Title page for ETD etd-06062008-154644


Type of Document Dissertation
Author Hassuneh, Mona Rushdi
URN etd-06062008-154644
Title Role of autocrine growth factors in the tumorigenic transformation of T cells
Degree PhD
Department Biology
Advisory Committee
Advisor Name Title
Nagarkatti, Mitzi Committee Co-Chair
Nagarkatti, Prakash S. Committee Co-Chair
Schurig, Gerhardt G. Committee Member
Tyson, John J. Committee Member
Wong, Eric A. Committee Member
Keywords
  • tumor cells
Date of Defense 1996-04-05
Availability restricted
Abstract

In the current study we tested the hypothesis that tumorigenic transformation of T cells may result from aberrant regulation of autocrine growth factor production. We describe for the first time characterization of several normal T cell lines that underwent spontaneous transformation resulting from constitutive expression of interleukin-2 (IL-2) and interleukin 2 receptor (IL-2R) genes. Such cell lines could induce tumors in vivo and furthermore, the growth of such transformed cells both ex vivo and in vivo could be inhibited by monoclonal antibodies (mAbs) or antisense oligonucleotides specific for IL-2 or IL-2R. Interestingly, an in vivo originated T cell lymphoma, LSA, was also found to be dependent on constitutive production of IL-2 and Interleul(in-4 (IL-4). Together, these data demonstrated that dysregulation in the production or respnsiveness to autocrine T cell growth factors, plays an important role in T cell transformation and tumorigenicity. Due to their ability to produce T cell growth factors, such tumor cells were found to be highly immunogenic. Thus it was surprising that some T cell lymphomas could still grow in an immunocompetent host and kill the host. To this effect, we investigated additional mechanisms used by such tumor cell lines to grow in an immunocompetent host. It was noted that the tumor cells used mechanisms such as failure to express MHC and production of immunosuppressive cytokines, such as, transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), to evade the action of the immune system. In addition, the T cell lymphomas constitutively expressed F as-ligand and triggered apoptosis of host T cells that expressed Fas. Together, the current study suggests that cytokines produced by the tumor cells play an important role in tumorigenic transformation as vvell as maintenance of tumor growth in an immunocompetent host.

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