Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes

Abstract

Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen-DR4()-restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group's daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell-specific CD8 T cells, and favorable β cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation.

Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route

“…In addition, similar to the initial NBI-6024 study, there was a trend toward modulation of the antigen-specific T-cell response with an increased frequency of IL-10-producing cells in the low-dose treatment group. A second clinical study with a single proinsulin peptide was performed in newly diagnosed patients [78]. In this study, monthly versus fortnightly intra-dermal injections of 10 µg of peptide were compared over a period of 6 months.…”

Harnessing the power of regulatory T‐cells to control autoimmune diabetes: overview and perspective

“…Studies performed in both rodents and humans suggest the notion that vaccination of short immunogenic peptides of disease‐related autoantigens may stimulate tolerogenic mechanisms and delay or prevent autoimmune diabetes. Although it is still not clear which antigen(s) should be selected to build the vaccine, epitopes of insulin/proinsulin B9–23 (the 9–23 amino acid region of the insulin B chain) and C19‐A3 (the proinsulin C‐A chain junction) are the most considered antigens and have been examined in diverse administration routes, including intrathymic, intramuscular, intradermal, subcutaneous and intranasal. These peptides, after being delivered in vivo , were capable of generating FoxP3 + T reg and/or antigen‐specific IL‐10‐producing T‐cells.…”

“…These peptides, after being delivered in vivo , were capable of generating FoxP3 + T reg and/or antigen‐specific IL‐10‐producing T‐cells. In a recently reported clinical trial, treatment of newly diagnosed (< 100 days) T1D patients with DR*04:01‐restricted proinsulin peptide C19‐A3 has been proven safe and well tolerated. C‐peptide decline and increased insulin use were not seen in the treated subjects during 12 months.…”

Have we pushed the needle for treatment of Type 1 diabetes?

“…However, a recent publication has shown that immunization with a proinsulin peptide C19-A3 was safe, and C-peptide decline and increased insulin use were not seen over 12 months [41]. There clearly are gaps in our knowledge including the adjuvants, mode of delivery, doses, and even the choice of antigen(s) [42].…”