In:
Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 3, No. 83 ( 2011-05-18)
Abstract:
Graft-versus-host disease (GVHD) is a frequent and severe complication after hematopoietic cell transplantation. Natural CD4 + CD25 + regulatory T cells (nT regs ) have proven highly effective in preventing GVHD and autoimmunity in murine models. Yet, clinical application of nT regs has been severely hampered by their low frequency and unfavorable ex vivo expansion properties. Previously, we demonstrated that umbilical cord blood (UCB) nT regs could be purified and expanded in vitro using good manufacturing practice (GMP) reagents; however, the initial number of nT regs in UCB units is limited, and average yield after expansion was only 1 × 10 9 nT regs . Therefore, we asked whether yield could be increased by using peripheral blood (PB), which contains far larger quantities of nT regs . PB nT regs were purified under GMP conditions and expanded 80-fold to yield 19 × 10 9 cells using anti-CD3 antibody–loaded, cell-based artificial antigen-presenting cells (aAPCs) that expressed the high-affinity Fc receptor and CD86. A single restimulation increased expansion to ~3000-fold and yield to 〉 600 × 10 9 cells while maintaining Foxp3 expression and suppressor function. nT reg expansion was ~50 million–fold when flow sort–purified nT regs were restimulated four times with aAPCs. Indeed, cryopreserved donor nT regs restimulated four times significantly reduced GVHD lethality induced by the infusion of human T cells into immune-deficient mice. The capability to efficiently produce donor cell banks of functional nT regs could transform the treatment of GVHD and autoimmunity by providing an off-the-shelf, cost-effective, and proven cellular therapy.
Type of Medium:
Online Resource
ISSN:
1946-6234
,
1946-6242
DOI:
10.1126/scitranslmed.3001809
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2011
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