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Blood, 1 August 2004, Vol. 104, No. 3, pp. 847-856.
Prepublished online as a Blood First Edition Paper on April 15, 2004; DOI 10.1182/blood-2003-10-3469.
 Previous Article | Next Article 
Submitted October 10, 2003
Accepted February 26, 2004
Attenuated Poxviruses Generate Clinically Relevant Frequencies of CMV-Specific T cells
Zhongde Wang, Corinna La Rosa, Shahram Mekhoubad, Simon F Lacey, Maria C Villacres, Susan Markel, Jeff Longmate, Joshua D Ellenhorn, Robert F Siliciano, Christopher Buck, William J Britt, and Don J Diamond*
Laboratory of Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, CA, USA
Division of Information Sciences, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
Division of General and Oncologic surgery, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
Division of Medicine, Johns Hopkins University Medical School, Baltimore, MD, USA
Department of Pediatrics, University of Alabama, Birmingham, AL, USA
* Corresponding author; email: ddiamond{at}coh.org.
Immunotherapeutic approaches to limit CMV morbidity and mortality after HSCT are currently under investigation as alternatives to antiviral drugs. In this context, we have inserted full length and ubiquitin-modified CMV pp65, pp150 and IE1 immunodominant antigens into the virulent Western Reserve strain of Vaccinia Virus (VV) and the highly attenuated strain, modified vaccinia Ankara (MVA). Recombinant (r)VV or rMVA stimulated vigorous expansion of CMV-specific CD8+ T cells in CMV-positive donor PBMC, which showed minimal alloreactivity and high levels of HLA tetramer binding, cytokine production and cytotoxicity. Ubiquitinated antigens had a profound effect, when expressed in VV. Single antigen rMVA expressing pp65 or IE1, either ubiquitin-modified or native, stimulated both CTL populations to be expanded up to 500-fold in a 60-ml blood draw from the same donor. This result demonstrates the clinical feasibility of simultaneously amplifying multiple CMV-CTL populations. Transgenic HLA A2.1 (HHD II) mice, immunized with the same rMVA as used with human PBMC, produced a robust cytotoxic response to both CMV pp65 and IE1. The specificity of the vigorous immunological response to rMVA, both in vitro and in vivo, makes them candidates for clinical evaluation in the context of adoptive immunotherapy for HSCT recipients or donor vaccination.
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