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