Induction of preferential cytotoxicity against allogeneic mouse lymphoma cells: in vitro and in vivo studies |
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Authors: | Benny Leshem Yael Dorfman Eli Kedar |
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Institution: | (1) The Lautenberg Center for General and Tumor Immunology, The Hebrew University-Hadassah Medical School, P.O. Box 12272, Jerusalem 91120, Israel Tel.: +972-2-675-8708 Fax: +972-2-642-4653 e-mail: Leshemb@cc.huji.ac.il, IL |
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Abstract: | The aim of this study was to activate, in mixed leukocyte/tumor cell cultures (MLTC), cytotoxic lymphocytes exhibiting preferential
activity in vitro and in vivo towards allogeneic mouse lymphoma cells. Whereas the lymphoma target cells were readily lysed
by the MLTC-derived lymphocytes, the cytotoxicity against the corresponding allogeneic concanavalin-A(ConA)-induced lymphoblasts
was more than tenfold lower. Both activities were mediated by CD3+, TCR+, CD8+, CD4− cytotoxic T cells (CTL). ConA-induced lymphoblasts were readily lysed by anti-Thy1.2 antibodies and complement, by CTL derived
from mixed leukocyte cultures (MLC) and by the MLTC-derived CTL in the presence of ConA, indicating that the lymphoblasts
are not merely less lysable than the lymphoma cells but that the latter are specifically recognized by the CTL. Lymphoblasts
poorly competed with 51Cr-labeled lymphoma cells in a “cold”-target competition assay, suggesting that the MLTC-derived CTL largely recognize epitopes
expressed only by the lymphoma cells. Furthermore, analysis of the cytotoxic activity of more than 500 MLTC-derived CTL oligoclones
and over 30 clones revealed that one-third of them were cytotoxic only against the allogeneic lymphoma cells, one-third were
reactive against both the lymphoma and the allogeneic lymphoblast target cells and the remainder were not cytotoxic at all.
Upon injection into sublethally irradiated, lymphoma-bearing allogeneic mice, the MLTC-derived CTL cured 56% of the recipients
and caused graft versus host disease (GVHD) is only 22%, whereas CTL activated in MLC against allogeneic splenocytes were
therapeutically ineffective and caused lethal GVHD in 89% of the recipients. Although the therapeutic efficacy of the in vitro-generated
antitumor CTL was demonstrated against experimental lymphoma lines, this strategy might prove effective in tumor immunotherapy
in conjunction with other modalities.
Received: 24 December 1998 / Accepted: 5 April 1999 |
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Keywords: | Allogeneic CTL GVH/GVL Lymphoma immunotherapy |
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