to encourage the notion that disease progression can be modulated by targeting the immune system [2,3,4,5,6]. In an effort to identify novel immune mechanisms that might be targeted therapeutically to treat and reverse T1D, our group has focused attention on a well-recognized natural phenomenon called partial remission, a period of improved glucose control experienced by many patients with T1D soon after diagnosis [7,8,9,10]. Identifying mechanisms that promote and extend partial remission might identify new targets for novel therapies to reduce short- and long-term complications

Methods

Results

Conclusion