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Multidrug resistance-1 (mdr-1): A new target for t cell-based immunotherapy

Academic Article
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Overview

authors

  • Niethammer, A. G.
  • Wodrich, H.
  • Loeffler, M.
  • Lode, H. N.
  • Emmerich, K.
  • Abdollahi, A.
  • Krempien, R.
  • Debus, J.
  • Huber, P. E.
  • Reisfeld, Ralph

publication date

  • 2005

journal

  • FASEB Journal  Journal

abstract

  • Acquired multidrug resistance (MDR) remains a major challenge in the treatment of cancer with chemotherapeutic drugs. It can be mediated by the up-regulated expression of different proteins within the tumor cell membrane. Here, we used murine multidrug resistance-1 (MDR-1) as a target-antigen for the immunotherapy of cancer. We successfully demonstrated that peripheral T cell tolerance can be broken by oral administration of a DNA vaccine encoding MDR-1 and carried by attenuated Salmonella typhimurium to secondary lymphoid organs. Thus, mice, immunized orally three times at 2-wk intervals and challenged 2 wk thereafter with either MDR-1 expressing CT-26 colon carcinoma cells or MDR-1 expressing Lewis lung carcinoma cells, revealed a significant increase in life span. This was evident, when compared with animals either vaccinated with the empty control vector or challenged with the parental cell lines lacking overexpression of MDR-1. The immune response induced was antigen-specific and CD8+ T cell-mediated. The presence of the target antigen led to up-regulation of activation markers on CD8+ T cells and resulted in a strong cytotoxic T cell response as well as lysis of tumor target cells in vitro. We furthermore established the vaccine to be an effective treatment for established multi-drug-resistant tumor metastases, resulting in a significantly increased life span of experimental animals. Absence of CD8+ T cells due to in vivo depletion led to abrogation of effectiveness. Taken together, our results demonstrate that T cell tolerance against the MDR-1 self-antigen can be broken. It is anticipated that the combination of such an approach with chemotherapy could lead to more effective treatments of cancer.

subject areas

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Animals
  • CD8-Positive T-Lymphocytes
  • Cancer Vaccines
  • Cell Line, Tumor
  • Colonic Neoplasms
  • Genes, MDR
  • Genetic Vectors
  • Immunity
  • Immunization
  • Immunotherapy
  • Lung Neoplasms
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Subcutaneous Tissue
  • T-Lymphocytes
  • Transduction, Genetic
  • Vaccination
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Identity

International Standard Serial Number (ISSN)

  • 0892-6638

Digital Object Identifier (DOI)

  • 10.1096/fj.04-2355fje

PubMed ID

  • 15498893
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Additional Document Info

start page

  • 158

end page

  • 159

volume

  • 19

issue

  • 1

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