Immunological efficacy of heat shock protein 60 peptide DiaPep277TM therapy in clinical type I diabetes

Abstract

SummaryAn immunogenic peptide (p277) from the 60-kDa heat shock protein (hsp60) arrested beta-cell destruction in non-obese diabetic mice. A randomized, double-blind, phase Ib/II clinical trial of DiaPep277 peptide treatment was performed in recent-onset type 1 diabetes patients with remaining insulin production. We studied the immunological efficacy of this peptide therapy and correlated this with clinical outcome. Forty-eight C-peptide-positive patients were assigned subcutaneous injections of 0·2, 1·0 or 2·5 mg p277 (n = 12 per dosage) at entry, and 1, 6 and 12 months, or four placebo injections (n = 12). T cell autoimmunity to hsp60, DiaPep277, glutamic acid decarboxylase and tetanus toxoid (recall response control) were assayed by proliferation and cytokine secretion assays (enzyme-linked immunospot) at regular intervals until 18 months after the first injection. All treated patients at each dosage of peptide demonstrated an altered immune response to DiaPep277, while the majority of placebo-treated patients remained non-responsive to treatment (P = 0·00001), indicating a 100% efficacy of immunization. Cytokine production in response to therapy was dominated by interleukin (IL)-10. IL-10 production before therapy and decreasing autoantigen-specific T cell proliferation were associated with beta-cell preservation. Third-party control immune responses were unaffected by therapy. No potentially adverse immunological side effects were noted. DiaPep277 is immunogenic in type 1 diabetic subjects and has immune modulating properties. Immunological monitoring distinguished therapy from placebo treatment and could determine immunological efficacy. Declining or temporary proliferative responses to peptide DiaPep277 treatment may serve as an immunological biomarker for clinical efficacy.

PAN–DR‐Binding Hsp60 self epitopes induce an interleukin‐10–mediated immune response in rheumatoid arthritis

“…Because these T cells are specific for self or almost-self antigens, it is expected that these cells are under the control of peripheral tolerance and thus do not proliferate vigorously (31,49).…”

Tolerization against atherosclerosis using heat shock protein 60

“…Thus, even if the tolerizing approach in mice may form the basis for the subsequent development of such a vaccine in humans, it is rather improbable that the same HSP60 peptide candidate will emerge as atherogenic in both species. However, promising results from clinical trials for treating rheumatoid arthritis and type I diabetes are currently ongoing (Prakken et al 2004;Raz et al 2001Raz et al , 2007Huurman et al 2007Huurman et al , 2008Lazar et al 2007;Koffeman et al 2009). A better understanding of these networks is highly warranted.…”

T cell recognition of naturally presented epitopes of self-heat shock protein 70

“…T cell reactivity toward HSP70 epitopes is not yet described in human autoimmune diseases. Nevertheless, T cell response toward other self-heat shock protein peptides (DiaPep277, pan-DR binding HSP60, DnaJp1) is present in autoimmune diseases such as in type I diabetes (Huurman et al 2008;Raz et al 2001), juvenile idiopathic arthritis, and rheumatoid arthritis (de Jong et al 2009;Kamphuis et al 2005;Koffeman et al 2009;Prakken et al 2004). Knowledge of T cell responses toward these self-epitopes in chronic inflammation could help find strategies to restore the immune balance in chronic inflammation.…”