Induction of Adult T-Cell Leukemia-Like Lymphoproliferative Disease and Its Inhibition by Adoptive Immunotherapy in T-Cell-Deficient Nude Rats Inoculated with Syngeneic Human T-Cell Leukemia Virus Type 1-Immortalized Cells

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) has been shown to be the etiologic agent of adult T-cell leukemia (ATL), but the in vivo mechanism by which the virus causes the malignant transformation is largely unknown. In order to investigate the mechanisms of HTLV-1 leukemogenesis, we developed a rat model system in which ATL-like disease was reproducibly observed, following inoculation of various rat HTLV-1-immortalized cell lines. When previously established cell lines, F344-S1 and TARS-1, but not TART-1 or W7TM-1, were inoculated, systemic multiple tumor development was observed in adult nude (nu/nu) rats. FPM1 cells, newly established from a heterozygous (nu/+) rat syngeneic to nu/nurats, caused transient tumors only at the injection site in adult nu/nu rats, but could progressively grow in newborn nu/nu rats and metastasize in lymph nodes. The derivative cell line (FPM1-V1AX) serially passed through newbornnu/nu rats acquired the potency to grow in adultnu/nu rats. These results indicated that only some with additional changes but not all of the in vitro HTLV-1-immortalized cell lines possessed in vivo tumorigenicity. Using the syngeneic system, we further showed the inhibition of tumor development by transferring splenic T cells from immunized rats, suggesting the involvement of T cells in the regression of tumors. This novel and reproducible nude rat model of human ATL would be useful for investigation of leukemogenesis and antitumor immune responses in HTLV-1 infection.

HTLV-1 Tax-Specific CTL Epitope–Pulsed Dendritic Cell Therapy Reduces Proviral Load in Infected Rats with Immune Tolerance against Tax

“…The cells were cultured for 2-3 wk before using for HTLV-1 infection of rats. FPM1-V1AX is an HTLV-1-immortalized rat T cell line, which was previously established in our laboratory (37). The cells were maintained in RPMI 1640 containing 10% FCS and 2-ME (10 25 M; Life Technologies).…”

Tumor immunity against adult T‐cell leukemia

“…To understand the influence of host immunity to HTLV‐I leukemogenesis in vivo , a series of experiments using rat models for HTLV‐I‐infected T‐cell lymphomas were carried out. In these models, a syngeneic HTLV‐I‐transformed T‐cell line underwent phenotypic evolution to cause fatal lymphomas in immune‐suppressed rats (35) . However, this cell line did not cause tumors in immune‐competent rats.…”

Activation and detection of HTLV-I Tax-specific CTLs by Epitope expressing Single-Chain Trimers of MHC Class I in a rat model

“…Rats have been used for a number of studies on HTLV-I infection, because they are susceptible to the virus and because the virus-transformed T cell lines can be established in vitro [ 33 , 34 ]. It has previously shown in a rat model that HTLV-I specific T cells were important to inhibit the growth of virus-infected cells in vivo [ 17 ]. Moreover, the association of elevated proviral load with insufficient T cell immunity has been also observed in a rat model of oral HTLV-I infection [ 35 ].…”

“…To understand the mechanism of ATL development, it is very important to dissect the interplay between the virus-specific CTLs and HTLV-I infected T cells. We have previously established a rat model of ATL-like disease, which allows examination of the growth and spread of HTLV-I infected cells, as well assessment of the effects of immune T cells on the development of the disease [ 17 , 18 ]. By using this model system, we also reported the therapeutic effect of Tax-coding DNA or peptide against the disease [ 19 , 20 ].…”