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Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 109-117
Rapid selection of antigen-specific T lymphocytes by retroviral
transduction
Guenther Koehne,
Humilidad F. Gallardo,
Michel Sadelain, and
Richard J. O'Reilly
From the Bone Marrow Transplant Service, Department of Pediatrics,
Memorial Hospital; Gene Transfer and Somatic Cell
Engineering Facility; Department of Human Genetics; and Immunology
Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer
Center, New York, NY.
Infusions of donor peripheral blood T cells can induce durable
remissions of Epstein-Barr virus (EBV) lymphomas complicating marrow
grafts, but they contain alloreactive T cells capable of inducing
graft-versus-host disease. EBV-specific T-cell lines or clones avoid
this problem but require 30 to 40 days of culture to establish. To
accelerate the generation of EBV-specific T cells, we tested whether
retroviral vectors, which only integrate in dividing cells, could be
used to transduce and select antigen-reactive T cells early after
sensitization to autologous EBV-transformed B cells. T cells were
transduced with a dicistronic retroviral vector, NIT, which encodes
low-affinity nerve growth factor receptor as an immunoselectable
marker and herpes simplex virus thymidine kinase as a suicide gene, at
different time points after sensitization. EBV-specific cytotoxic T
lymphocyte precursor (CTLp) frequencies in purified NIT+
T-cell fractions transduced on day 8 of culture were comparable to
those of EBV-specific T-cell lines cultured for 30 days or more.
Alloreactive CTLp frequencies were markedly reduced in the NIT+ fraction relative to the untransduced T-cell
population. NIT+ fractions transduced on day 8 possessed
more CD4+ T cells than the cell lines at day 30 and
exhibited the same selective pattern of reactivity against
immunodominant antigens presented by specific HLA alleles. In contrast,
T cells transduced with NIT 5 days after stimulation with mitogen and
interleukin-2 were relatively depleted of T cells specific for
autologous EBV-transformed cells. Thus, retroviral vectors may be used
for rapid selection of viral antigen-reactive T cells depleted of
alloreactive T cells.
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