Therapy of type 1 diabetes with CD4⁺CD25^highCD127-regulatory T cells prolongs survival of pancreatic islets — Results of one year follow-up

Highlights

• This study shows first-in-man treatment of type 1 diabetes with T regulatory cells.

• It has been found that repetitive administration of Tregs in DM1 children is safe.

• The administration of Tregs prolonged survival of β cells in DM1 patients.

Abstract

It is hypothesized that CD4⁺CD25⁺FoxP3⁺ regulatory T cells (Tregs) can prevent destruction of pancreatic islets protecting from type 1 diabetes (DM1).

Here we present results of one year follow-up of 12 DM1 children treated with autologous expanded ex vivo Tregs. Patients received either a single or double Tregs infusion up to the total dose of 30 × 10⁶/kg.

No severe adverse effects were observed. The treatment did not impair post-immunization antibody responses. Tregs infusion was followed by increase in Tregs number in peripheral blood. Most of the patients responded to the therapy with increase in C-peptide levels (8/12 and 4/6 after the first and the second dose, respectively). Tregs administration resulted also in lower requirement for exogenous insulin (8/12 treated patients versus 2/10 untreated controls in remission) with two children completely insulin independent at one year. Repetitive administration of Tregs is safe and can prolong survival of β-cells in DM1 (registration: ISRCTN06128462).

Introduction

The primary factors responsible for destruction of β cells in type 1 diabetes mellitus (DM1) still remain unknown. Initial histological changes observed in affected pancreatic islets are described as insulitis and are considered to be a manifestation of T cell dependent autoimmune attack [1]. According to the current knowledge one of the most important factors in etiology of DM1 is an impaired regulation of the immune system, thus autoaggressive effector T cells are not controlled by suppressive regulatory T cells [2]. Therefore, the majority of the current studies that aim to preserve β cells in DM1 are focused on suppression of autoreactive T cells and boosting activity of regulatory T cells [3].

Here we present a prospective, non-randomized safety and efficacy pilot study of cellular therapy of recent-onset DM1 with ex vivo expanded CD4⁺CD25^highCD127-regulatory T cells (Tregs). Over a year ago, we applied Tregs to DM1 patients in an aim to restore regulation in the immune system and stop or at least delay progress of the disease. Our initial results with dose acceleration from 10 × 10⁶ cells/kg of body weight (b.w.) to 20 × 10⁶ cells/kg b.w. were promising [4]. However, data collected upon follow-up suggested that additional acceleration of the dose of Tregs may be beneficial for the patients. As our laboratory has a 6 year of uneventful experience with clinical therapy with ex vivo expanded Tregs, including the first-in-man clinical application of Tregs in graft versus host disease (GvHD) [5], [6], we decided to administer the second accelerating dose of Tregs to 6 patients (amended approval of Bioethics Committee NKEBN/8/2010). Hence, the highest total dose of administered Tregs was  30 × 10⁶ cells/kg of b.w.

In the present paper we show the results of the one year follow-up of the outcomes.