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Ex Vivo-Generated Autologous iTregs as a Cell-Based Therapy for Acquired Aplastic Anemia

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[Technical Report, Annual Report]

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University of Massachusetts Amherst

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Patients with acquired AA show aberrant activation of T effector Teff cells and naturally occurring regulatory T cells nTregs that are frequently dysfunctional. Immunosuppressive therapies that use Tregs, rely on isolating and expanding rare populations of nTregs from the circulating blood. nTregs with in vitro suppressive functions have been successfully expanded from AA patients. However, the extremely low numbers of circulating nTregs, coupled with the long process up to several months of expanding these cells in culture, underscores the practical challenges of this approach for AA patients. We have developed a means of using synthetic cell-penetrating peptide mimics CPPM to deliver functional antibodies into human CD4 T cells. Delivering anti-pPKCTheta into CD4 T cells generates iTregs anti-pPKCTheta-iTregs with superior in vitro and in vivo suppressive functions and, in proof-of-concept experiments, provide a significant survival benefit in a humanized mouse model of AA, when given at the time of BMF induction. We determined that inhibiting PKCTheta or the protein repair methyltransferase, PCMT1, alters the cellular location and protein-protein association of key iTreg-destabilizing proteins, increases surface expression of the immune-inhibitory receptor, PD1, and increases demethylation the FOXP3 promoter. We conclude that these alterations contribute to a more suppressive iTreg phenotype in vitro and in vivo.

Subject Categories:

  • Medicine and Medical Research
  • Pharmacology

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[A, Approved For Public Release]