Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 13, Issue 11, Pages 3010-3020Publisher
WILEY
DOI: 10.1111/ajt.12433
Keywords
Cellular therapy; clinical application; regulatory T cells; tolerance induction
Categories
Funding
- Nicholas Family
- UCSF Department of Surgery
- JDRF
- UCSF CTSI
- NIH [R34 AI095135, P30DK063720]
- British Heart Foundation, UK
- Genentech Graduate Student Fellowship
- Medical Research Council (MRC)
- National Institute for Health Research (NIHR), Biomedical Research Centre at Guy's, St Thomas' NHS Foundation Trust
- National Institute for Health Research (NIHR), Biomedical Research Centre at King's College London
- MRC Centre for Transplantation
- MRC [G1002000] Funding Source: UKRI
- British Heart Foundation [RG/08/005/25303, RG/13/12/30395] Funding Source: researchfish
- Medical Research Council [G1002000, MR/J006742/1, MR/K025538/1] Funding Source: researchfish
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Regulatory T cell (Treg) therapy has the potential to induce transplantation tolerance so that immunosuppression and associated morbidity can be minimized. Alloantigen-reactive Tregs (arTregs) are more effective at preventing graft rejection than polyclonally expanded Tregs (PolyTregs) in murine models. We have developed a manufacturing process to expand human arTregs in short-term cultures using good manufacturing practice-compliant reagents. This process uses CD40L-activated allogeneic B cells to selectively expand arTregs followed by polyclonal restimulation to increase yield. Tregs expanded 100- to 1600-fold were highly alloantigen reactive and expressed the phenotype of stable Tregs. The alloantigen-expanded Tregs had a diverse TCR repertoire. They were more potent than PolyTregs in vitro and more effective at controlling allograft injuries in vivo in a humanized mouse model. This study details a good manufacturing practice-compliant process for short-term selective expansion of donoralloantigen-reactive regulatory T cells for therapeutic applications in transplantation.
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