Background & Purpose

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PURPOSE

A number of beta cell neoepitopes, modified forms of native antigen, have been described and implicated in Type 1 Diabetes (T1D) pathogenesis. However, to date the utility of T1D neoepitopes either as biomarkers for improved disease staging/prognostication or as therapeutic intervention points has not been determined. This RFA is intended to support research projects that explicitly address these questions.

BACKGROUND

To date, evidence demarcating the break in tolerance that precipitates the destruction of the β cell in T1D has not been shown. In T1D and other autoimmune diseases, a growing hypothesis is that the generation of modified antigens that differ from the native form may represent the loss of tolerance. Central and peripheral tolerance mechanisms are suited to remove autoreactive immune responses to native antigen so as to prevent future autoimmunity. However, biochemical modification of these antigens may camouflage them from tolerance mechanisms and allow the persistence of cellular and humoral immunity to these neoepitopes.

Multiple lines of evidence demonstrate that these neoepitopes can be formed under beta cell stress and other situations. Both cellular and humoral responses to these have been detected in individuals with T1D. In other autoimmune diseases, neoepitope responses have been directly linked to the pathogenesis of the disease and been successfully utilized as disease biomarkers or as the basis for therapeutic interventions such as citrullinated peptides in rheumatoid arthritis.

However, in T1D, limited data regarding the timing, prevalence, and phenotypes of these responses precludes utilizing neoepitope responses for questions of staging or stratification or to inform therapeutic interventions. Given that multiple neoepitopes have been identified in T1D, this RFA prompts investigators to apply these findings to:

– Inform on the causation and pathology of the disease
– Improve on the current stratification and staging paradigms
– Inform on existing or devise novel therapeutic approaches based on these responses