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Blood, 1 November 2003, Vol. 102, No. 9, pp. 3100-3107.
Prepublished online as a Blood First Edition Paper on July 10, 2003; DOI 10.1182/blood-2002-11-3580.


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GENE THERAPY

Testing recombinant adeno-associated virus-gene loading of dendritic cells for generating potent cytotoxic T lymphocytes against a prototype self-antigen, multiple myeloma HM1.24

Maurizio Chiriva-Internati, Yong Liu, Jon A. Weidanz, Fabio Grizzi, Hong You, Weiping Zhou, Klaus Bumm, Barthel Barlogie, Jawahar L. Mehta, and Paul L. Hermonat

From the Departments of Internal Medicine, Gene Therapy Center in Cardiology, and Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock; Department of Microbiology and Immunology, Texas Tech University, Lubbock; Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Lubbock; Department of Internal Medicine, Texas Tech University, Amarillo; Scientific Direction, Instituto Clinico Humanitas, Rozzano, Milano, Italy; and Institute for Viral Hepatitis, Chongqing Medical University, People's Republic of China.

Recent studies demonstrate that recombinant adeno-associated virus (rAAV)–based antigen loading of dendritic cells (DCs) generates significant and rapid (one stimulation per week) cytotoxic T-lymphocyte (CTL) responses in vitro against viral antigens. As a more extensive analysis of the rAAV system, we have used a self-antigen, HM1.24, expressed in multiple myeloma (MM). Again, with one stimulation, significant major histocompatibility complex (MHC) class 1–restricted, anti-HM1.24–specific CTL killing was demonstrated against MM cells. Furthermore, higher expression of interferon-{gamma} (IFN-{gamma}) in T cells and higher expression levels of, in order of significance, CD80 (2.6- to 3.8-fold increase), CD86, and CD40 on DCs were also observed. The use of synthetic HM1.24-positive target cells further demonstrated the antigen specificity of these CTLs. There was also no evidence of natural killer cell involvement. These data extend our earlier studies and suggest that the rAAV-loading of DCs may be a particularly good protocol for generating CTLs against self-antigens, which may not otherwise be considered good targets because of their low immunogenicity. We also show that HM1.24 may be an effective antigen for targeting MM.


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