HTLV-1-infected HIS Rag2-/-γc-/- mice, a suitable model for in vivo investigating the effects of drugs in ATL treatment?

Abstract

Adult T cell Leukemia, an aggressive T-cell malignancy linked to HTLV-1 infection, is resistant to chemotherapy. Recently, promising results were obtained with the combination of arsenic trioxide, interferon alpha and zidovudine. However, the cellular and molecular mechanisms of their anti-leukemia activity remain to be investigated. To that aim, we have relied on HIS (Human Immune System) Rag2-/-γc-/- mice. We have indeed observed that when infected with HTLV-1, these mice displayed, five months later, an elevated number of human Tax-expressing T cells in the thymus, the spleen and the mesenteric lymph nodes. Some of them also developed T lymphoproliferative diseases. To determine the effects of these three drugs on the apparition of these pathological features, Rag2-/-γc-/- mice were infected with HTLV-1 and, 16 weeks after infection, daily treated with the drugs for one week and sacrificed. Untreated HIS mice infected with HTLV-1 were used as control. Treatment resulted in a significant decrease in the spleen weight as compared to untreated controls. Interestingly, we also noted a decrease of the proviral load in thymocytes as well as a drop in the number of mature activated T cells in the spleen and in lymph nodes. These data clearly indicate that the HIS mouse model provides us with the opportunity not only for the pre-clinical evaluation of therapeutic approaches against the leukemogenic process associated with HTLV-1 infection, but also for unraveling the corresponding mechanisms.