Details

Autor(en) / Beteiligte

• Shimozawa, Katsuyoshi
• Contreras‐Ruiz, Laura
• Sousa, Sofia
• Zhang, Ruan
• Bhatia, Urvashi
• Crisalli, Kerry C.
• Brennan, Lisa L.
• Turka, Laurence A.
• Markmann, James F.
• Guinan, Eva C.

Titel

Ex vivo generation of regulatory T cells from liver transplant recipients using costimulation blockade

Ist Teil von

• American journal of transplantation, 2022-02, Vol.22 (2), p.504-518

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• The potential of adoptive cell therapy with regulatory T cells (Tregs) to promote transplant tolerance is under active exploration. However, the impact of specific transplant settings and protocols on Treg manufacturing is not well‐delineated. Here, we compared the use of peripheral blood mononuclear cells (PBMCs) from patients before or after liver transplantation to the use of healthy control PBMCs to determine their suitability for Treg manufacture using ex vivo costimulatory blockade with belatacept. Despite liver failure or immunosuppressive therapy, the capacity for Treg expansion during the manufacturing process was preserved. These experiments did not identify performance or quality issues that disqualified the use of posttransplant PBMCs—the currently favored protocol design. However, as Treg input correlated with output, significant CD4‐lymphopenia in both pre‐ and posttransplant patients limited Treg yield. We therefore turned to leukapheresis posttransplant to improve absolute yield. To make deceased donor use feasible, we also developed protocols to substitute splenocytes for PBMCs as allostimulators. In addition to demonstrating that this Treg expansion strategy works in a liver transplant context, this preclinical study illustrates how characterizing cellular input populations and their performance can both inform and respond to clinical trial design and Treg manufacturing requirements. This study establishes that regulatory T cell expansion using ex vivo costimulatory blockade can be successfully performed using cells obtained either prior to or after liver transplantation and illustrates the importance of characterizing context‐ specific cellular components to optimize manufacturing processes, pre‐clinical and clinical trial decisions.