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Blood, 1 December 2000, Vol. 96, No. 12, pp. 3827-3837
IMMUNOBIOLOGY
CD2-mediated IL-12-dependent signals render human   -T cells
resistant to mitogen-induced apoptosis, permitting the large-scale
ex vivo expansion of functionally distinct lymphocytes:
implications for the development of adoptive immunotherapy
strategies
Richard D. Lopez,
Shan Xu,
Ben Guo,
Robert S. Negrin, and
Edmund K. Waller
From the Division of Bone Marrow Transplantation,
Stanford University School of Medicine, Stanford, CA; the Division of
Hematology/Oncology, Bone Marrow Transplant-Leukemia Program, Emory
University School of Medicine, Atlanta, GA; and the Bone Marrow
Transplantation Program, University of Alabama at Birmingham, AL.
The ability of human   -T cells to mediate a number of
in vitro functions, including innate antitumor and antiviral activity, suggests these cells can be exploited in selected examples of adoptive
immunotherapy. To date, however, studies to examine such issues on a
clinical scale have not been possible, owing in large measure to the
difficulty of obtaining sufficient numbers of viable human -T
cells given their relative infrequency in readily available tissues.
Standard methods used to expand human T cells often use a combination
of mitogens, such as anti-T-cell receptor antibody OKT3 and
interleukin (IL)-2. These stimuli, though promoting the expansion of
  -T cells, usually do not promote the efficient expansion of
-T cells. CD2-mediated, IL-12-dependent signals that result
in the selective expansion of human -T cells from cultures of
mitogen-stimulated human peripheral blood mononuclear cells are
identified. It is first established that human -T cells are
exquisitely sensitive to apoptosis induced by T-cell mitogens OKT3 and
IL-2. Next it is shown that the CD2-mediated IL-12-dependent signals,
which lead to the expansion of -T cells, do so by selectively
protecting subsets of human -T cells from mitogen-induced
apoptosis. Finally, it is demonstrated that apoptosis-resistant -T cells are capable of mediating significant antitumor
cytotoxicity against a panel of human-derived tumor cell lines in
vitro. Both the biologic and the practical implications of induced
resistance to apoptosis in -T cells are considered and discussed
because these findings may play a role in the development of new forms of adoptive cellular immunotherapy.
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