Biology subjects

Barra, J. M.

Publications and source records attributed to Barra, J. M..

3 recordsLinked to original sources

bioRxiv2025

Inhibition of cell-mediated immunity in type 1 diabetes by beta cell-targeted PD-1 agonists in pancreas tissue slices

Tissue-targeted immunotherapies for type 1 diabetes (T1D) hold potential to protect pancreatic beta cells while minimizing systemic immunosuppression. We used a bispecific agonist called Immune Modulating Monoclonal-TCR Against Autoimmune Disease (ImmTAAI), consisting of a T cell receptor (TCR) targeting domain fused with a PD-1 agonist to specifically bind beta cells and suppress autoreactive T cells. We used live pancreas slices to demonstrate targeting of ImmTAAI molecules to pre-proinsulin peptide-HLA-A2 complexes on human beta cells. ImmTAAI protected beta cells from T cell killing by increasing T cell motility and inhibiting cytokine secretion. ImmTAAI treatment also increased the motility of islet-infiltrating T cells in slices from a donor with recent-onset T1D and preserved insulin secretion in slices co-cultured with T cell avatars transduced with diabetogenic TCRs. These data demonstrate that ImmTAAI molecules have the potential to limit T cell activity locally, making this an attractive platform to elicit targeted immunoregulation in T1D. One Sentence SummaryWe demonstrate inhibition of cellular immunity in human type 1 diabetes using a beta cell-targeting, affinity-enhanced TCR fused to a PD-1 agonist.

bioengineering↗

bioRxiv2025

Human Stem Cell-Derived β-cells Expressing An Optimized CD155 Reduce Cytotoxic Immune Cell Function for Application in Type 1 Diabetes

Insulin-producing {beta}-cell replacement therapies offers a potential treatment for type 1 diabetes (T1D) but faces challenges from donor shortages and immune rejection. Stem cell-derived {beta}-cells (sBC) provide a renewable source but remain vulnerable to immune attack. We engineered human pluripotent stem cells to express either the wildtype (WT) or a high-affinity mutant (Mut) variant (rs1058402, G>A; Ala67Thr) of the NK and T cell checkpoint inhibitor CD155 before differentiation into sBC. Modified sBC maintained upregulated CD155 expression and showed enhanced binding to co-receptor ligands. Co-culture studies revealed that CD155 Mut-expressing sBC suppressed CD8+ T cell and NK cell activation and proliferation by preferentially engaging the co-inhibitory receptor TIGIT. Both CD155 Mut sBC lines reduced autoreactive CD8+ T cell- and NK cell-mediated sBC destruction and cytotoxic molecule secretion. This protection was lost with TIGIT blockade, confirming the role of CD155-TIGIT signaling in antagonizing immune cell-mediated killing. Our findings suggest that high-affinity CD155 expression enhances immune evasion of sBC, improving their potential for restorative therapy in T1D. TeaserEngineered {beta}-cells with a mutant CD155 help evade immune attack, offering a promising therapeutic approach for type 1 diabetes.

immunology↗

bioRxiv2024

Peptide Coated Polycaprolactone-Benzalkonium Chloride Nanocapsules for Targeted Drug Delivery to the Pancreatic β-Cell

Targeting of current therapies to treat or prevent loss of pancreatic islet {beta}-cells in Type 1 Diabetes (T1D) may provide improved efficacy and reduce off target effects. Current efforts to target the {beta}-cell are limited by a lack of {beta}-cell specific targets and the inability to test multiple targeting moieties with the same delivery vehicle. Here we fabricate a novel tailorable polycaprolactone nanocapsule (NC) where multiple different targeting peptides can be interchangeably attached for {beta}-cell specific delivery. Incorporation of a cationic surfactant in the NC shell allows for the attachment of Exendin-4 and an antibody for ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3) for {beta}-cell specific targeting. The average NC size ranges from 250-300nm with a polydispersity index under 0.2. The NCs are non-toxic, stable in media culture, and can be lyophilized and reconstituted. NCs coated with targeting peptide were taken up by human cadaveric islet {beta}-cells and human stem cell-derived {beta}-like cells (sBC) in vitro with a high level of specificity. Furthermore, NCs successfully delivered both hydrophobic and hydrophilic cargo to human {beta}-cells. Finally, Exendin-4 coated NCs were stable and targeted the mouse pancreatic islet {beta}-cell in vivo. Our unique NC design allows for the interchangeable coating of targeting peptides for future screening of targets with improved cell specificity. The ability to target and deliver thera-peutics to human pancreatic {beta}-cells opens avenues for improved therapies and treatments to help the delay onset, prevent, or reverse T1D.

bioengineering↗