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Transplantation Immunology (TRAN)

Immune Mechanisms and Therapeutic Strategies in Transplantation

(753) Inhibition of Innate Immune Allorecognition Using Nanobiologics Effectively Overturns Ongoing T Cell Mediated Allograft Rejection

Friday, April 17, 2026
11:30 AM - 12:30 PM US ET
Location: Exhibit Hall

    Author(s)

  • MS

    Megan Stasik, BSc (she/her/hers)

    Research Trainee
    Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical School
    Pittsburgh, Pennsylvania, United States

Disclosure(s):
Megan Stasik, BSc: No financial relationships to disclose
Introduction/Rationale: Acute T cell mediated rejection (TCMR) episodes are inadequately controlled by rejection treatment and impede long-term survival. Given that TCMR is driven by innate allorecognition memory (Allo-IMem), we investigated whether specifically inhibiting Allo-IMem using nanobiologics would overturn TCMR.

Methods: WT B6 recipients of Balb/c islet allografts were left untreated and then treated at the peak of TCMR (days 7-12) with innate immune cell specific high-density lipoprotein nanobiologics. Nanobiologics were either unloaded (control; U-NB) or loaded with the mTOR inhibitor rapamycin (mTORi-NB; 5mg/kg) and compared to free rapamycin (Rapa; 5mg/kg).

Results: We uncovered that Allo-IMem signals through mTOR, and unlike Rapa treatment, mTORi-NB inhibits Allo-IMem compared to U-NB. Remarkably, mTORi-NB treatment at the peak of TCMR overturned rejection in 90% of recipients and was therapeutically advantageous over Rapa treatment. scRNA-seq analysis of graft-infiltrating innate cells (day 10) demonstrated that mTORi-NB inhibited cell cycle, glycolysis, and type I/II interferon signaling, and promoted TGF-β signaling pathways, compared to U-NB. Multiphoton intravital microscopy of islet allografts on day 10 revealed that mTORi-NB significantly reduced both the dynamics (speed and distance traveled) and intracellular Ca+ signaling in effector T cells, compared to U-NB. Mechanistically, mTORi-NB significantly reduced the antigenic presentation capacity of graft-infiltrating innate cells compared to U-NB. In addition, both graft infiltrating effector T cell proliferation and IFNγ+ numbers were significantly decreased with mTORi-NB compared to U-NB.

Conclusion: Taken together, we demonstrate that inhibiting Allo-IMem using innate cell specific mTORi-NB effectively overturns TCMR, thus providing a novel targeted therapeutic treatment for acute rejection in transplant patients.