Tolerogenic insulin peptide therapy precipitates type 1 diabetes

Abstract

Daniel et al. (https://doi.org/10.1084/jem.20110574) have previously published in JEM a study on the preventive effect of tolerogenic vaccination with a strong agonist insulin mimetope in type 1 diabetes. Our study now challenges these results and shows that osmotic pump delivery of the modified insulin peptide R22E did not prevent hyperglycemia, accelerated disease onset, increased its incidence, and worsened insulitis.

Figure 1.

R22E treatment anticipates disease onset and increases T1D incidence. NOD females selected for serum IAA titers <0.1 were treated with the indicated peptides (filled symbols) for 14 d (filled area), and glycemia was monitored weekly from 10 to 30 wk of age. (A and B) Screen and osmotic pump insertion were performed at 4 wk of age in females from colonies #1 (A) and #2 (B). Control mice from colony #2 (B) underwent sham surgeries (Ctrl-Sham). (C–E) Females from colony #1, IAA^low at 6 wk of age, were implanted 1 wk later with osmotic pumps containing R22E (C) or were first submitted to sham-thymectomy (SHAM-TX; D) or full thymectomy (TX; E). (F) As in C, except B9:23-containing osmotic pumps. Treated mice are from two (A, C, and F), four (B), and three (D and E) independent experiments with n = 1 and 11 in A; n = 3, 5, 6, and 6 in B; n = 9 and 12 in C; n = 5, 1, and 4 in D; n = 7, 2, and 5 in E; and n = 5 and 7 in F. Log-rank tests statistical differences for T1D incidence in Kaplan-Meier survival plots: not significant in A (P = 0.977) and B (P = 0.3365); significant in C (P = 0.0240), D (P = 0.0221), E (P = 0.0017), and F (P = 0.0345). Controls are different animals between panel C and F, and from those presented in Fig. S1.

Figure 2.

R22E treatment worsens insulitis in normoglycemic mice. Pancreas sections from nine control and six R22E-treated females normoglycemic at 30 wk of age (see Fig. 1 C) were scored blindly, all together at once, for insulitis severity. (A and B) Representative stainings used to identify insulin-producing islets (insulin/glucagon/Hoechst; A) and to score islets infiltration (hematoxylin and eosin; B). Bars, 100 µm. (C) Frequency of insulin-producing islets. (D) Frequency of infiltrated islets along a severity score (4 is most severe). ND, <50 islets detected.