Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
*Purpose: Naturally occurring CD4+CD25highFOXP3+ Regulatory T cells (Tregs) function as mediators of immune homeostasis. So, they are beginning to be utilized for controlling hyper-immunity and transplant tolerance induction. To circumvent their relative rarity, however, these cells have to be expanded ex vivo to therapeutic quantities. Currently, there are two approaches to expand “recipient” Tregs by stimulating: (i) polyclonally with anti-CD3/anti-CD28 beads (Poly-Tregs), (ii) donor-specifically with engineered donor antigen presenting cells (Ds-Tregs). It is suggested that compared to Poly-Tregs, Ds-Tregs have the potential advantage of being more potent and specific in controlling alloimmune responses.
*Methods: To test this, we have generated Poly-Tregs and Ds-Tregs using our well-established expansion protocols, and then directly compared their in vivo safety and efficacy in the NSG mouse human skin graft model.
*Results: Human donor skin grafts were spontaneously accepted by the mice by day ~30; the healed grafts showed normal morphology and histology. Injection of 20×106 human PBMC allogeneic to the skin graft (effector PBMC), resulted in significant cellular infiltration and graft rejection within 3 weeks and development of graft versus host disease (GVHD) within 2 months.
(A) Testing safety of Tregs: When 1×106 or 4×106 of expanded Tregs (alone without effector PBMC) were infused, (i) they did not cause skin graft rejection or GVHD, (ii) migrated to the liver and spleen, and (iii) maintained high FOXP3 and CD25 expressions stably without converting to IL17+ pathogenic effector cells, demonstrating their use to be safe.
(B) Testing Efficacy of Tregs: Co-injection of even 4×106 Ds-Tregs autologous to and along with 20×106 effector PBMC prolonged graft survival and prevented GVHD, whereas 5-times higher dose of Poly-Tregs was required for the same effect. Flow cytometric analysis of graft and liver infiltrating cells revealed significant reduction in cytotoxic CD8 effector T cells in mice that received Ds-Tregs plus effector PBMC when compared to mice that received effector PBMC alone. This suggested that down-regulation of CD8+ effector T cells was a mechanism by which Ds-Tregs prevented graft rejection and GVHD.
*Conclusions: In summation, both Poly-Treg and Ds-Treg therapies are safe, but Ds-Tregs are more effective in controlling alloimmunity and GVHD, indicating that our Ds-Treg technology can also be now safely translated clinically.
To cite this abstract in AMA style:Voss JH, Zheng F, Jendrisak MD, Leventhal JR, Zhang ZJ, Mathew JM. Superiority of Donor-Specifically vs. Polyclonally Expanded Regulatory T Cells in Controlling Graft Rejection in the NSG Mouse Human Skin Graft Model [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/superiority-of-donor-specifically-vs-polyclonally-expanded-regulatory-t-cells-in-controlling-graft-rejection-in-the-nsg-mouse-human-skin-graft-model/. Accessed January 17, 2020.
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