3rd Conference on Retroviruses and Opportunistic Infections Washington, DC - January 28-February 1, 1996

Conf Retroviruses Opportunistic Infect 1996 Jan 28-Feb 1; 3rd:59 (abstract no. 37)

Grossman WJ, Ratner L
Washington University School of Medicine, St. Louis, MO.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell lymphoma/leukemia, and has been implicated in the pathogenesis of large granular lymphocytic (LGL) leukemia. We previously described the development of LGL leukemia in mice transgenic for the tax gene of HTLV-1 (Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):1057-61.). Primary tumors in these mice developed on the ears, legs and tails. Histological and flow cytometry analysis of these tumors showed them to be composed of LGLs (10-25%), neutrophils (60-800%), and lymphocytes (10-25%). Progression of tumor masses resulted in dissemination of LGLs into the bronchus epitheliums, hepatic sinusoids, and lymph nodes. Peripheral blood smears of transgenic mice revealed marked granulocytosis and circulating LGLs. The bone marrow showed the LGLs to represent 33.7 ± 2.5% of bone marrow cells. Additional flow cytometry analysis demonstrated that these LGLs expressed surface markers associated with early natural killer (NK) cell progenitors: Fcγ receptor (CD16/32), Thy1.2, CD44, IL-2R β chain, and the NK cell marker, 5E6. In vitro cultures of tumor cell suspensions resulted in the establishment of several LGL cell lines propagated for > 2 years that were morphologically/phenotypically similar to the LGLs found in the tumors and peripheral blood of the transgenic mice. Tumor transfer of LGL cll lines into SCID mice was successful in 4/4 attempts, and resulted in similar altered blood differentials. RT-PCR analysis of cytokine expression demonstrated that peripheral tumors expressed IL-2 alpha and β, GM-CSF,and IFNγ, and LGL cell lines produced GM-CSF and IFNγ. An IFNγ ELISA on established LGL cell lines showed IFNγ expression at levels between 125-825 U/mL. It is possible that production of GM-CSF by these LGLs may be responsible for the observed neutrophilia in these transgenic mice, and that IFNγ production may induce LGL cell transformation through an autocrine stimulation loop.

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