HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Smythe, J. A. Articles by Alexander, I. E. Search for Related Content PubMed PubMed Citation Articles by Smythe, J. A. Articles by Alexander, I. E.

Human Fibroblasts Transduced with CD80 or CD86 Efficiently trans-Costimulate CD4⁺ and CD8⁺ T Lymphocytes in HLA-Restricted Reactions: Implications for Immune Augmentation Cancer Therapy and Autoimmunity¹

Jason A. Smythe^2,*, Peter D. Fink^*, Grant J. Logan^*, Jacqueline Lees^*, Peter B. Rowe^* and Ian E. Alexander

The Gene Therapy Research Unit of ^* The Children’s Medical Research Institute and The New Children’s Hospital, Wentworthville, Australia

Augmenting immunogenicity by genetically modifying tumor cells to express costimulatory molecules has proven to be a promising therapeutic strategy in murine tumor models and is currently under investigation in human clinical trials for metastatic cancer. However, there are significant technical and logistic problems associated with implementing strategies requiring direct gene modification of primary tumor cells. In an effort to circumvent these problems, we are developing a strategy in which the costimulatory signal required for tumor-specific T lymphocyte activation is provided by a genetically modified human fibroblast (trans-costimulation). We have evaluated the efficiency of CD80- and CD86-mediated trans-costimulation in the activation of human CD8⁺ and CD4⁺ T lymphocytes in MHC class I- and class II-restricted lymphoproliferation reactions. Our studies demonstrate that the efficiency of CD80- or CD86-mediated trans-costimulation of purified human CD8⁺ and CD4⁺ T lymphocytes is comparable to cis-costimulation under defined conditions. Moreover, a dose-response relationship consistent with the predicted two-hit kinetics of the reaction was evident in trans-costimulation reactions in which the ratio of target cells expressing either signal 1 or signal 2 was varied incrementally from 1:10 to 10:1. Importantly, the level of cell-surface CD86 required for trans-costimulation is equivalent to that constitutively expressed by human peripheral blood monocytes. These results may have significant implications for the clinical implementation of this type of cancer immunotherapy and also raise questions about the possibility of trans-costimulating autoreactive T lymphocytes in vivo.

This article has been cited by other articles:

				M. Sanchez-Lockhart and J. Miller Engagement of CD28 Outside of the Immunological Synapse Results in Up-Regulation of IL-2 mRNA Stability but Not IL-2 Transcription. J. Immunol., April 15, 2006; 176(8): 4778 - 4784. [Abstract] [Full Text] [PDF]

				S. Leung, A. Holbrook, B. King, H.-T. Lu, V. Evans, N. Miyamoto, C. Mallari, S. Harvey, D. Davey, E. Ho, et al. Differential Inhibition of Inducible T Cell Cytokine Secretion by Potent Iron Chelators J Biomol Screen, March 1, 2005; 10(2): 157 - 167. [Abstract] [PDF]

				D. Laderach, M. Movassagh, A. Johnson, R. S. Mittler, and A. Galy 4-1BB co-stimulation enhances human CD8+ T cell priming by augmenting the proliferation and survival of effector CD8+ T cells Int. Immunol., October 1, 2002; 14(10): 1155 - 1167. [Abstract] [Full Text] [PDF]

				M. S. von Bergwelt-Baildon, R. H. Vonderheide, B. Maecker, N. Hirano, K. S. Anderson, M. O. Butler, Z. Xia, W. Y. Zeng, K. W. Wucherpfennig, L. M. Nadler, et al. Human primary and memory cytotoxic T lymphocyte responses are efficiently induced by means of CD40-activated B cells as antigen-presenting cells: potential for clinical application Blood, May 1, 2002; 99(9): 3319 - 3325. [Abstract] [Full Text] [PDF]