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Identification of prostate-specific HLA-A*0201-restricted peptides and detection of prostate antigen-directed T cells in the blood of prostate cancer patients
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
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Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-92712OAI: oai:DiVA.org:uu-92712DiVA: diva2:165889
Available from: 2005-03-17 Created: 2005-03-17 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Adoptive T Cell Therapy of Viral Infection and Cancer: Ex vivo Expansion of Cytomegalovirus- and Prostate Antigen-specific T Cells
Open this publication in new window or tab >>Adoptive T Cell Therapy of Viral Infection and Cancer: Ex vivo Expansion of Cytomegalovirus- and Prostate Antigen-specific T Cells
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The main focus of my thesis has been to develop protocols for generating antigen-specific cytotoxic T lymphocytes (CTLs) and T helper cells (TH) for adoptive transfer to treat cytomegalovirus (CMV) disease and prostate cancer. CMV viremia is a severe complication in immunocompromised stem cell transplanted patients. Prostate cancer is a leading cause of death for men in Western countries. Although different in nature, CMV-infected cells and prostate cancer cells can both be eliminated through specific activation of the adaptive immune system.

To generate CMV pp65-specific T cells, I utilized dendritic cells (DCs) modified with an HLA-A*0201/pp65495-503 peptide, a recombinant adenovirus coding for pp65, in vitro transcribed pp65 mRNA and a recombinant pp65 protein. Peptide stimulation yielded large numbers of peptide-specific CD8+ T cells with high lytic activity while adenovirus or mRNA stimulation resulted in the expansion of CTLs against multiple pp65 epitopes. The recombinant protein activated primarily CD4+ TH cells. Stimulation with DCs co-modified with pp65 mRNA and pp65 protein simultaneously generated both pp65-specific CTLs and TH cells. Such T cells would cover all pp65 epitopes while avoiding potential virus related biohazards. The mRNA/protein combinatory approach can be used to stimulate T cells ex vivo from virtually all stem cell donors for adoptive T cell transfer.

I have identified two immunogenic HLA-A*0201-restricted peptide epitopes from the prostate tissue antigen TARP. Repeated stimulations with TARP peptide-pulsed DCs yielded up to 20% TARP-directed CD8+ T cells even when starting from undetectable frequencies (<0.01%). The T cells could be sorted to 99% purity and expanded 1000-fold with retained specificity and activity. We also detected TARP-directed CD8+ T cells in the blood of prostate cancer patients. Therefore, TARP seems to have potential as antigen in DC vaccination or adoptive T cell therapy of prostate cancer.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 65 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 15
Immunology, Immunotherapy, Adoptive T cell therapy, Dendritic cell, T cell, Tetramer, Cytomegalovirus, Transplantation, pp65, Prostate cancer, TARP, Prostate antigens, Immunologi
National Category
Immunology in the medical area
urn:nbn:se:uu:diva-4821 (URN)91-554-6167-0 (ISBN)
Public defence
2005-04-15, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskölds väg 20, Uppsala, 13:15
Available from: 2005-03-17 Created: 2005-03-17Bibliographically approved

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