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S Ijichi

Publications and source records attributed to S Ijichi.

At least 19 recordsLinked to original sources
PubMed1998

Reflux of HTLV-I infected lymphocytes from the privileged compartment(s) to peripheral blood flow in patients with HTLV-I-associated myelopathy.

To understand the mechanisms involved in the pathogenesis of human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), three in vivo phenomena which have been observed in the peripheral blood of patients and differing from that in asymptomatic HTLV-I carriers must be taken into consideration: (a) the presence of increased HTLV-I viral load, (b) a higher immune responsiveness against HTLV-I antigens, and (c) biased nucleotide substitutions in the HTLV-I pX region which indicate a decreased selection pressure for viral amino acid changes. We now propose a hypothesis which focuses on the in vivo dynamics of HTLV-I infected lymphocyte migration and which incorporates these features. In addition, the hypothesis assumes the existence of a deviation in immune surveillance for HTLV-I in the central nervous system (CNS) in spite of the presence of frequent specific immune effectors. We suggest that in the active phase of HAM/TSP, accompanied with or following autoaggressive interactions between infected lymphocytes and immunocompetent cells in the CNS, there is a consequential reflux of the infected lymphocytes to the peripheral blood. The reflux of infected cells would be expected to provide peripheral blood with tissue-derived HTLV-I proviruses which have been indulged and propagated in an immune-privileged site. This process would result in and account for the observed increase in viral load and the substitution bias in HTLV-I sequences in the peripheral blood.

Deltaretrovirus Antibodies↗
PubMed1997

Alteration of cytokine levels by fosfomycin and prednisolone in spontaneous proliferation of cultured lymphocytes from patients with HTLV-I-associated myelopathy (HAM/TSP).

Fosfomycin has recently been reported as an antibiotic with immunomodulatory activities. To evaluate the possibility of clinical administration of fosfomycin in patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), the effects of this agent on the HTLV-I-induced in vitro phenomenon were studied. The influence of fosfomycin on in vitro spontaneous proliferation (SP) of peripheral blood mononuclear cells (PBMCs) from four patients with HAM/TSP was measured by thymidine incorporation into the cells, and the concentration of several cytokines in the culture supernatants was examined in three HAM/TSP patients. Enzyme-linked immunosorbent assays (ELISAs) were employed to detect the concentrations of interleukin-4 (IL-4), IL-6, IL-10, interferon-gamma (IFN-gamma), transforming growth factor-beta1 (TGF-beta1), and macrophage inflammatory protein-1alpha (MIP-1alpha). The data were compared to the changes by prednisolone which is known to regulate the HTLV-I-associated in vitro phenomenon and to have a therapeutic benefit in patients with HAM/TSP. Production of IL-6, IFN-gamma and MIP-1alpha from the spontaneously proliferating cells were demonstrated. Fosfomycin could not suppress the HTLV-I-associated SP, but had the properties to decrease the levels of TGF-beta1 and MIP-1alpha. It was also demonstrated that the concentrations of IFN-gamma and MIP-1alpha in the cultures in the presence of prednisolone were apparently decreased, suggesting a possible involvement of these cytokines in the pathogenesis of HAM/TSP. These findings support the hypothesis that fosfomycin may have immunomodulatory potentials in HTLV-I-related cellular interactions in a different manner from ordinary immunomodulatory agents.

Adult↗
PubMed1997

In vitro virus propagation and high cellular responsiveness to the infected cells in patients with HTLV-I-associated myelopathy (HAM/TSP).

The reasons for the development of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in certain infected individuals remain poorly understood, but the susceptibility should involve both viral factors and host conditions. To assess simultaneously both virus-induced activation of infected cells and the cellular response to virus producing cells, an analysis of fractionated peripheral blood lymphocytes obtained from patients with HAM/TSP (n = 15) were compared with those of asymptomatic HTLV-I carriers (n = 9) in an age-matched manner. The in vitro propagation of HTLV-I infection was evaluated as the spontaneous thymidine incorporation into CD4+ cells, and proliferative response of CD8+ cells against cultured and irradiated autologous CD4+ cells was employed to analyze the HTLV-I-induced cellular response. The comparative analysis using these two parameters demonstrated that HAM/TSP patients were characterized by the concomitance of a high inducibility of HTLV-I propagation and a high cellular responsiveness against HTLV-I as compared with asymptomatic HTLV-I carriers, suggesting the involvement of both of these factors in disease susceptibility. In addition, the coupled evaluation of these two in vitro phenomena may offer a better diagnostic hallmark for HTLV-I seropositive myelopathy cases with other known cause of myelopathy.

Adult↗
PubMed1997

[HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP)].

Human T lymphotropic virus type I(HTLV-I) is associated with the nonfatal neurologic disease, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Many clinical signs of involvement outside the central nervous system (CNS) have been described in some patients with HAM/TSP and have triggered the discovery of some HTLV-I-associated concepts in the infected individuals without signs of CNS involvement. Most of these HTLV-I-associated diseases exhibit common possible viroimmunologic characteristics that include a distributional bias of HTLV-I activation between the blood flow and the affected lesions and accumulated cellular immune responses in the lesions. This review summarizes the recent perspectives of the molecular pathogenesis of HAM/TSP and other HTLV-I-associated diseases. Furthermore, the feasible pathogenic involvement of cellular interactions between infected cells and responding immunocompetent cells in the affected tissues is emphasized (bystander auto-aggressiveness).

Humans↗
PubMed1996

A kinetic comparative study on lymphocyte responses to superantigen and phytohemagglutinin: reciprocal presentation of superantigen on the surface of activated lymphocytes.

The kinetics of thymidine incorporation into fractionated T lymphocytes responding to bacterial superantigens were compared to those of cells activated by phytohemagglutinin (PHA). Evident differences between the kinetics of cell proliferation induced by PHA-P and staphylococcal enterotoxin B (SEB) emerged after Day 4 of culture. PHA-P-induced proliferative responses of peripheral blood mononuclear cells (PBMCs) and fractionated cells were apparent on Day 4 because of the presence of accessory cells in the initial cell suspensions. This gradually diminished in correlation with the decline of accessory cells in the cultures. The SEB-induced cell growth (PBMCs and CD4+ cells), however, continued until Day 9 of the culture. This finding suggests the reciprocal usage of MHC class II molecules to present SEB by activated T lymphocytes for superantigen-induced T cell activation and suggests that superantigen-related immune activation may depend in part on the potential of activated T lymphocytes to mediate reciprocal cell-to-cell interactions in the presence of superantigens. The decline observed in the CD8+ cell response to SEB and toxic shock syndrome toxin-1 after Day 4 was revived by exogenous recombinant interleukin-2 (rIL-2) supplementation, suggesting that the consequent autocrine or paracrine secretion of IL-2 from the responding cells is essential for subsequent cell proliferation. SEB-induced cell proliferation was significantly suppressed by anti-CD11a (lymphocyte function-associated antigen-1; LFA-1, alpha-chain) monoclonal antibody, and the inhibitory effect was most obvious in 6-day cultured CD8+ lymphocytes. The results suggest that the lymphocyte response associated with the cell-to-cell copresentation of superantigens involves LFA-1 molecules as an accessory factor, particularly in CD8+ lymphocytes.

Antibodies, Monoclonal↗
PubMed1996

Diversity of intrathecal antibody synthesis against HTLV-I and its relation to HTLV-I associated myelopathy.

The humoral immune response against human T-cell lymphotropic virus type I (HTLV-I) in the central nervous system (CNS) compartment and in the blood was investigated by enzyme immunoassay using 16 synthetic peptides corresponding to HTLV-I core and envelope sequences. We evaluated paired samples of cerebrospinal fluid and serum from HTLV-I seropositive Japanese patients, classified as follows: HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP; n = 39), patients with spinal cord disease ascribed to either HAM/TSP or to some concomitant, HTLV-I-unrelated disease (possible HAM/TSP; n = 6) or carriers without any clinical signs of HAM/TSP (n = 15). HTLV-I-peptide-specific intrathecal antibody synthesis was found in 79% of HAM/TSP patients, but only in 20% of carriers without HAM/TSP. The group of carriers without HAM/TSP showed local synthesis for some peptides (on average 0.3 peptides per patient). In most HAM/TSP patients, however, there was a diverse intrathecal immune response to several HTLV-I synthetic peptides (on average against 3.6 peptides per HAM/TSP patient), most frequently against gag p19 100-130, env gp21 458-488, and env gp46 175-199 and 288-317. The intrathecal antibody synthesis against several HTLV-I determinants may represent a pathogenic immune response in HAM/TSP and is possibly related to the infiltration of virus-infected T-cells in the spinal cord.

Amino Acid Sequence↗
PubMed1996

Choroideremia with leukoencephalopathy and arylsulfatase A pseudodeficiency.

A 33-year-old male patient was admitted to our hospital because of progressive gait disturbance and involuntary movement of the neck. He showed choroideremia, distal motor neuropathy, and leukoencephalopathy on T2-weighted brain magnetic resonance imaging (MRI). Choroideremia is a rare X-linked, progressive, degenerative disease of retina and choroid. There have been some reports of choroideremia patients with neurological complications. Recent studies have assigned its genetic locus to a small segment of Xq21.3 and it encodes a protein that resembles component A of rat Rab geranyl-geranyl transferase, a protein essential for cell function. This patient did not have the reported genetic abnormalities for choroideremia. Known disorders causing leukoencephalopathy were not detected except for a partial deficiency of arylsulfatase A (17.3% of normal controls in lymphocytes and 13.7% in fibroblasts). Deficiency of arylsulfatase A activity occurs in the late infantile, juvenile, and adult forms of metachromatic leukodystrophy (MLD) which is also an inherited disorder of myelin metabolism, but because of its unstability, it occurs in normal individuals and in patients with other neurological diseases. Consequently, we suspect that this patient had partial deficiency of arylsulfatase A and choroideremia as predisposing factors for white matter degeneration.

Adult↗
PubMed1996

HAM/TSP: recent perspectives in Japan.

Neurologic diseases associated with human T-cell lymphotropic virus type I (HTLV-I) infection have a clinical spectrum that includes myelopathy (HTLV-I-associated myelopathy/tropical spastic paraparesis, HAM/TSP) as the central manifestation. Many clinical signs of involvement outside the central nervous system (CNS) have been described in some patients with HAM/TSP and have triggered and advanced the discovery of some HTLV-I-associated concepts in HTLV-I-infected individuals without signs of CNS involvement. Most of these HTLV-I-associated diseases exhibit common viroimmunologic characteristics that include a distributional bias of HTLV-I activation between the blood flow and the affected lesions and accumulated cellular immune responses in the lesions. These facts suggest that the vulnerable tissue(s) in some HTLV-I-infected individuals may not be defined by an exclusive tissue specificity, but that common steps of HTLV-I-versus-host interactions may have an important role in the pathologic process(es) in these diseases. This review summarizes the recent perspectives of the clinical spectrum and the pathogenesis of HAM/TSP in Japan. Furthermore, the feasible pathogenic involvement of cellular interactions between infected cells and responding immunocompetent cells in the affected tissues is emphasized.

Adult↗
PubMed1996

Intrathecal humoral immune response in HAM/TSP in relation to HLA haplotype analysis.

INTRODUCTION: In HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), we correlated human leukocyte antigen (HLA) haplotypes to the fine specificities of intrathecally synthesized IgG antibodies against HTLV-1. PATIENTS AND METHODS: HLA haplotypes of HAM/TSP patients were determined by the standard NIH microcytotoxicity test and family HLA studies. IgG antibodies against HTLV-1 synthetic peptides in paired CSF and serum were measured by enzyme immunoassay, and intrathecal synthesis of antibodies was evaluated. RESULTS: HAM/TSP patients with particular HLA haplotypes (A24Cw7B7DR1DQ5, A2Cw7B7DR1DQ5, A24Cw-B52DR15DQ6, A11Cw1B54DR4DQ4, and A24Cw1B54DR4DQ4) showed more frequently intrathecal synthesis of antibodies against HTLV-1 synthetic peptides, especially against HTLV-1 env gp21 synthetic peptides. CONCLUSION: In HAM/TSP, a retrovirus-induced human chronic inflammatory disease of the CNS, this is the first report to provide evidence that the intrathecal antiviral immune response is influenced by immunogenetic factors of the HLA complex.

Antibody Formation↗
PubMed1996

Identification and characterization of a new and distinct molecular subtype of human T-cell lymphotropic virus type 2.

Molecular studies have demonstrated the existence of at least two major subtypes of human T-cell lymphotropic virus type 2 (HTLV-2), designated HTLV-2a and HTLV-2b. To further investigate the heterogeneity of this family of viruses, we have characterized the HTLV-2 subtypes present in several urban areas in Brazil. DNAs from peripheral blood mononuclear cells of a large number of infected individuals, the majority of whom were intravenous drug abusers, were analyzed by using PCR with restriction fragment length polymorphism and nucleotide sequencing analysis. Restriction fragment length polymorphism analysis of the env region suggested that all individuals were infected with the HTLV-2a subtype, and this was confirmed by nucleotide sequence analysis. In contrast, nucleotide sequence analysis of the long terminal repeat demonstrated that although the viruses were more related to the HTLV-2a than to the HTLV-2b subtype, they clustered in a distinct phylogenetic group, suggesting that they may represent a new and distinct molecular subtype of HTLV-2. This conclusion was supported by nucleotide sequence analysis of the pX region, which demonstrated that the Tax proteins of the Brazilian viruses differed from that of prototype HTLV-2a isolates but were more similar to that of HTLV-2b in that they would be expected to have an additional 25 amino acids at the carboxy terminus. In transient expression assays, the extended Tax protein of the prototype HTLV-2a subtype. The studies suggest that the Brazilian viruses analyzed in this study, while being phylogenetically related to the prototypic HTLV-2a seen in North America, are phenotypically more related to HTLV-2b and can be justifiably classified as a new molecular subtype, which has been tentatively designated HTLV-2c.

Amino Acid Sequence↗
PubMed1995

Differential effect of TGF-beta 1 on the in vitro activation of HTLV-I and the proliferative response of CD8+ T lymphocytes in patients with HTLV-I-associated myelopathy (HAM/TSP).

While considerable information is available on the pathogenesis of human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), fundamental questions remain unanswered. In particular the clinicopathological uniformity of the disorder among patients remains poorly understood. The potential role of TGF-beta as a preferential immune regulator in the CNS and the functional heterogeneity of TGF-beta has led us to assess the possible involvement of this cytokine in the pathogenic process. To investigate this, the modulatory effects of TGF-beta 1 on HTLV-I-induced in vitro phenomena were evaluated using fractionated lymphocytes from patients with HAM/TSP. It could be shown that the proliferative response of CD8+ cells against cultured and irradiated autologous CD4+ cells possessing HTLV-I antigens was significantly inhibited by TGF-beta 1. However, the in vitro activation of HTLV-I, which was evaluated by spontaneous proliferation of CD4+ cells, was unaffected by TGF-beta 1. The induction of intracytoplasmic HTLV-I antigens in cultured CD4+ cells was facilitated by TGF-beta 1 in a dose-dependent manner. These findings suggest that TGF-beta may have a critical role in localized viral activation within the CNS in patients with HAM/TSP.

Adult↗
PubMed1995

Anti-viral and immunomodulatory effects of interferon-alpha on cultured lymphocytes from patients with human T lymphotropic virus type I-associated myelopathy (HAM/TSP).

In contrast to therapeutic benefits of interferon-alpha (IFN-alpha) in patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), little is known about the mechanisms underlying its clinical efficacy. To investigate the anti-viral and/or immunomodulatory properties of IFN-alpha in HTLV-I infection, the effects of IFN-alpha on HTLV-I-induced in vitro phenomena were evaluated. In vitro activation of HTLV-I in fractionated CD4+ T lymphocyte-rich cells (CD4+ cells) could be demonstrated by increased thymidine incorporation into the cells, detection of proviral HTLV-I and viral RNA, and by assays of reverse transcriptase activities in culture supernatants. T cell immune responses were evaluated by thymidine incorporation into CD8+ T lymphocyte-rich cells (CD8+ cells) responding to cultured and irradiated autologous CD4+ cells possessing HTLV-I antigens. It could be shown that IFN-alpha suppressed both the in vitro activation of HTLV-I and the CD8+ cell response. Moreover, 1 day supplementation of IFN-alpha as a pretreatment was sufficient for the induction of these properties. These findings, together with the clinical efficacy of IFN-alpha administration in patients with HAM/TSP, support the view that viral activation and T cell responses are critical components in the pathogenic processes involved in HAM/TSP.

Antiviral Agents↗
PubMed1995

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP): recent perspectives.

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a well-defined clinicopathological entity, and approximately 1,900 patients with HAM/TSP have been reported in the world. Improved polymerase chain reaction (PCR)-based in situ techniques have allowed a better appreciation of the cellular localization of the virus activation in infected patients, and there is accumulating evidence that HAM/TSP is characterized by a distributional bias of viral activation between the blood flow and central nervous system (CNS). This review summarizes the current status of our understanding of HAM/TSP, and emphasizes the possible pathogenic involvement of cellular interactions between infected cells and responding immunocompetent cells in the CNS of patients with HAM/TSP. In addition, the notable systemic manifestations with or without myelopathy in HTLV-I-infected individuals are described.

Humans↗
PubMed1995

HTLV-I-associated myelopathy: analysis of 213 patients based on clinical features and laboratory findings.

We studied the clinical features and laboratory findings in 213 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis as diagnosed in Kagoshima University Hospital. Some aspects of clinical features in HTLV-I-associated myelopathy/tropical spastic paraparesis were characterized by mode of HTLV-I transmission and age of onset. The patients with onset after 15 years old and no history of blood transfusion before the onset of the disease (151 patients, group I) showed a shorter interval between the time of disease onset and that of inability to walk. The patients with onset before 15 years old and without history of blood transfusion (21 patients, group II) had short stature and slow progression of the disease. The interval time and the progression of the disease in patients with history of blood transfusion before onset of disease (41 patients, group III) were in between those of the above two groups. Patients whose ages of onset were older than 61 years old showed a faster progression than those with younger onset regardless of the mode of HTLV-I transmission. HTLV-I-associated myelopathy/tropical spastic paraparesis patients often also showed other organ disorders such as leukoencephalopathy (69%), abnormal findings on chest X-ray (50%), Sjögren syndrome (25%) and arthropathy (17%). The patients with low anti-HTLV-I antibody titers in the cerebrospinal fluid (2X-8X by PA method) had an older age of onset on average, milder clinical symptoms and lesser increase of neopterin in the cerebrospinal fluid than those in the high titer subgroup whose titers were higher than 1024X in cerebrospinal fluid regardless of the mode of HTLV-I transmission. We speculate that the clinical course of HTLV-I-associated myelopathy/tropical spastic paraparesis mainly shows a slow progression which consists of an initial progressive phase (probably an inflammatory phase) and a latter chronic phase, although some patients showed acute/subacute onset and rapid progression.

Acute Disease↗