Platelet gene therapy induces robust immune tolerance even in a primed model via peripheral clonal deletion of antigen-specific T cells. Mol Ther Nucleic Acids 2021 Mar 05;23:719-730
Date
02/13/2021Pubmed ID
33575117Pubmed Central ID
PMC7851450DOI
10.1016/j.omtn.2020.12.026Scopus ID
2-s2.0-85099917698 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
While platelet-specific gene therapy is effective in inducing immune tolerance to a targeted protein, how the reactivity of pre-existing immunity affects the efficacy, and whether CD8 T cells were involved in tolerization, is unclear. In this study, ovalbumin (OVA) was used as a surrogate protein. Platelet-OVA expression was introduced by 2bOVA lentivirus transduction of Sca-1+ cells from either wild-type (WT)/CD45.2 or OT-II/CD45.2 donors followed by transplantation into OVA-primed WT/CD45.1 recipients preconditioned with 6.6 Gy of irradiation. Sustained platelet-OVA expression was achieved in >85% of OVA-primed recipients but abolished in animals with high-reactive pre-existing immunity. As confirmed by OVA rechallenge and skin graft transplantation, immune tolerance was achieved in 2bOVA-transduced recipients. We found that there is a negative correlation between platelet-OVA expression and the percentage of OVA-specific CD4 T cells and a positive correlation with the OVA-specific regulatory T (Treg) cells. Using the OT-I/WT model, we showed that antigen-specific CD8 T cells were partially deleted in recipients after platelet-targeted gene transfer. Taken together, our studies demonstrate that robust antigen-specific immune tolerance can be achieved through platelet-specific gene therapy via peripheral clonal deletion of antigen-specific CD4 and CD8 T effector cells and induction of antigen-specific Treg cells. There is an antagonistic dynamic process between immune responses and immune tolerance after platelet-targeted gene therapy.
Author List
Li J, Chen J, Schroeder JA, Hu J, Williams CB, Shi QAuthors
Qizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of WisconsinCalvin B. Williams MD, PhD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
