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The role of B7 costimulation by murine acute myeloid leukemia in the
generation and function of a CD8+ T-cell line with potent in vivo graft-
versus-leukemia properties
MW Boyer, DA Vallera, PA Taylor, GS Gray, E Katsanis, K Gorden, PJ Orchard and BR Blazar
Department of Pediatrics, University of Minnesota Hospital and Clinic,
Minneapolis, USA.
Relapse is more frequent after autologous than allogeneic bone marrow
transplantation (BMT), due in part to lack of T-lymphocyte mediated
allogeneic graft-versus-leukemia (GVL) effects. Infusions of leukemia-
reactive T cells to patients after autologous BMT may be a means for
providing a GVL effect. Costimulation of T cells by binding of the CD28
receptor on T cells with B7-counter receptors on antigen presenting cells
amplifies antigen-specific T-cell responses. To enhance generation of
leukemia reactive cytotoxic T lymphocytes (CTL), the murine B7-1- and
B7-2-costimulatory molecule cDNAs were introduced into the MHC class I+,
class II-, murine meyloid leukemia cell line C1498. B7-1 expression greatly
enhanced the ability of the leukemia cells to generate and expand leukemia
reactive CTL in vitro. A highly cytolytic and C1498 specific CD8+ CTL line
was generated by B7-1 costimulation. This CTL line proliferated
autonomously and produced interleukin-2 when provided B7-1 or B7-2
costimulation by C1498 leukemia cells. To test the in vivo antileukemia
properties of this CTL line, irradiated syngeneic BMT recipients were given
graded doses of leukemia cells on day 0, followed by CTL infusions
beginning on day 1 post-BMT. Recipients of 10(7) CTL had a 3 log reduction
in leukemia burden such that 100% of mice were protected from a supralethal
leukemic cell dose. Sustained immune responses were detectable up to 3
months postinfusion of the CTL line. B7-1 or B7-2 costimulation in vivo did
not augment antileukemia effects of infused CTL post BMT. These results
suggest that B7 costimulation of leukemia reactive CTL may be important for
their ex vivo generation and expansion for use in human adoptive
immunotherapy of leukemia.
Volume 89,
Issue 9,
pp. 3477-3485,
05/01/1997
Copyright © 1997 by The American Society of Hematology
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