Eradication of B-CLL by autologous and allogeneic host nonreactive anti-third-party CTLs.
Establishment of cell lines capable of killing leukemia cells, in the absence of alloreactivity against normal host cells, represents a most desirable goal in bone marrow transplantation (BMT) and cancer immunotherapy. By using a human --> mouse chimeric model, we demonstrate that allogeneic anti-third-party cytotoxic T lymphocytes (CTLs) depleted of alloreactivity are endowed with a potent anti-B-cell chronic lymphocytic leukemia (B-CLL) reactivity. Likewise, CTL preparations generated from autologous T cells of the same patients with B-CLL exhibited comparable leukemia eradication, suggesting that the reactivity of allogeneic anti-third-party CTLs is not mediated by residual antihost clones. This specificity was also exhibited in vitro, and annexin staining revealed that B-CLL killing is mediated by apoptosis. While the CTLs killing of third-party cells could be blocked by anti-CD3 antibody, the lysis of the B-CLL cells was not inhibited by this antibody, suggesting a T-cell receptor (TCR)-independent cytotoxicity. The role of cell contact leading to apoptosis of B-CLL cells is shown in transwell plates and by anti-lymphocyte function-associated antigen-1 (LFA-1)-blocking antibody. Up-regulation of CD54 and the subsequent apoptosis of B-CLL cells depend on the initial LFA-1/ICAM-1 (intercellular adhesion molecule 1) interaction. Taken together, these results suggest that allogeneic or autologous host nonreactive anti-third-party CTLs may represent a new therapeutic approach for patients with B-CLL.
Arditti
Fabian D
FD
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Aviner
Shraga
S
Dekel
Benjamin
B
Krauthgamer
Rita
R
Gan
Judith
J
Nagler
Arnon
A
Tabilio
Antonio
A
Martelli
Massimo
M
Berrebi
Alain
A
Reisner
Yair
Y
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D016026:Bone Marrow Transplantation; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D053222:Fas Ligand Protein; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000628:therapy*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism
D000906:Antibodies; D017252:CD3 Complex; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007519:Isoantigens; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D018799:Intercellular Adhesion Molecule-1