Elsevier

The Lancet

Volume 358, Issue 9295, 24 November 2001, Pages 1749-1753
The Lancet

Articles
β-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial

https://doi.org/10.1016/S0140-6736(01)06801-5Get rights and content

Summary

Background

Type 1 diabetes results from autoimmune destruction of insulin-producing pancreatic β cells. The 60 kDa heat-shock protein (hsp60) is one of the known target self antigens. An immunomodulatory peptide from hsp60, p277, arrested β-cell destruction and maintained insulin production in newly diabetic NOD mice. We did a randomised, double-blind, phase II study of peptide treatment in patients with newly diagnosed (<6 months) type 1 diabetes.

Methods

35 patients with type 1 diabetes and basal C-peptide concentrations above 0·1 nmol/L were assigned subcutaneous injections of 1 mg p277 and 40 mg mannitol in vegetable oil (DiaPep277; n=18) at entry, 1 month, and 6 months, or three placebo injections (mannitol in vehicle; placebo; n=17). The primary endpoint was glucagon-stimulated C-peptide production. Secondary endpoints were metabolic control and T-cell autoimmunity to hsp60 and to p277 (assayed by cytokine secretion). 31 patients completed 10 months of follow-up and were included in the intention-to-treat analysis.

Findings

At 10 months, mean C-peptide concentrations had fallen in the placebo group (n=16) but were maintained in the DiaPep277 group (n=15; 0·26 [SD 0·11] vs 0·93 [0·35] nmol/L; p=0·039). Need for exogenous insulin was higher in the placebo than in the DiaPep277 group (0·67 [0·33] vs 0·43 [0·17] U/kg; p=0·042). Haemoglobin A1c concentrations were low (around 7%) in both groups. T-cell reactivity to hsp60 and p277 in the DiaPep277 group showed an enhanced T‐helper‐2 cytokine phenotype. No adverse effects were noted.

Interpretation

Although this study was small, treatment of newly diagnosed type 1 diabetes with DiaPep277 seems to preserve endogenous insulin production, perhaps through induction of a shift from T-helper-1 to T‐helper‐2 cytokines produced by the autoimmune T cells.

Introduction

Type 1 diabetes mellitus is caused by the progressive destruction of the insulin-producing β cells through an autoimmune process.1 Autoimmune destruction remains subclinical until the number of β cells is insufficient to produce the amount of insulin needed to maintain glucose homeostasis. At this point, diabetes becomes apparent. To some degree, insulin replacement repairs the secondary endocrine disease, but it cannot stop autoimmune destruction of β cells. Primary cure of type 1 diabetes would require stopping the autoimmune process in time to rescue the β cells.

The autoimmunity that brings about type 1 diabetes has been studied in NOD mice.2 Despite the differences between the species, this model has been helpful in raising fundamental questions about human disease.3 Autoimmune T cells in NOD mice react spontaneously to many different self antigens,3 one of which is the 60 kDa heat-shock protein (hsp60).4 The basis for our study was the observation that treatment of NOD mice with a peptide of hsp60, peptide p277, could save residual β-cell function even late in the course of autoimmunity, after the onset of clinical hyperglycaemia.5 Cessation of β-cell destruction seemed to result from the induction by p277 of a shift in the cytokine profile of hsp60 autoimmunity from a proinflammatory T-helper-1 (Th1) phenotype to an anti-inflammatory T‐helper‐2 (Th2) phenotype.6, 7, 8 The immunomodulation of hsp60 autoimmunity induced by p277 was specific; Th1 immunity to bacterial antigens was not affected by p277 treatment.7

In view of the observation that patients with type 1 diabetes, like NOD mice, show spontaneous T-cell autoimmunity to hsp60,9 we set out to test whether the p277 peptide might be used to prevent the autoimmune destruction of β cells in human beings. The ideal candidates for such treatment would be people with preclinical disease who have not yet lost a large proportion of β cells. However, the diagnosis of preclinical type 1 diabetes still has a degree of uncertainty,10 and a prevention trial would inevitably include individuals who might never develop the disease. Knowing that p277 treatment was effective even in clinically hyperglycaemic NOD mice,5 we elected to test the treatment in people recently diagnosed as having clinical type 1 diabetes. The primary endpoint of the study at 10 months was preservation of β-cell function detected by a halt in the loss of C-peptide production, and the secondary endpoints were a decreased need for exogenous insulin, the concentration of haemoglobin A1c, and a shift in the cytokine phenotype of the autoimmunity to hsp60 and p277.

Section snippets

Patients and study design

We screened men, aged 16–55 years, who were consecutively diagnosed as having type 1 diabetes at the Endocrine Clinic of the Hadassah University Hospital. Although a phase I study of DiaPep277 injection in 16 adults with long-term diabetes showed no toxic effects at doses up to 2·5 mg per injection (data not shown), we excluded young children and women to obtain additional safety data in adults without a risk of pregnancy. Inclusion criteria were: presentation with acute hyperglycaemia and

Results

Of 47 patients screened, 35 were eliglible. 18 were assigned DiaPep277 and 17 placebo (figure 1). By the end of the follow-up period, four patients had been lost to follow-up (one was excluded for drug use and three refused to undergo the glucagon stimulation assay). The DiaPep277 and placebo groups were similar in terms of age (29·3 [SD 11·9] vs 23·1 [6·9] years), body-mass index (22·1 [2·9] vs 21·9 [2·7] kg/m2), duration of disease (14·5 [9·9] vs 12·6 [6·6] weeks), baseline C-peptide

Discussion

The results of this clinical study are generally similar to our earlier experience with peptide p277 administered in incomplete Freund's adjuvant to newly diabetic NOD mice.5 The patients in the placebo group showed a fall in their ability to produce C-peptide and an increasing need for exogenous insulin over the period of 10 months after treatment. Both these changes can be attributed to the progressive loss of the few β cells that were still functional at the time the patients entered the

References (27)

  • D Elias et al.

    Hsp60 peptide therapy of NOD mouse diabetes induces a Th2 cytokine burst and down-regulates autoimmunity to various beta-cell antigens

    Diabetes

    (1997)
  • CF Verge et al.

    Combined use of autoantibodies (IA-2 autoantibody, GAD autoantibody, insulin autoantibody, cytoplasmic islet cell antibodies) in type 1 diabetes: Combinatorial Islet Autoantibody Workshop

    Diabetes

    (1998)
  • B Berger et al.

    Random C-peptide in the classification of diabetes

    Scand J Clin Lab Invest

    (2000)
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