HTLV I Associated

  • View
    215

  • Download
    0

Embed Size (px)

Text of HTLV I Associated

  • 8/8/2019 HTLV I Associated

    1/13

    Folia Neuropathologica 2009; 47/2182

    HTLV-I-associated myelopathy/tropical spastic paraparesis

    (HAM/TSP): the role of HTLV-I-infected Th1 cellsin the pathogenesis, and therapeutic strategy

    Tatsufumi Nakamura

    Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan

    Folia Neuropathol 2009; 47 (2): 182-194

    A b s t r a c t

    Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic

    progressive myelopathy characterized by bilateral pyramidal tract involvement with sphincteric disturbances. The primary

    neuropathological feature of HAM/TSP is chronic myelitis characterized by perivascular cuffing and parenchymal in-

    filtration of lymphocytes. Although the exact cellular and molecular events underlying the induction of chronic

    inflammation in the spinal cord by HTLV-I are still unclear, a long-standing bystander mechanism, such as the destruction

    of surrounding nervous tissue by the interaction between HTLV-I-infected CD4+ T cells and HTLV-I-specific cytotoxic T cells

    in the spinal cord, is probably critical in the immunopathogenesis of HAM/TSP. In this review, the role of HTLV-I-infected

    CD4+ T cells as activated Th1 cells in the peripheral blood will be discussed as the first responders of this mechanism in

    the immunopathogenesis of HAM/TSP.

    Since the discovery of HAM/TSP, various therapeutic approaches, such as immunomodulatory or anti-viral drugs, have

    been used for HAM/TSP patients. However, an effective therapeutic strategy against HAM/TSP is still unavailable. As

    HTLV-I-infected CD4+ T cells are the first responders in the immunopathogenesis of HAM/TSP, the ideal treatment is the

    elimination of HTLV-I-infected cells from the peripheral blood. In this review, the focus will be on therapeutic strategies

    aimed at targeting HTLV-I-infected CD4+ T cells in HAM/TSP patients.

    Key words: HAM/TSP, HTLV-I, Th1, treatment.

    Communicating author:

    Tatsufumi Nakamura, M.D., Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki

    University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan, tel.: +81 95 819 72 65, fax: +81 95 849 72 70, Email: tatsu@net.nagasaki-u.ac.jp

    IntroductionHuman T lymphotropic virus type I (HTLV-I)-asso-

    ciated myelopathy/tropical spastic paraparesis

    (HAM/TSP) is a chronic progressive myelopathy

    caused by HTLV-I, a member of the exogenous human

    retroviruses [19,58]. In 1985, Gessain and colleagues

    first reported the high prevalence of anti-HTLV-I anti-bodies in the sera of patients with TSP in Martinique

    (French West Indies) [18]. Subsequently, Rodgers-

    Johnson and Gajdusek reported similar findings in

  • 8/8/2019 HTLV I Associated

    2/13

    Folia Neuropathologica 2009; 47/2 183

    Pathogenesis and treatment of HAM/TSP

    Spinal cord

    Vessel

    Bystandermechanism

    HTLV-Ispecific

    CD8+ CTL

    HTLV-I

    Infected

    CD4+ T cell

    HTLV-I

    Infected

    CD4+ T cell

    Chronic myelitis

    Immunomodulatorytherapy

    Anti-viral therapyTh1

    Th1

    Cytokine Cytokine

    CytokineCytokine

    Cytokine

    Fig. 1. Immunopathogenesis of and therapeutic strategies in HAM/TSP. The bystander mechanism, such as

    the destruction of surrounding tissues by inflammatory cytokine expression, during the interaction

    between HTLV-I-infected CD4+ T cells and HTLV-I-specific CD8+ CTL, is probably critical as the cause of

    chronic myelitis. The increase of HTLV-I-infected CD4+ T cells, in the peripheral blood of HAM/TSP patients,

    having the characteristics of Th1-activated status with the transmigrating activity into the tissues enough

    to trigger this mechanism, plays an important role in the first step of the immunopathogenesis ofHAM/TSP. The therapeutic strategies in HAM/TSP are divided into two directions as shown by ;

    1) immunomodulatory therapy, such as a) suppression of immune activation, particularly for activated

    HTLV-I-infected cells, b) inhibition of the transmigration of activated HTLV-I-infected cells to the spinal cord,

    c) reduction of chronic inflammation in the spinal cord; and 2) anti-viral therapy, such as a) suppression of

    HTLV-I expression and/or replication, b) inhibition of the proliferation of HTLV-I-infected cells, c) elimination

    of HTLV-I-infected cells. Quotation from Ref. [51].

    patients with TSP in Jamaica and Colombia [62].

    Thereafter, similar findings were documented from

    other countries of the tropical zone, and the contri-

    bution of HTLV-I infection to the development of TSP

    was confirmed [19,23]. Although these areas, which

    are highly endemic for HTLV-I, are located in the

    tropical zone, such as the Caribbean, equatorial

    Africa, the Seychelles, and Central and South America,

    Japan, which is located in the temperate zone,

    particularly southern Japan, is also an area which is

    highly endemic for HTLV-I. In 1986, Osame and co-

    workers reported the association between HTLV-I

    infection and spastic paraparesis and proposed that

    spastic paraparesis associated with elevated anti-

    bodies to HTLV-I should be named HTLV-I-associated

    myelopathy (HAM) and considered a new clinical

    entity [59]. Based on the accumulated evidence,

    a WHO scientific group on HTLV-I infections and its

    associated diseases, in a meeting held in Kagoshima,

    Japan on 1988, concluded that HTLV-I-seropositive

    TSP and HAM were identical diseases, and proposed

    the name HAM/TSP [61].

    The principal clinical manifestation of HAM/TSP is

    spastic paraplegia or paraparesis, characterized by

    a slowly progressive course of prominent upper motor

    neuron involvement and mild sensory deficit with

  • 8/8/2019 HTLV I Associated

    3/13

    Folia Neuropathologica 2009; 47/2184

    A. Therapies focusing on immunomodulatory effects

    Effectsa) suppression of immune activation, particularly for activated HTLV-I-infected cellsb) inhibition of transmigration of activated HTLV-I-infected cells to the spinal cordc) reduction of chronic inflammation in the spinal cord

    Therapies1) corticosteroid hormone2) blood purification3) pentoxifylline4) heparin5) high dose-intravenous gamma globulin6) intermittent high-dose vitamin C7) fosfomycin and erythromycin8) fermented milk drink

    B. Therapies focusing on anti-viral effects

    Effectsa) suppression of HTLV-I expression and/or replicationb) inhibition of proliferation of HTLV-I-infected cellsc) elimination of HTLV-I-infected cells

    Therapies1) interferon- and -2) reverse transcriptase inhibitors3) humanized anti-Tac4) histone deacetylase enzyme inhibitor5) prosultiamine

    Table I. Therapeutic trials in HAM/TSP patients (Quotation from [51])

    sphincteric disturbance [19,23,58]. The primary patho-

    logical feature of HAM/TSP is chronic myelitis charac-

    terized by chronic inflammation in the spinal cord,

    mainly the lower thoracic cord, with perivascular

    cuffing and parenchymal infiltration of mononuclear

    cells [28]. With the discovery of HAM/TSP, it has

    become evident that HTLV-I has the remarkable

    capacity for not only aggressive lymphoproliferation,

    as in adult T-cell leukaemia (ATL), but also profound

    chronic inflammation. However, the exact mechanisms

    by which HTLV-I causes these disparate clinical condi-

    tions, an aggressive lymphoproliferative malignancy on

    the one hand and chronic neuroinflammation on the

    other, are still unknown. Also, although HTLV-I infects

    approximately 10-20 million people worldwide [10],

    with large endemic areas in southern Japan and the

    tropical zone [23] as described above, it is still unclear

    why only a very small proportion of HTLV-I-infected

    individuals develop either of these HTLV-I-associated

    diseases.

    Although the molecular mechanisms by which

    HTLV-I infection induces the chronic inflammation in

    the spinal cord still remain unresolved, a long-stan-

    ding bystander mechanism, such as the destruction

    of surrounding tissues by the interaction between

    HTLV-I-infected CD4+ T cells and HTLV-I-specific CD8+

    cytotoxic T cells (CTL), is probably critical in the patho-

    genesis of HAM/TSP [25,60]. That is, chronic inflam-

    mation, induced by soluble factors, such as inflam-

    matory cytokines released during the encounter

    between transmigrated HTLV-I-infected CD4+ T cells

    and HTLV-I-specific CD8+ CTL in the spinal cord, is

    operative (Fig. 1). In a point of view on the virological

    abnormalities in HAM/TSP, it is well known that the

    HTLV-I proviral load in the peripheral blood is signi-

    ficantly higher in HAM/TSP patients than HTLV-I

    asymptomatic carriers, and high HTLV-I proviral load

    in the peripheral blood is the most important pre-

    requisite in the development of HAM/TSP [31,47]. On

    the other hand, numerous immunological dysregu-

    lations mostly mediated by HTLV-I tax expression are

    detected in the peripheral blood of HAM/TSP patients

    [5,50]. Therefore, when considering the immunopatho-

    genesis of HAM/TSP, it is plausible that the increase

    Tatsufumi Nakamura

  • 8/8/2019 HTLV I Associated

    4/13

    Folia Neuropathologica 2009; 47/2 185

    of HTLV-I-infected CD4+ T cells possessing up-regu-

    lated transmigrating activity to the spinal cord plays

    an important