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Measles Virotherapy in Adult T cell Leukemia

Machado Parrula, Maria Cecilia
http://rave.ohiolink.edu/etdc/view?acc_num=osu1261413581

Abstract Details

2009, Doctor of Philosophy, Ohio State University, Veterinary Biosciences.
Adult T cell leukemia (ATL) is a proliferative disorder of CD4+ T cells caused by human T cell lymphotropic type I virus infection. ATL is refractory to current therapies and consequently, new therapeutic approaches are necessary for the treatment of ATL. The goal of this work was to evaluate measles virotherapy pre-clinically in ATL. For this purpose, a mouse model of ATL was established by characterizing the engraftment of different HTLV-I infected cells, MET-1, MT-2 and C8166-45, in immunodeficient mice. Inoculation of MET-1 cells in NOD/SCID mice proved to be the best model and was used to evaluate measles virotherapy in mice with small and large tumor burden. Treatment with measles virus (MV) led to marked tumor regression in both small and large tumor burden, and prolonged survival in mice with large tumor burden, but was not able to completely eliminate residual tumor. Therefore, to try to enhance measles virotherapy, a recombinant measles virus expressing HSP72 (MV-HSP72) was produced. The hypothesis behind the use of this virus was that it would replicate faster due to the reported effect of HSP72 on measles viral gene transcription, and the increased expression of HSP72 on the cell surface of tumor following infection would stimulate the antitumor Natural Killer cell activity. Survival studies comparing treatment with MV and MV-HSP72 in mice with large tumor burden showed that treatment with MV-HSP72 significantly increased survival in comparison to treatment with MV, although the difference between both viruses decreased overtime. Although MV therapy was very efficient in the MET-1 model of ATL, we also investigated its effect on other HTLV-1 infected cell lines, MT-1, MT-2, MT-4, C8166-45. Two HTLV-1 negative cell lines, Jurkat and CCRF-CEM, served as controls. All cell lines were susceptible to MV mediated cytolosis except MT-1 and CCRF-CEM cells which were resistant. This resistance was due to IFNβ, which was secreted only by these two cell lines. In vivo, MV treatment of tumors produced by MT-1 cells which secrete interferon was less effective than treatment of tumors produced by MET-1 cells which do not secrete interferon. These results indicate that interferon secretion markedly interferes with the outcome of MV therapy. So far, our work was performed by inoculating human cells into immune deficient mice. In order to be able to investigate the interaction between tumors, immune system and MV therapy, efforts were made to establish a syngeneic immunocompetent cotton rat tumor model. Cotton rats are the only laboratory rodents that are permissive to MV infection. Three different cotton rat tumor cell lines , CCRT, VCRT and LCRT, were karyotyped. All three cell lines produced tumors after subcutaneous inoculation. CCRT and VCRT were susceptible to MV infection in vitro. In vivo, tumors induced by CCRT cells could be infected with MV, and our data will provide the basis for further studies. In summary, our work showed that MV therapy is a very promising therapeutic approach for the treatment of ATL, especially in ATL cells deficient in interferon.
Stefan Niewiesk, PhD (Advisor)
Michael Lairmore, Phd (Committee Member)
Thomas Rosol, PhD (Committee Member)
Maxey Wellman, PhD (Committee Member)
149 p.
Oncology; Virology
HTLV-1; ATL; measles; immunodeficient mice; type I interferon; cotton rat

Recommended Citations

Citations

  • Machado Parrula, M. C. (2009). Measles Virotherapy in Adult T cell Leukemia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1261413581

    APA Style (7th edition)

  • Machado Parrula, Maria. Measles Virotherapy in Adult T cell Leukemia. 2009. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1261413581.

    MLA Style (8th edition)

  • Machado Parrula, Maria. "Measles Virotherapy in Adult T cell Leukemia." Doctoral dissertation, Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1261413581

    Chicago Manual of Style (17th edition)

osu1261413581
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© 2009, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.