title: Beta-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial.
abstract: BACKGROUND
  Type 1 diabetes results from autoimmune destruction of insulin-producing pancreatic beta cells. The 60 kDa heat-shock protein (hsp60) is one of the known target self antigens. An immunomodulatory peptide from hsp60, p277, arrested beta-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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine, Hadassah-Hebrew University Medical School, Jerusalem, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Raz
authors.forename: D
authors.initials: D
authors.lastname: Elias
authors.forename: A
authors.initials: A
authors.lastname: Avron
authors.forename: M
authors.initials: M
authors.lastname: Tamir
authors.forename: M
authors.initials: M
authors.lastname: Metzger
authors.forename: I R
authors.initials: IR
authors.lastname: Cohen
mesh_terms: D000328:Adult; D002096:C-Peptide / Q000096:biosynthesis; D018834:Chaperonin 60; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D004311:Double-Blind Method; D006360:Heat-Shock Proteins / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism; D000078790:Insulin Secretion; D007378:Interleukins / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010446:Peptide Fragments / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D002096:C-Peptide; D018834:Chaperonin 60; D006360:Heat-Shock Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D007378:Interleukins; D010446:Peptide Fragments; C095402:peptide 277, heat shock protein 60