Generation in vitro of B-cell chronic lymphocytic leukaemia-proliferative and specific HLA class-II-restricted cytotoxic T-cell responses using autologous dendritic cells pulsed with tumour cell lysate
R. V. Goddard,
A. G. Prentice,
J. A. Copplestone,
E. R. Kaminski,
R. V. Goddard
Plymouth Postgraduate Medical School, Derriford Combined Laboratory, Derriford Hospital, Plymouth, UK
Search for more papers by this authorA. G. Prentice
Plymouth Postgraduate Medical School, Derriford Combined Laboratory, Derriford Hospital, Plymouth, UK
Search for more papers by this authorJ. A. Copplestone
Plymouth Postgraduate Medical School, Derriford Combined Laboratory, Derriford Hospital, Plymouth, UK
Search for more papers by this authorE. R. Kaminski
Plymouth Postgraduate Medical School, Derriford Combined Laboratory, Derriford Hospital, Plymouth, UK
Search for more papers by this authorR. V. Goddard,
A. G. Prentice,
J. A. Copplestone,
E. R. Kaminski,
R. V. Goddard
Plymouth Postgraduate Medical School, Derriford Combined Laboratory, Derriford Hospital, Plymouth, UK
Search for more papers by this authorA. G. Prentice
Plymouth Postgraduate Medical School, Derriford Combined Laboratory, Derriford Hospital, Plymouth, UK
Search for more papers by this authorJ. A. Copplestone
Plymouth Postgraduate Medical School, Derriford Combined Laboratory, Derriford Hospital, Plymouth, UK
Search for more papers by this authorE. R. Kaminski
Plymouth Postgraduate Medical School, Derriford Combined Laboratory, Derriford Hospital, Plymouth, UK
Search for more papers by this author Mrs Ruth Victoria Goddard, Combined Laboratory, Derriford Hospital, Plymouth, Devon., PL6 8DH, UK. E-mail: [email protected]
Abstract
Immunotherapy using dendritic cells has shown encouraging results in both haematological and non-haematological malignancies. In this study, monocyte-derived dendritic cells from patients with B-CLL were cultured for 6 days in the presence of IL-4 and GM-CSF. Autologous B-CLL T-cells were cultured alone or with B-CLL lysate-pulsed and unpulsed autologous dendritic cells. IFN-γ secretion was assessed using ELISA. Cytotoxicity was assessed, after 21 days in culture and re-stimulation, using flow cytometry with and without blockade by anti-HLA class I, anti-HLA class II, anti-CD4, anti-CD8 and anti-TCRαβ monoclonal antibodies. B-CLL T cells stimulated with B-CLL lysate-pulsed autologous dendritic cells showed a significant (P = 0·0004) increase in IFN-γ secretion and a significant (P = 0·0008) increase in specific cytotoxicity to autologous B-cell targets, but none to autologous T cell or B cell targets from healthy individuals. B-CLL T cells cultured with (non-B-CLL) B-cell lysate-pulsed B-CLL dendritic cells showed no significant response. Pulsing dendritic cells from healthy volunteers with an autologous (non-B-CLL) B-cell lysate did not stimulate proliferation, cytokine production or cytotoxicity by autologous T cells. Pulsing B-CLL dendritic cells with allogeneic B-CLL lysates and culturing with autologous T-cells elicited cytotoxicity against autologous B-CLL targets in some cases, but not in others. Cytotoxicity was significantly reduced by blocking with anti-HLA class II (P = 0·001), anti-TCRαβ (P = 0·03) and anti-CD4 (P = 0·046) antibodies. Phenotyping of the responding T-cell population demonstrated the majority to be CD4 positive. Our data demonstrate that HLA class II-restricted proliferative and cytotoxic T-cell responses to B-CLL can be generated using autologous dendritic cells pulsed with tumour cell lysate.
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