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Blood, 1 August 2001, Vol. 98, No. 3, pp. 505-512
PLENARY PAPER
Isolation and expansion of cytomegalovirus-specific cytotoxic T
lymphocytes to clinical scale from a single blood draw using dendritic
cells and HLA-tetramers
Susann Szmania,
Amanda Galloway,
Mary Bruorton,
Philip Musk,
Geraldine Aubert,
Andrew Arthur,
Haywood Pyle,
Nancy Hensel,
Nga Ta,
Lawrence Lamb Jr,
Toni Dodi,
Alejandro Madrigal,
John Barrett,
Jean Henslee-Downey, and
Frits van Rhee
From the Division of Transplantation Medicine,
South Carolina Cancer Center, Palmetto Health Alliance and University
of South Carolina School of Medicine, Columbia, South Carolina; Bone
Marrow Transplant Unit, Hematology Branch, National Heart, Lung and
Blood Institute, National Institutes of Health, Bethesda, Maryland; and
Anthony Nolan Research Institute, London, United Kingdom.
Cytomegalovirus (CMV) reactivation in immunocompromised recipients
of allogeneic stem cell transplantation is a cause of morbidity and
mortality from viral pneumonitis. Antiviral drugs given to reactivating
patients have reduced the mortality from CMV but have toxic side
effects and do not always prevent late CMV disease. Cellular
immunotherapy to prevent CMV disease is less toxic and could provide
prolonged protection. However, a practical approach to generating
sufficient quantities of CMV-specific cytotoxic T cells (CTLs) is
required. This study describes a system for generating sufficient
CMV-specific CTLs for adoptive immunotherapy of HLA-A*0201 bone marrow
transplant recipients from 200 mL donor blood. Donor monocytes are used
to generate dendritic cells (DCs) in medium with autologous plasma,
interleukin 4, granulocyte-macrophage colony-stimulating factor, and
CD40 ligand. The DCs are pulsed with the immunodominant
HLA-A*0201-restricted CMV peptide pp65495-503, and incubated with donor T cells. These cultures are restimulated twice
with peptide-pulsed lymphoblastoid cell lines (LCLs) or CD40-ligated B
cells and purified with phycoerythrin (PE)-labeled pp65495-503/HLA-A*0201 tetramers by flow sorting, or with
anti-PE paramagnetic beads. The pure tetramer-positive population is
then rapidly expanded to obtain sufficient cells for clinical
immunotherapy. The expanded CTLs are more than 80% pure, of memory
phenotype, with a Tc1 cytokine profile. They efficiently kill
CMV-infected fibroblasts and express the integrin VLA-4, suggesting
that the CTLs could cross endothelial barriers. This technique is
reproducible and could be used for generating CMV-specific CTLs to
prevent CMV disease after allogeneic blood and marrow transplantation.
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