The combination of arsenic, interferon-alpha, and zidovudine restores an “immunocompetent-like” cytokine expression profile in patients with adult T-cell leukemia lymphoma

Abstract

BackgroundHTLV-I associated adult T-cell leukemia/lymphoma (ATL) carries a dismal prognosis due to chemo-resistance and immuno-compromised micro-environment. The combination of zidovudine and interferon-alpha (IFN) significantly improved survival in ATL. Promising results were reported by adding arsenic trioxide to zidovudine and IFN.ResultsHere we assessed Th1/Th2/Treg cytokine gene expression profiles in 16 ATL patients before and 30 days after treatment with arsenic/IFN/zidovudine, in comparison with HTLV-I healthy carriers and sero-negative blood donors. ATL patients at diagnosis displayed a Treg/Th2 cytokine profile with significantly elevated transcript levels of Foxp3, interleukin-10 (IL-10), and IL-4 and had a reduced Th1 profile evidenced by decreased transcript levels of interferon-γ (IFN-γ) and IL-2. Most patients (15/16) responded, with CD4+CD25+ cells significantly decreasing after therapy, paralleled by decreases in Foxp3 transcript. Importantly, arsenic/IFN/zidovudine therapy sharply diminished IL-10 transcript and serum levels concomittant with decrease in IL-4 and increases in IFN-γ and IL-2 mRNA, whether or not values were adjusted to the percentage of CD4+CD25+ cells. Finally, IL-10 transcript level negatively correlated with clinical response at Day 30.ConclusionsThe observed shift from a Treg/Th2 phenotype before treatment toward a Th1 phenotype after treatment with arsenic/IFN/zidovudine may play an important role in restoring an immuno-competent micro-environment, which enhances the eradication of ATL cells and the prevention of opportunistic infections.

Triple Therapy with Prednisolone, Pegylated Interferon and Sodium Valproate Improves Clinical Outcome and Reduces Human T-Cell Leukemia Virus Type 1 (HTLV-1) Proviral Load, Tax and HBZ mRNA Expression in Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

“…Therefore, 20 years of investigation to find an effective treatment for HAM/TSP and ATL led us to test a combination therapy of peg-IFN as an immunomodulator, sodium valproate as a deacetylase inhibitor, and prednisolone as an anti-inflammatory agent in patients with HAM/TSP [10,20,25,43]. In the present study, significant improvements were observed in clinical aspects such as motor disability, spasticity, and antibody titer of HTLV-1 virus after 6 months of triple therapy; however, urinary findings and sensory disturbances with lower back pain improved marginally.…”

“…Consequently, antiviral drugs combined with the immunomodulators may be more effective for the treatment of patients with HAM/TSP. Our recent study [20] demonstrated that triple therapy with arsenic, IFN-α, and zidovudine shifts the cytokine expression from a regulatory T cell and T helper 2 phenotype to a T helper 1 phenotype. This shift enhances the eradication of ATL cells and prevents the emergence of opportunistic infections.…”

“…HBZ expression has a positive effect on HTLV-1 viral replication [17]. Moreover, a significant positive correlation has been previously reported between HBZ mRNA expression and HAM/TSP disease severity [18][19][20]. HTLV-1-infected cells circulate in the body; hence, blood samples provide an easily accessible source of information and, in particular, a large number of viruses for the understanding and monitoring of HTLV-1-associated diseases.…”

“…The immune suppression and deregulation of the immune system in HTLV-1-infected people result in autoimmunity to neurons and provide a microenvironment for inducing HAM/TSP. This immunosuppressive microenvironment enables HTLV-1-infected cells to evade from the host immune responses and induce HTLV-1-associated diseases [20].…”

Reducing the global burden of HTLV-1 infection: An agenda for research and action

“…valproic acid or arsenic trioxide) (Kchour et al, 2013;Olindo et al, 2011); -collaborating with industrial partners to investigate the off-label use of newly developed agents used in HTLV-1-negative T-cell lymphoma (e.g. anti-CCR4 and anti-CD30).…”