Prevention of diabetes by manipulation of anti-IGRP autoimmunity: high efficiency of a low-affinity peptide

Abstract

Weaker is better ntigenic therapy researchers have long relied on repeated dosing of high-affinity ligands to inactivate select T cells by causing over-stimulation that leads to apoptosis. Contrary to this strategy, Bingye Han, Pau Serra, Pere Santamaria (University of Calgary, Alberta, Canada), and colleagues now show that low-affinity peptides targeting autoreactive T cells protect mice more effectively against diabetes than do high-affinity peptides. Peptides that are similar in sequence to a portion of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) that strongly bound to autoreactive T cells nearly completely obliterated this T cell pool in mice. But lurking in the background were smaller pools of autoreactive T cells that were impervious to the high-affinity peptide, yet reactive against other portions of IGRP. Once their competition had been eliminated, these cells emerged to fill in the vacant niche. The high-affinity peptide thus failed to protect against diabetes. Low-affinity peptides, by contrast, selectively eliminated the most menacing of IGRP-reactive T cells, while maintaining a substantial population of more benign T cells that recognized, but were not harmed by, the peptides. By becoming established as the dominant population, the nonpathogenic T cells effectively blocked more reactive but less prevalent T cells from taking over. Now with a better grasp on the fine balance between ligand binding and dosage, Santamaria says, "targeting multiple epitopes simultaneously is likely to be more practical than finding the optimal dose for deletion of high-avidity subtypes while preserving low-avidity subtypes."

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

“…For example, the encephalitogenic peptide, myelin basic protein [73][74][75][76][77][78][79][80][81][82][83][84][85][86][87] , has been shown to bind poorly to class II molecules [30]. While some high-affinity pathogenic epitopes have been shown to be associated with some autoimmune diseases, low-affinity epitopes have also been implicated in inflammatory diseases such as diabetes, autoimmune encephalitis, uveoretinitis and experimental myasthenia gravis [41][42][43][44]. Our data in conjunction with the previous findings of the association of low to moderate affinity of select disease-associated epitopes suggest that many autoantigenic epitopes may be presented by DM-negative nonprofessional APC.…”

Deletion of the gene encoding the islet-specific glucose-6-phosphatase catalytic subunit-related protein autoantigen results in a mild metabolic phenotype

“…Most importantly, G6PC2 has recently also been shown to be an autoantigen in human type 1 diabetes [5] and in humanised NOD mice [6]. Given the observations that administration of G6PC2-derived peptides abrogate or delay the disease process in NOD mice [4,7] and that NOD mice expressing a nonantigenic form of insulin do not develop diabetes [8], it is possible that strategies designed to suppress G6pc2 expression might also be used to delay or prevent the onset of this disease. However, since the function of G6PC2 is unclear, the concern with such an approach is that the absence of G6PC2 might itself have deleterious consequences.…”

The Cross-Priming Capacity and Direct Presentation Potential of an Autoantigen Are Separable and Inversely Related Properties

“…IGRP is a major target of the diabetogenic CD8 + T cell response, where it functions as the source of numerous epitopes (12). b-cells do not express costimulatory molecules or MHC class II molecules and thus cannot directly prime the diabetogenic autoimmune response.…”

“…Remarkably, these T cells are prevalent in the peripheral repertoire, particularly as clinical disease nears (11). Nevertheless, islet-associated CD8 + T cells in T1D target numerous other islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) epitopes (12), indicating that IGRP is a prevalent source of diabetogenic epitopes.…”