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Interleukin-15: biology, pathophysiology, and pre-clinical application in disease

Roychowdhury, Sameek
http://rave.ohiolink.edu/etdc/view?acc_num=osu1084884532

Abstract Details

2004, Doctor of Philosophy, Ohio State University, Medical Microbiology and Immunology.
A dysregulated immune system that is either too weak or too strong may lead to disease states such as cancer or autoimmunity. Specifically, this dissertation presents data on a growth factor, interleukin-15 (IL-15), and its pre-clinical application for cancer treatment and its role in the pathophysiology of graft-versus-host disease (GVHD). Provision of tumor-specific T cells, or adoptive immunotherapy, has emerged as a valid approach for prevention or treatment of human cancers such as melanoma and Epstein Barr virus-positive lymphoma. To improve immunotherapy, we hypothesized that IL-15 could be applied as a single agent to enhance tumor immunity through the maintenance of tumor specific CD8+ memory T cells. Tumor-bearing mice were treated with an adoptive transfer of transgenic tumor specific T cells and then randomized to receive daily low dose IL-15 or PBS treatment. Mice receiving tumor-specific T cells and IL-15 experienced a significantly delayed tumor relapse or no relapse at all. Analysis of peripheral blood 21 days after adoptive transfer demonstrated the persistence of tumor specific T cells in mice treated with IL-15 as compared to PBS. These data support the notion that low dose exogenous IL-15 can sustain tumor-specific T cells in vivo and result in clinical benefit. IL-15 is a pleiotropic pro-inflammatory cytokine with inefficient post-transcriptional processing. We hypothesized that alteration of endogenous IL-15 gene regulation could adversely impact disease progression in the well described C57Bl/6 (B6) > (C57Bl/6 x DBA/2)F1 (B6D2F1) murine model of acute allogeneic graft versus host disease (GVHD). B6D2F1 allogeneic recipients were transplanted with B6 bone marrow cells expressing a murine IL-15 transgene (IL-15 tg) modified for efficient translation and secretion. These mice had a dramatically decreased median survival time (MST) compared to mice transplanted with wild type (wt) B6 bone marrow. Blinded analysis of histopathology revealed a significant increase in intestinal epithelial damage and inflammation of the liver. The new findings discussed here suggest that IL-15 may be a valuable component of cancer therapies that aim to expand and maintain tumor-specific T cells, but that it also may have adverse side effects when applied in the setting of allogeneic bone marrow transplantation.
Michael Caligiuri (Advisor)
129 p.
Interleukin-15; T cells; Graft-versus-host disease; Cancer; Immunotherapy

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Citations

  • Roychowdhury, S. (2004). Interleukin-15: biology, pathophysiology, and pre-clinical application in disease [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1084884532

    APA Style (7th edition)

  • Roychowdhury, Sameek. Interleukin-15: biology, pathophysiology, and pre-clinical application in disease. 2004. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1084884532.

    MLA Style (8th edition)

  • Roychowdhury, Sameek. "Interleukin-15: biology, pathophysiology, and pre-clinical application in disease." Doctoral dissertation, Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1084884532

    Chicago Manual of Style (17th edition)

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© 2004, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.