Targeted DNA vaccines eliciting crossreactive anti-idiotypic antibody responses against human B cell malignancies in mic
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RESEARCH
Open Access
Targeted DNA vaccines eliciting crossreactive anti-idiotypic antibody responses against human B cell malignancies in mice Pier Adelchi Ruffini1,4*, Audun Os1,4, Riccardo Dolcetti3, Geir E Tjønnfjord2,4, Ludvig A Munthe1,4 and Bjarne Bogen1,4,5*
Abstract Background: Therapeutic idiotypic (Id) vaccination is an experimental treatment for selected B cell malignancies. A broader use of Id-based vaccination, however, is hampered by the complexity and costs due to the individualized production of protein vaccines. These limitations may be overcome by targeted DNA vaccines encoding stereotyped immunoglobulin V regions of B cell malignancies. We have here investigated whether such vaccines might elicit cross-reactive immune responses thus offering the possibility to immunize subsets of patients with the same vaccine. Methods: Fusion vaccines targeting patient Id to mouse Major Histocompatibility Complex (MHC) class II molecules (chimeric mouse/human) or chemokine receptors (fully human) on antigen-presenting cells (APC) were genetically constructed for two Chronic Lymphocytic Leukemia (CLL) patients and one prototypic stereotyped B-cell receptor (BCR) commonly expressed by Hepatitis C Virus (HCV)-associated Non Hodgkin Lymphoma (NHL). The A20 murine B lymphoma cells were engineered to express prototypic HCV-associated B cell lymphoma BCR. Anti-Id antibody responses were studied against stereotyped and non-stereotyped BCRs on CLL patients’ cells as well as transfected A20 cells. Results: DNA vaccination of mice with Id vaccines that target APC elicited increased amounts of antibodies specific for the patient’s Id as compared with non targeted control vaccines. Anti–Id antibodies cross-reacted between CLL cells with closely related BCR. A20 cells engineered to express patients’ V regions were not tumorigenic in mice, preventing tumor challenge experiments. Conclusions: These findings provide experimental support for use of APC-targeted fusion Id DNA vaccines for the treatment of B cell lymphoma and CLL that express stereotyped BCRs. Keywords: Lymphoma, Cancer vaccine, Idiotype, Chemokine, CLL
Background B cell malignancies express a highly tumor-specific antigen, the variable (V) regions of the monoclonal immunoglobulin (Ig), which contain antigenic determinants called idiotopes collectively known as idiotype (Id). Protein Id vaccination has been pursued as a therapeutic approach to B cell malignancies over the last 20 years [1]. Immunologic * Correspondence: [email protected]; [email protected] 1 Department of Immunology, Centre for Immune Regulation, University of Oslo, Oslo University Hospital, Rikshospitalet, NO-0424 Oslo, Norway 5 K.G. Jebsen Centre for Research on Influenza Vaccines, University of Oslo and Oslo University Hospital, Oslo, Norway Full list of author information is available at the end of the article
and clinical responses have been detected [1], whereas demonstration of clinical benefit is so far limited to follicular lymphoma [2,3]. Because of the very n
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