Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 14, Issue 665, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abn1716
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Funding
- Leona M. and Harry B. Helmsley Charitable Trust
- GentiBio Inc.
- Seattle Children's Research Institute (SCRI) Program for Cell and Gene Therapy (PCGT)
- Children's Guild Association Endowed Chair in Pediatric Immunology
- Hansen Investigator in Pediatric Innovation Endowment
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The adoptive transfer of engineered T-regs (EngT(regs)) specific to islet antigens shows therapeutic potential in preventing type 1 diabetes by suppressing both effector T cells recognizing the same islet antigen and bystander effector T cells. EngT(regs) can home to the pancreas and block diabetes triggered by specific or polyclonal effector T cells. This approach demonstrates the promise of antigen-specific EngT(regs) as a targeted therapy for T1D.
Adoptive transfer of regulatory T cells (T-regs) is therapeutic in type 1 diabetes (T1D) mouse models. T-regs that are specific for pancreatic islets are more potent than polyclonal T-regs in preventing disease. However, the frequency of antigen-specific natural Tregs is extremely low, and ex vivo expansion may destabilize T-regs, leading to an effector phenotype. Here, we generated durable, antigen-specific engineered T-regs (EngT(regs)) from primary human CD4(+) T cells by combining FOXP3 homology-directed repair editing and lentiviral T cell receptor (TCR) delivery. Using TCRs derived from clonally expanded CD4(+) T cells isolated from patients with T1D, we generated islet-specific EngT(regs) that suppressed effector T cell (T-eff) proliferation and cytokine production. EngT(regs) suppressed T-effs recognizing the same islet antigen in addition to bystander Teffs recognizing other islet antigens through production of soluble mediators and both direct and indirect mechanisms. Adoptively transferred murine islet-specific EngT(regs) homed to the pancreas and blocked diabetes triggered by islet-specific T-effs or diabetogenic polyclonal T-effs in recipient mice. These data demonstrate the potential of antigen-specific EngT(regs) as a targeted therapy for preventing T1D.
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