Polyclonal Anti-T-Cell Therapy for Type 1 Diabetes Mellitus of Recent Onset

Abstract

■ AbstractThe destruction of pancreatic β-cells in type 1 diabetes mellitus is mediated by autoreactive T-lymphocyte clones. We initiated a prospective randomized controlled trial of polyclonal rabbit anti-T-cell globulin (ATG) in patients with type 1 diabetes within 4 weeks of diagnosis and with residual post-glucagon C-peptide levels still over 0.3 nmol/l. ATG was administered as an initial bolus of 9 mg/kg followed by 3 consecutive doses of 3 mg/kg. An interim analysis was performed to establish whether any significant changes in Cpeptide production and insulin requirement had occurred that would justify the continuation of this pilot study. By May 2004, 11 subjects were assigned to treatment with ATG along with intensified insulin therapy and 6 to intensified insulin therapy with placebo, and were followed for a period of at least 6 months. During the first 12 months a significant difference in the insulin dose trends was found between the groups (p = 0.010) with a lower insulin dosage in the ATG group. There was also a difference in the glucagon stimulated C-peptide level trends of marginal significance (p = 0.068). Compared to values at screening, stimulated Cpeptide levels significantly improved in the ATG group (p = 0.012) but not in the placebo group. Complete diabetes remission occurred in 2 patients in the ATG and in none of the placebo group. Glycosylated hemoglobin at 12 months tended to be lower in the ATG group (p = 0.088). Significant adverse effects of ATG treatment, mainly transient fever and moderate symptoms of serum sickness (7 and 6 subjects, respectively) were observed during the first month only. The interim analysis of this ongoing study suggests that short-term ATG therapy in type 1 diabetes of recent onset contributes to the preservation of residual C-peptide production and to lower insulin requirements in the first year following diagnosis.

T cells in the control of organ-specific autoimmunity

“…Given that Tregs work in a dominant manner through bystander suppression and induce "infectious tolerance" (127), many immunotherapies currently under development target Treg defects identified in preclinical studies, with the goal of restoring Treg function (15,128). Antithymocyte globulin (ATG) has shown promising results in NOD mice and a small clinical trial in patients with T1D (129,130) with tolerogenic potential suggested by its favorable effect on the Treg compartment in mice and humans (130)(131)(132). Recent phase II trials in patients with new-onset T1D showed no clear benefit for ATG monotherapy (133); however, a combination of low-dose ATG and G-CSF tended to preserve β cell function at 12 months following initiation of therapy (134).…”

Clinical Immunologic Interventions for the Treatment of Type 1 Diabetes

“…Another study in 2004 reported on 11 patients who received rabbit ATG and were followed for 1 year. Clinical remission was observed in treated patients (two patients reached insulin independency) (Saudek et al 2004). Side effects were transient fever and moderate symptoms of serum sickness (Saudek et al 2004).…”

“…Clinical remission was observed in treated patients (two patients reached insulin independency) (Saudek et al 2004). Side effects were transient fever and moderate symptoms of serum sickness (Saudek et al 2004). The START trial (study of thymoglobulin to arrest type 1 diabetes), headed by S. Gitelman at UCSF in partnership with the Immune Tolerance Network is including patients with recent-onset T1D aged 12-35 yr to test the capacity of ATG to halt disease progression.…”

Tolerance and Autoimmunity in Type 1 Diabetes

“…A pilot trial involving new-onset T1D patients has shown a reduction of insulin requirement (Eisenbarth et al, 1985). In a more recent study, ATG (Fresenius) retarded the loss of C-peptide in new-onset patients without the need for continuous drug administration (Saudek et al, 2004) but additional studies are being performed to confirm these findings.…”