Reversal of type 1 diabetes by a new MHC II‐peptide chimera: “Single‐epitope‐mediated suppression” to stabilize a polyclonal autoimmune T‐cell process

Abstract

Polyclonality of self-reactive CD41 T cells is the hallmark of several autoimmune diseases like type 1 diabetes. We have previously reported that a soluble dimeric MHC II-peptide chimera prevents and reverses type 1 diabetes induced by a monoclonal diabetogenic T-cell population in double Tg mice [Casares, S. et al., Nat. Immunol. 2002. 3: 383-391].Since most of the glutamic acid decarboxylase 65 (GAD65)-specific CD4 1 T cells in the NOD mouse are tolerogenic but unable to function in an autoimmune environment, we have activated a silent, monoclonal T-regulatory cell population (GAD65 217-230 -specific CD4 1 T cells) using a soluble I-A ab g7 /GAD65 217-230 /Fcg2a dimer, and measured the effect on the ongoing polyclonal diabetogenic T-cell process. Activated GAD65 217-230 -specific T cells and a fraction of the diabetogenic (B 9-23 -specific) T cells were polarized toward the IL-10-secreting T-regulatory type 1-like function in the pancreas of diabetic NOD mice. More importantly, this led to the reversal of hyperglycemia for more than 2 months post-therapy in 80% of mice in the context of stabilization of pancreatic insulitis and improved insulin secretion by the b cells. These findings argue for the stabilization of a polyclonal selfreactive T-cell process by a single epitope-mediated bystander suppression. Dimeric MHC class II-peptide chimeras-like approach may provide rational grounds for the development of more efficient antigen-specific therapies in type 1 diabetes.

Long-term silencing of autoimmune diabetes and improved life expectancy by a soluble pHLA-DR4 chimera in a newly-humanized NOD/DR4/B7 mouse

“…3B). The results indicated that, likewise the murine DEF-GAD65 reagent, [13][14][15] the human DEF-GAD65 reagent was able to stabilize the pancreatic insulitis.…”

“…[13][14][15] Indeed, prolonged survival observed in the non responder, hyperglycemic mice treated with hu DEF-GAD65 may be explained by the formation of a protective, stabilized peri-islet pancreatic infiltration, which in turn may provide a limited, but sufficient amount of insulin to stabilize glycemia.…”

“…10 We and others reported that a new class of antigen-specific reagents, namely soluble peptide-MHC class II chimeras (DEF reagents, "Diabetes Eliminating Factor") can delay the pre-clinical stage of diabetes, and more importantly reverse the early T1D onset in mouse models in the absence of side-effects and more efficiently than the synthetic peptide preparations. [11][12][13][14] A murine DEF reagent was also able to protect grafted pancreatic islets against the re-emerging diabetes. 15 DEF reagents have a 2 to 3-d life-span in vivo, 16 do not require adjuvant to reach the therapeutic effect, and are devoid of side effects.…”

“…15 DEF reagents have a 2 to 3-d life-span in vivo, 16 do not require adjuvant to reach the therapeutic effect, and are devoid of side effects. [13][14][15][16] On a molar basis, a soluble DEF dimer can deliver ≈1000-times more tolerogenic peptide than the APC-expressing MHC class II molecules can naturally load in vivo. 17 DEF anti-diabetogenicity was shown to rely mostly on the induction of IL-4-secreting Th2 cells and IL-10-secreting TR-1 suppressor cells in the pancreas.…”

Antigen-Specific Therapeutic Approaches in Type 1 Diabetes

“…Administration of dimeric pMHC have proved effective in the prevention of diabetes in spontaneous and transfer models (Masteller et al 2003;Li et al 2009;Lin et al 2010) and reversal of hyperglycemia (Casares et al 2002;Lin et al 2010). These outcomes were attributed to the generation of anergic IL-10-producing CD4 þ T cells.…”