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Blood, 15 July 2002, Vol. 100, No. 2, pp. 654-660
NEOPLASIA
An animal model for human cellular immunotherapy: specific
eradication of human acute lymphoblastic leukemia by cytotoxic T
lymphocytes in NOD/scid mice
Bart A. Nijmeijer,
Roel Willemze, and
J. H. Frederik Falkenburg
From the Department of Hematology, Leiden University
Medical Center, Leiden, The Netherlands.
Adoptive immunotherapy using in vitro-generated donor-derived
cytotoxic T lymphocytes (CTLs) can be effective in the treatment of
relapsed leukemia after allogeneic transplantation. To determine effector cell characteristics that result in optimal in vivo
antileukemic efficacy, we developed an animal model for human CTL
therapy. Nonobese diabetic/severe combined immunodeficiency
(NOD/scid) mice were inoculated with either of 2 primary human
acute lymphoblastic leukemia (ALL), denoted as SK and OF.
Anti-SK and anti-OF CTLs were generated in vitro by repeated
stimulation of donor peripheral blood mononuclear cells with
either SK or OF cells. Both CTL lines displayed HLA-restricted
reactivity against the original targets and non-major
histocompatibility class (MHC)-restricted cross-reactivity in vitro.
The CTLs were administered intravenously weekly for 3 consecutive weeks
to mice engrafted with either SK or OF leukemia. In 3 of 8 SK-engrafted
and anti-SK-treated mice, complete remissions were achieved in blood,
spleen, and bone marrow. In the remaining 5 animals partial remissions
were observed. In 4 of 4 OF-engrafted anti-OF-treated mice partial
remissions were observed. The antileukemic effect of specific CTLs
was exerted immediately after administration and correlated with the
degree of HLA disparity of the donor-patient combination. In
cross-combination-treated animals, no effect on leukemic progression
was observed indicating that in vivo antileukemic reactivity is
mediated by MHC-restricted effector cells. The CTLs, however,
displayed an impaired in vivo proliferative capacity. Ex vivo analysis
showed decreased reactivity as compared to the moment of infusion. We
therefore conclude that the model can be used to explore the
requirements for optimal in vivo efficacy of in vitro- generated CTLs.
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