Kunihiko Nagasato

Presence of serum anti-human T-lymphotropic virus type I (HTLV-I) IgM antibodies means persistent active replication of HTLV-I in HTLV-I-associated myelopathy

We investigated serum IgM antibodies against human T-lymphotropic virus type I (HTLV-I) in 29 HTLV-I associated myelopathy (HAM) patients and 34 HTLV-I carriers, using western blot analysis. Anti-HTLV-I IgM was detected in all 6 post-transfusional HAM patients and in 19 of 23 (83%) HAM patients with no history of blood transfusion, but in only 4 of 21 (19%) HTLV-I carriers. In HAM patients, HTLV-I proviral DNA integrated into peripheral blood lymphocyte (PBL) was detected by Southern blot analysis in all of the 6 (100%) and 18 of the 23 (78%). In contrast, it was detected in only 2 of 25 (8%) HTLV-I carriers. For the serum anti-HTLV-I IgM and HTLV-I provirus in PBL, the differences between the HAM and HTLV-I carriers were statistically significant (P less than 0.01). Our data indicate that the increased HTLV-I proviral DNA in PBL is produced by the persistent active replication of HTLV-I in HAM. Furthermore, Southern blot analysis showed intense bands in HAM patients with histories of blood transfusion, in whom the progression of the disease had been rapid. We conclude that the persistent active replication of HTLV-I is an important factor in the pathogenesis of HAM.

Two different clinical phenotypes of Creutzfeldt-Jakob disease with a M232R substitution.

ObjectiveTo describe the clinical features of Creutzfeldt-Jakob disease with a substitution of arginine for methionine (M232R substitution) at codon 232 (CJD232) of the prion protein gene (PRNP).Patients and methodsWe evaluated the clinical and laboratory features of 20 CJD232 patients: age of onset, initial symptoms, duration until becoming akinetic and mute, duration until occurrence of periodic sharp and wave complexes on EEG (PSWC), MRI findings, and the presence of CSF 14-3-3 protein. Immunohistochemically, prion protein (PrP) deposition was studied.ResultsNone of the patients had a family history of CJD. We recognized two clinical phenotypes: a rapidly progressive type (rapidtype) and a slowly progressive type (slow-type). Out of 20 patients, 15 became akinetic and mute, demonstrated myoclonus, and showed PSWC within a mean duration of 3.1, 2.4, and 2.8 months, respectively (rapid-type). Five showed slowly progressive clinical courses (slow-type). Five became akinetic and mute and four demonstrated myoclonus within a mean duration of 20.6 and 15.3 months, respectively, which were significantly longer than those in the rapid-type. Only one demonstrated PSWC 13 months after the onset. Diffuse synaptic-type deposition was demonstrated in four rapidtype patients, and perivacuolar and diffuse synaptic-type deposition in two, and diffuse synaptic-type deposition in one slow-type patient. Three of 50 suspected but non-CJD patients had the M232R substitution.ConclusionsPatients with CJD232 had no family history like patients with sCJD, and showed two different clinical phenotypes in spite of having the same PRNP genotype. More studies are needed to determine whether M232R substitution causes the disease and influences the disease progression.

Characterization of adherent T cells to human endothelial cells in patients with HTLV-I-associated myelopathy

To clarify the phenomenon of increased adherence of T cells to endothelial cells (EC) in patients with HTLV-I-associated myelopathy (HAM), we determined the surface markers and expression of lymphocyte function antigen-1 (LFA-1) in T cells adherent or nonadherent to EC. The percentage of activated or HLA-DR+ T cells and the expression of LFA-1 in the adherent cell population were significantly higher than those in the nonadherent cell population. Moreover, the CD4 to CD8 ratio of the HLA-DR+ cells in the EC-adherent T cells was significantly higher than that in the nonadherent cells. Collectively, these results indicate that increased adherence of T cells to EC in HAM patients is based on the increase of activated T cells with high density LFA-1 expression in the peripheral blood. Moreover, CD4+ HLA-DR+ cells exhibited more adhesive activity to EC than CD8+ HLA-DR+ cells, suggesting that activated CD4+ cells, rather than activated CD8+ cells, may be important as the first trigger for T cell-infiltration to the central nervous system in the immunopathogenesis of HAM.

Active production of anti-human T-lymphotropic virus type I (HTLV-I) IgM antibody in HTLV-I-associated myelopathy

We investigated the presence of anti-human T-lymphotropic virus type I (HTLV-I) IgM in sera and cerebrospinal fluid from patients with HTLV-I-associated myelopathy (HAM) by Western blot analysis. Analyses of 36 serum samples revealed that most patients (31/36; 86.1%) had anti-HTLV-I IgM, whereas only four of 23 (17.4%) HTLV-I carriers had it. In studies of cerebrospinal fluid, anti-HTLV-I IgM was detected in 24 of 36 (66.7%) HAM patients, whereas none was detected in nine HTLV-I carriers. The differences were statistically significant (p less than 0.01). These results suggest that persistent active replication of HTLV-I occurs in the central nervous system as well as in the peripheral blood of HAM patients, and may contribute to the development of HAM.

Interferon-alpha treatment in HTLV-I-associated myelopathy: Studies of clinical and immunological aspects

We treated 17 patients with HTLV-I-associated myelopathy (HAM) with interferon-alpha (IFN-alpha) in an open, nonrandomized, uncontrolled study. They were administered 1.5-9.0 x 10(6) international units of IFN-alpha daily for 4 weeks, and 4 patients showed a marked clinical response, 7 showed a moderate response and the others did not show any clinical response. Increased unstimulated (spontaneous) peripheral blood lymphocyte (PBL) proliferation was observed in all patients who were measured lymphocyte transformation. Spontaneous PBL proliferation was significantly inhibited by IFN-alpha treatment (P less than 0.01), whereas anti-HTLV-I-antibodies did not show any significant changes. Likewise, decreased stimulation indices to phytohemagglutinin (SI) due to increased spontaneous PBL proliferation were significantly increased after IFN-alpha treatment (P less than 0.01). In the patients who showed marked clinical responses, the changes of SI in IFN-alpha treatment were higher than those in other patients. These data indicate that further studies are warranted for evaluation of IFN-alpha treatment of HAM in a randomized, controlled study.

LONG-TERM FOLLOW-UP OF IMMUNOMODULATION IN TREATMENT OF HTLV-I-ASSOCIATED MYELOPATHY

tick bites and health problems over the preceding five years. Blood samples were tested for B burgdorferi antibody by indirect ELISA at the microbiology department, Charing Cross Hospital, London. 32 of the 33 workers were men and the age range was 22-63. Of the 33 Nature Conservancy workers 27 recorded tick bites, while all 10 Red Deer Commission workers had been frequently bitten, several over 18-28 years. Symptoms previously described in Lyme disease

Antiproliferative factor against the human glioblastoma cell line T98G identified in culture supernatants of CD4+ cells from patients with HTLV-I-associated myelopathy

We investigated culture supernatants of peripheral blood mononuclear cells (MNC) derived from patients with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) for antiproliferative activity against the human glioblastoma cell line T98G. When T98G cells were cultured with condition medium containing culture supernatants of MNC from patients with HAM, the proliferation of T98G cells was significantly suppressed, compared with that of supernatants from HTLV-I seropositive carriers or seronegative controls. To clarify which population of MNC produced the antiproliferative humoral factor for T98G cells, we separated MNC into macrophage-depleted or B cell depleted populations, and further to both CD4+ and CD8+ T cells by using the panning method or plastic adherence. These studies demonstrated that the antiproliferative activity was mediated by a humoral factor produced by T cells, specifically CD4+ cells. This activity was blocked by a neutralizing monoclonal antibody against interferon-gamma (IFN-gamma). Moreover, IFN-gamma levels were elevated in the culture supernatants of CD4+ cells from HAM patients. Thus, the antiproliferative activity against T98G cells is mainly due to IFN-gamma derived from CD4+ cells of patients with HAM.

Heparin treatment in patients with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy: A preliminary study

Ten patients with HTLV-I-associated myelopathy (HAM) were treated in an uncontrolled preliminary trial of heparin. In 7 patients, motor dysfunction improved substantially and the effect continued for more than a month after the discontinuation of therapy. Sensory and urinary disturbances also improved in 3 of 4 and in 2 of 10 patients, respectively. Heparin did not alter the subsets of peripheral blood lymphocytes nor the titers of anti-HTLV-I antibodies in serum and cerebrospinal fluid. Spontaneous proliferation of peripheral blood lymphocytes, however, was depressed significantly (P < 0.05) in all cases. Heparin therapy has some advantages in cost, ease of administration and fewer side effects compared to other therapies such as plasmapheresis and interferon-alpha. We conclude that heparin can be administered safely to HAM, and that a double-blind placebo-controlled trial is warranted to determine its efficacy in HAM.

Efficacy of prosultiamine treatment in patients with human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis: results from an open-label clinical trial

BackgroundHuman T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic myelopathy characterized by motor dysfunction of the lower extremities and urinary disturbance. Immunomodulatory treatments are the main strategy for HAM/TSP, but several issues are associated with long-term treatment. We conducted a clinical trial with prosultiamine (which has apoptotic activity against HTLV-I-infected cells) as a novel therapy in HAM/TSP patients.MethodsWe enrolled 24 HAM/TSP patients in this open-label clinical trial. Prosultiamine (300 mg, orally) was administered once daily for 12 weeks. We monitored changes in the motor function of the lower extremities and urinary function as well as copy numbers of the HTLV-I provirus in peripheral blood mononuclear cells (PBMCs).ResultsImprovement in the motor function of the lower extremities based on a reduction in spasticity (for example, decrease in time required for walking and descending a flight of stairs) was observed. In an urodynamic study (UDS), bladder capacity and detrusor pressure and then maximum flow rate increased significantly. Detrusor overactivity and detrusor-sphincter dyssynergia improved in 68.8% and 45.5% of patients observed at pretreatment, respectively. Improvement in UDS corresponded with improvements in the score of nocturia-quality of life questionnaire. HTLV-I proviral copy numbers in PBMCs decreased significantly (approximately 15.4%) compared with pretreatment levels.ConclusionsThese data suggest that prosultiamine can safely improve motor dysfunction of the lower extremities and urinary disturbance as well as reduce HTLV-I provirus levels in peripheral blood. It therefore has potential as a new therapeutic tool for HAM/TSP patients.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number, UMIN000005969.Please see related commentary: http://www.biomedcentral.com/1741-7015/11/183.

Anti-cyclic citrullinated peptide antibody (anti-CCP antibody) is present in the sera of patients with dementia of Alzheimer's type in Asian

Satoh K, Kawakami A, Shirabe S, Tamai M, Sato A, Tsujihata M, Nagasato K, Eguchi K. Anti‐cyclic citrullinated peptide antibody (anti‐CCP antibody) is present in the sera of patients with dementia of Alzheimer’s type in Asian.
Acta Neurol Scand. 2010: 121: 338–341.
© 2009 The Authors Journal compilation