Costimulatory Blockade and Allo-Specific Treg Therapy for Liver Transplant Recipients: Preclinical Data
1Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 2Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 3Center of Transplantation Sciences, Massachussetts General Hosp., Boston, MA
Meeting: 2019 American Transplant Congress
Abstract number: D34
Keywords: Co-stimulation, Liver transplantation, T cells, Tolerance
Session Information
Date: Tuesday, June 4, 2019
Session Name: Poster Session D: Stem Cell, Cellular Therapies and Regenerative Medicine
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
*Purpose: Adoptive transfer of ex vivo generated donor-specific regulatory T cells (Treg) by using CD28/B7 costimulatory blockade (CSB) to induce transplant (TX) tolerance and minimize use of immunosuppressants (IS) has shown promise in a pilot renal TX study. A new trial in liver TX recipients was designed to use post-TX PBMC as the source of donor-specific Treg generated by ex vivo CSB. However, the immune status of patients on IS after liver TX is incompletely characterized and IS effects on the ability to generate recipient Treg using CSB unknown. We therefore characterized the immune profile of PBMC from liver recipients post-TX and the feasibility donor-specific Treg expansion from those PBMC using an ex vivo CSB strategy.
*Methods: PBMCs were isolated from liver recipients (n=41, age 58±12) 1-4 months post-TX on IS (tacrolimus, mycophenolate mofetil, and prednisone), and from healthy volunteers (n=9). T cell subsets (CD4/CD8, Th1/Th2, Th17/Treg), TCR signaling (pArK, pErk, pS6) and IL-2 production in response to TCR stimulation were evaluated by FACS and PCR. To expand donor-specific Treg, post-TX recipient PBMC were cocultured with healthy donor irradiated PBMC for 72h in the presence of belatacept for CSB. Proliferation was assessed in 1°MLR. Treg expansion was evaluated by FACS after 1°MLR culture and after 2°MLR (to model in vivo re-exposure to alloantigen). Treg function and specificity were studied in suppression assays.
*Results: Except for moderate lymphopenia, the immune status of recipient PBMC post-TX was equivalent to that of healthy volunteers, with no significant differences in CD4/CD8 and Th1/Th2/Th17 subsets. Despite IS, CD3/CD28 stimulation of post-TX PBMC resulted in comparable TCR signaling (phosphorylation levels of Akt, Erk, S6) and IL-2 production. Liver recipients post-TX PBMC had a significantly reduced Treg frequency. However, use of post-TX PBMC during CSB resulted in 1) equivalent inhibition of proliferation in 1°CSB and 2) comparable expansion of functional and allospecific Treg, to that of healthy volunteers.
*Conclusions: The peripheral immune status of liver recipients post-TX appears similar to that of healthy volunteers. Ex vivo expansion of Treg using CSB can be performed using liver recipient post-TX PBMC.
To cite this abstract in AMA style:
Contreras-Ruiz L, Shimozawa K, Zhang R, Turka L, Markmann JF, Guinan EC. Costimulatory Blockade and Allo-Specific Treg Therapy for Liver Transplant Recipients: Preclinical Data [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/costimulatory-blockade-and-allo-specific-treg-therapy-for-liver-transplant-recipients-preclinical-data/. Accessed March 1, 2021.« Back to 2019 American Transplant Congress