Lack of Recall Response to Tax in ATL and HAM/TSP Patients But Not in Asymptomatic Carriers of Human T-cell Leukemia Virus Type 1

Manuel, Sharrón L.; Sehgal, Mohit; Connolly, John E.; Makedonas, George; Khan, Zafar K.; Gardner, Jay; Betts, Michael R.

doi:10.1007/s10875-013-9918-x

Cited by 19 publications

(22 citation statements)

References 67 publications

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“…Given the inhibitory effects of Hu‐Mikβ1 on T cell function, we asked whether Hu‐Mikβ1 administration also modulated additional aspects of CD8 + T cell function. In HAM/TSP patients, alternative expressions of various inhibitory receptors, such as PD‐1, CD244, and Tim‐3, have been demonstrated on CD8 + T cells . To determine whether the cells expressing the inhibitory receptors (PD‐1, CD244, and Tim‐3) were affected by Hu‐Mikβ1 administration, we examined the frequencies of PD‐1 + , CD244 + , and Tim‐3 + cells in CD8 + T cells of HVs and HAM/TSP patients and compared their frequencies in HAM/TSP patients (group 2 and 3) at pretreatment and at week 9 of Hu‐Mikβ1 treatment.…”

Section: Resultsmentioning

confidence: 99%

Clinical trial of a humanized anti‐IL‐2/IL‐15 receptor β chain in HAM/TSP

Enose-Akahata

Ohayon

et al. 2019

Ann Clin Transl Neurol

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Objective Human T cell lymphotropic virus 1 (HTLV‐1)‐associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neurological disease. Chronic activation of CD8+ T cells, as evidenced by increased spontaneous lymphoproliferation and HTLV‐1‐specific cytotoxic T cells, has been demonstrated in HAM/TSP patients. Since IL‐2 and IL‐15 stimulate memory CD8+ T cell activity, these cytokines have been implicated in the immunopathogenesis of HAM/TSP. In this phase I trial, we evaluated the safety, pharmacokinetics, and ability of Hu‐Mikβ1, a humanized monoclonal antibody directed toward the IL‐2/IL‐15 receptor β‐chain (IL‐2/IL‐15Rβ: CD122), to saturate CD122 and regulate abnormal immune responses in patients with HAM/TSP by inhibition of IL‐15 action. Methods Hu‐Mikβ1 was administered intravenously at doses of 0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg in a total of nine HAM/TSP patients. Five doses of Hu‐Mikβ1 were administered at 3‐week intervals. The clinical response was evaluated using standardized scales. Viral and immunologic outcome measures were examined including HTLV‐1 proviral load, T cell phenotypic analysis and spontaneous lymphoproliferation in HAM/TSP patients. Results There was no significant toxicity associated with Hu‐Mikβ1 administration in HAM/TSP patients. Saturation of CD122 by Hu‐Mikβ1 was achieved in five out of nine HAM/TSP patients. Administration of Hu‐Mikβ1 was associated with inhibition of aberrant CD8+ T cell function including spontaneous lymphoproliferation and degranulation and IFN‐γ expression, especially in HAM/TSP patients that achieved CD122 saturation. Interpretation The treatment with Hu‐Mikβ1 had a number of immunological effects on HAM/TSP patients although no clinical efficacy was observed. We also did not see any dose‐related toxicity.

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Section: Resultsmentioning

confidence: 99%

Clinical trial of a humanized anti‐IL‐2/IL‐15 receptor β chain in HAM/TSP

Enose-Akahata

Ohayon

et al. 2019

Ann Clin Transl Neurol

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“…Whether or not the cytotoxic activity of HTLV‐1‐specific CTL is different between HAM/TSP patients and AC is also controversial. Several studies have reported that the cytokine production and degranulation activity of CTL are decreased in HAM/TSP patients when compared with those in AC . However, the work in these reports might have methodological problems.…”

Section: Immune Response To Htlv‐1mentioning

confidence: 99%

“…Three different groups reported that the PD‐1 expression of HTLV‐1 Tax‐specific CTL is lower in HAM/TSP patients compared with that in AC . Another group claimed that HAM/TSP patients show upregulated PD‐1 expression in both their total CD8+ T cells and their Tax‐specific CTL based on work using pooled Tax peptides . Additionally, two groups reported that the Tim‐3 expression of Tax‐specific CTL is downregulated in HAM/TSP patients compared with that in AC .…”

Section: Immune Response To Htlv‐1mentioning

confidence: 99%

Pathogenesis of human T‐lymphotropic virus type 1‐associated myelopathy/tropical spastic paraparesis

Kubota

2017

Clinical & Exp Neuroim

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Human T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus that preferentially infects CD4+ lymphocytes in vivo. The virus causes a hematological malignancy known as adult T-cell leukemia, and an inflammatory disease in the central nervous system (CNS) called HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP). Approximately 0.3% of HTLV-1-infected individuals develop HAM/TSP. HAM/TSP patients show spastic paraparesis and sphincter dysfunction, as well as sensory disturbance of the lower extremities, which corresponds to pathological lesions in the spinal cord. Although the majority of HAM/TSP patients progress slowly, this disease progresses rapidly in some patients. An increased HTLV-1 proviral load is more common in HAM/TSP patients than in asymptomatic HTLV-1 carriers, and is considered to be a strong risk factor for HAM/TSP development. A prominent cellular immune response in HAM/TSP patients is a significantly elevated number of HTLV-1 Tax-specific CD8+ cytotoxic T lymphocytes (CTL) in peripheral blood mononuclear cells compared with asymptomatic HTLV-1 carriers. Additionally, CD4+ and CD8+ lymphocytes accumulate in the perivascular areas of spinal cords in HAM/TSP patients. Viral DNA, mRNA and proteins are detected only in infiltrating CD4+ T cells, but not in neural cells. A high proportion of HTLV-1-specific CTL infiltrates the CNS. Furthermore, some neural cells surrounding the CTL, predominantly oligodendrocytes, undergo apoptosis. These findings suggest the pathogenesis that the HTLV-1-specific inflammation induced by the interaction of HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ CTL causes bystander damage in the CNS. In the present review, a more exact pathogenesis of HAM/TSP is discussed based on virology, immunology and neuropathology.

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“…The majority of the co-inhibitory receptors belong to the immunoglobulin and tumor necrosis factor receptor superfamily (IgSF and TNFRSF) (Chen and Flies 2013). In earlier studies, we observed a direct correlation between programmed cell death-1 (PD-1), its ligand Programmed death-ligand 1 (PD-L1) and CTL dysfunctions in ATL and HAM/TSP patients (Manuel et al 2013a; Manuel et al 2013b). In our earlier studies with 10 HTLV-1 negative and 10 HTLV-1 positive subjects, we observed a 3-fold increase in co-expression of PD-1 and T-cell Ig and ITIM domain (TIGIT) on both CD4 + and CD8 + T cells from infected samples compared to control with the expression being more pronounced in Tax positive T cells.…”

Section: Introductionmentioning

confidence: 97%

“…In previous studies with Jamaican cohort, HTLV-1 infected subjects present a decreased amount of plasmacytoid DCs (pDCs) in ATL and HAM/TSP patients as compared to asymptomatic carriers (ACs). Additionally, myeloid DCs (mDCs) showed a decreased expression of HLA-DR in HAM/TSP patients but an increased expression of CD86 was seen in both pDCs and mDCs compared to other groups (Manuel et al 2013a; Manuel et al 2013b). …”

Section: Introductionmentioning

confidence: 99%

HTLV-1 Infection and Neuropathogenesis in the Context of Rag1-/-γc-/- (RAG1-Hu) and BLT Mice

Ginwala

Caruso

Khan

et al. 2017

J Neuroimmune Pharmacol

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To date, the lack of a suitable small animal model has hindered our understanding of Human T-cell lymphotropic virus (HTLV)-1 chronic infection and associated neuropathogenesis defined as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The host immune response plays a critical role in the outcome of HTLV-1 infection, which could be better tested in the context of humanized (hu) mice. Thus, we employ here the Balb/c-Rag1−/−γc−/− or Rag1 as well as Bone marrow-Liver-Thymic (BLT) mouse models for engraftment of human CD34+ hematopoietic stem cells. Flow cytometry and histological analyses confirmed reconstitution of Rag1 and BLT mice with human immune cells. Following HTLV-1 infection, proviral load (PVL) was detected in the blood of Rag-1 and BLT hu-mice as early as 2 weeks post-infection (wpi) with sustained elevation in the subsequent weeks followed by Tax expression. Additionally, infection was compared between adult and neonatal Rag1 mice with both PVL and Tax expression considerably higher in the adult Rag1 mice as compared to the neonates. Establishment of peripheral infection led to lymphocytic infiltration with concomitant Tax expression and resulting myelin disruption within the central nervous system of infected mice. In addition, up-regulation in the expression of several immune checkpoint mediators such as programmed cell death-1 (PD-1), T-cell Ig and ITIM domain (TIGIT), and T cell Ig and mucin domain-3 protein (Tim-3) were observed on CD8+ T cells in various organs including the CNS of infected hu-mice. Collectively, these studies represent the first attempt to establish HTLV-1 neuropathogenesis in the context of Rag-1 and BLT hu-mice as potential novel tools for understanding HTLV-1 neuropathogenesis and testing of novel therapies such as immune checkpoint blockade in the amelioration of chronic HTLV-1 infection.

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Lack of Recall Response to Tax in ATL and HAM/TSP Patients But Not in Asymptomatic Carriers of Human T-cell Leukemia Virus Type 1

Cited by 19 publications

References 67 publications

Clinical trial of a humanized anti‐IL‐2/IL‐15 receptor β chain in HAM/TSP

Clinical trial of a humanized anti‐IL‐2/IL‐15 receptor β chain in HAM/TSP

Pathogenesis of human T‐lymphotropic virus type 1‐associated myelopathy/tropical spastic paraparesis

HTLV-1 Infection and Neuropathogenesis in the Context of Rag1-/-γc-/- (RAG1-Hu) and BLT Mice

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