Type 1 Diabetes - January 2021

Type 1 Diabetes - January 2021

Preclinical results in mice targeting transcriptional coregulator OCA-B/Pou2af1 and its effect on Type 1 Diabetes

09 Dec 2020

  • Objective:
    • To assess if T cell-specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes/ Type 1 Diabetes
  • Methods:
    • Investigators developed an OCA-B conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background
  • Results:
    • T cell-specific OCA-B loss protected mice from spontaneous disease
    • Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present but associated with anergic phenotypes
    • The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice but diminished in monoclonal models specific to artificial or neoantigens
    • Rationally designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels and reduced T cell infiltration and proinflammatory cytokine expression in newly diabetic NOD mice
  • Conclusion:
    • The results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition

OCA-B promotes pro-inflammatory T cell phenotypes needed in Type 1 Diabetes and can be targeted pharmacologically

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CI Scientists Remarks: 

  • In Type 1 Diabetes, the immune system is misled towards antigens associated with beta cells of the endocrine pancreas
  • OCA-B (Pou2af1/OBF-1/Bob.1) promotes memory T cell function in CD4 T cells via the maintenance of poised gene expression states at multiple direct immunomodulatory target genes (e.g. IL2, IL21, IFNG, and IL2ra)
  • OCA-B is not expressed in naïve CD4 T cells but becomes stably expressed upon stable antigen exposure
  • Memory T cell phenotypes can promote autoimmunity (including T1D), even in cases of persistent self-antigens.
  • Consistently, OCA-B levels are strongly elevated in central memory CD4 T cells but are even more elevated in islet-reactive, pancreas-infiltrating CD4 T cells in T1D
  • Preclinical results showed that rationally-designed peptide inhibitor of OCA-B downstream effector function and improve glucose levels in NOD mice genetically pre-disposed to T1D
  • Together with these results along with earlier studies, targeting OCA-B pharmacologically can be a valid approach in T1D patients

– Dr. Kowndinya, CI Scientists

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