Severe anaphylactic reactions to glutamic acid decarboxylase (GAD) self peptides in NOD mice that spontaneously develop autoimmune type 1 diabetes mellitus

Here we show that NOD mice, that spontaneously develop T1DM, can develop fatal anaphylactic reactions upon challenge with preparations of immunodominant GAD65 self peptides after immunization with these peptides to modify the development of T1DM.These findings document severe anaphylaxis to self peptide preparations used in an attempt to devise immunotherapy for a spontaneous autoimmune disease. Taken together with the findings in EAE, these results suggest that peptide therapies designed to induce a TH1 to TH2 shift carry a risk for the development of anaphylactic reactivity to the therapeutic peptides.Type 1 diabetes mellitus (T1DM) is a T cell-mediated autoimmune disease characterized by lymphocytic infiltration of the pancreatic islets of Langerhans with subsequent destruction of the insulin-producing beta cells [1]. Non-obese diabetic (NOD) female mice, a murine model for T1DM, spontaneously develop diabetes by 30 weeks-of-age, with infiltrating cells appearing around the pancreatic islets as early as at 3–4 weeks-of-age [2].T1DM susceptibility in the NOD mouse is linked to I-Ag7, the murine MHC class II gene that encodes a histidine at position 56 and a serine at position 57 in the β chain, in place of the more frequent proline 56β and aspartic acid 57β [3]. The development of diabetes is prevented in NOD.PD mice (which are NOD mice with I-Ag7) that carry a β chain transgene with site-specific mutations that restore proline and aspartic acid at positions 56β and 57β, respectively [4]. Furthermore, because of the two amino acid changes in the additional (transgenic) MHC class II allele β chain in NOD.PD mice, NOD.PD mice recognize three additional peptide epitopes in the glutamic acid decarboxylase 65 (GAD65) autoantigen [5].Among beta-cell autoantigens, GAD65 is an important initial target of the immune response that results in beta-cell destruction and diabetes, in both humans and NOD mice [6-9]. While both humoral and cellular responses to GAD65 occur as ear