Background: Autoimmunity is a consequence of low/unfit antigen-specific Tregs. If antigen-specific Tregs could be produced on demand against a desire autoimmune target, suppression of autoimmune diseases would be achievable. Here, we developed pancreatic beta cell-specific GAD65 CAR Tregs and explored their therapeutic potential against T1D.

Methods: Two GAD65 B cell epitopes known to interact with two immunodominant regions in the N-terminal (CAR-N) and Middle (CAR-M) regions were selected for assembly onto T cell receptors (CD28 hinge-transmembrane-intracellular regions and CD3ζ intracellular domain) (1). These GAD65 CAR Tregs were used to prevent/treat diabetes in our humanized mouse model of T1D.

Results: Adoptive transfer of CAR-N Tregs to the diabetic T1D mice (2) revealed that administration of beta-cell specific Tregs leads to enrichment of Treg cells at the pancreas level. Confocal images demonstrated the homing of CAR Tregs to peri-insular areas 48 hours after intravenous immunization. 30-day follow up, fasting blood glucoses and GTT/insulin secretion tests significantly deteriorated in control Groups as compared with CAR-N/M Tregs treated Groups. The pancreatic islet localization of GAD65 CAR Tregs was still demonstrable at 30 days.

Conclusions: This is the first time a therapeutic approach is successful in abrogating the diabetes phenotype in T1D mice model. Conceivably, antigen-specific Treg redirection using antigen-specific CAR Tregs and consequent Teff downregulation will allow for recovery and reconstitution of beta cells in humans as well.

References: 1)S Imam, Jaume JC. “CAR T Preventive/Therapeutic approach for type 1 Diabetes” U.S. Provisional Patent #60439-US-PSP. http://utoledo.technologypublisher.com/technology/31853 (2019).

2)S Imam, M Alfonso-Jaume, JC Jaume Spontaneous Autoimmune Diabetes in Humanized Mice Carrying Human Type 1 Diabetes Susceptibility and Uses Therefor - US Patent App.16/530,452, 2020.

Disclosure

S. Imam: None. P. Dar: None. M.A. Alfonso-Jaume: None. J.C. Jaume: None.

Funding

University of Toledo (to J.C.J.)

© 2020 by the American Diabetes Association
2020
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