| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke,
Experimental Immunology Branch and
Viral Epidemiology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, TNF-
, and IL-2, which
were significantly elevated in HAM/TSP patients. The proportion of
CD8+ cells producing IFN- in HAM/TSP patients,
asymptomatic carriers, and healthy controls were, on average, 4.9, 0.4,
and 0.3%, respectively. IFN- production by these CD8+
cells was suppressed by anti-HLA-class I Ab. Purified
CD8+ cells from an HLA-A2 HAM/TSP patient produced IFN-
by cocultivation with autologous CD4 cells, the main reservoir of
HTLV-I in vivo, or allogenic HLA-A2+ B cells pulsed with a
known immunodominant HTLV-I tax peptide. These data suggest that high
levels of circulating HTLV-I-specific CD8+ T lymphocytes
have the potential to produce proinflammatory cytokines and may promote
inflammatory responses to HTLV-I in HAM/TSP
patients. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In HAM/TSP, an increase in activated lymphocytes has been shown in PBL
and cerebrospinal fluid (22, 23), and high levels of
several inflammatory cytokines such as IFN-, TNF-, and IL-6 in
sera and cerebrospinal fluid have been reported (24, 25, 26).
In addition, mRNA expression of IL-1ß, IL-2, TNF-, and IFN- has
been shown to be up-regulated in HAM/TSP PBL (27, 28). In
the central nervous system (CNS), the expression of inflammatory
cytokines, including IL-1ß, TNF-, and IFN-, have been
demonstrated in the spinal cord of HAM/TSP patients with a short
duration of illness (29).
HTLV-I tax is a strong transactivator that can up-regulate host gene expression including several cytokines (30). Since HTLV-I is preferentially detected in CD4+ lymphocytes in vivo (31), CD4+ cells have been suggested to be a source of increased cytokine expression. However, it is unclear whether the highly immunoreactive HTLV-I-specific CD8+ T cells can also produce cytokines. To address these issues, we employed flow cytometric analysis for intracellular cytokine production from PBL of HAM/TSP patients, which allows us not only to identify individual cytokine-producing cells, but also to observe the cellular or humoral interactions associated with cytokine secretion.
In the present study, we demonstrated that peripheral CD8+
T lymphocytes produce IL-2, IFN-, and TNF- in HAM/TSP patients
and that the frequency of IFN-+ CD8+ cells
was significantly higher than that of asymptomatic carriers and healthy
controls. This high IFN- production was shown to be associated with
HTLV-I Ag-HLA class I complex on self-CD4 cells in HAM/TSP patients.
These results suggest that high levels of circulating HTLV-I-specific
CD8+ T lymphocytes, which have the potential to produce
proinflammatory cytokines, may contribute to the immunopathogenesis of
HAM/TSP.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
PBL from eight HAM/TSP patients, nine HTLV-I-infected asymptomatic carriers, and seven HTLV-I-noninfected healthy controls were tested. HTLV-I infection was confirmed by Western blot in serum of HAM/TSP patients and asymptomatic carriers. The diagnosis of HAM/TSP was made using the World Health Organization criteria and is based on the patients’ neurologic symptoms and a serologic test for HTLV-I (32). PBL were isolated by Ficoll-Hypaque centrifugation and stored in liquid nitrogen until use.
Antibodies
Mouse anti-human CD3-phycoerythrin (PE)-conjugated mAb,
anti-CD4- PE- or FITC-conjugated Ab or anti-CD8-
TRI-COLOR-conjugated Ab (Caltag Laboratories, South San Francisco, CA)
was used to detect cell surface molecules of lymphocytes.
Anti-TNF--PE-conjugated mAb, anti-IFN--FITC-conjugated Ab,
and anti-IL-2-PE-conjugated Ab (PharMingen, San Diego, CA) were
utilized for intracellular cytokine staining.
Mouse-IgG1-FITC-conjugated Ig and mouse-IgG1-PE-conjugated Ig (Caltag)
were used as an isotype control for intracellular protein staining.
Staining of cell surface molecules, intracellular cytokines, and flow cytometric analysis
The method to detect intracellular cytokines was established by
Sander et al. (33). Cultured PBL were harvested and washed
in cold staining buffer containing 1% FCS and 0.1% sodium azide in
PBS (pH 7.4). Cells were pretreated with 10 µg/µl of human
globulin at 4°C for 5 min to reduce nonspecific Ab binding and
followed staining with 0.3 µg of mAbs to cell surface molecules in 10
µl of staining buffer at 4°C for 30 min. Cells were washed and
fixed with 100 µl of 4% paraformaldehyde in PBS (pH 7.4) at 4°C
for 20 min. After fixation, cells were washed and resuspended in 50
µl of permeabilization buffer that contained 0.1% saponin, 1% FCS,
and 0.1% sodium azide in PBS (pH 7.4). Cells were pretreated with 2
µg/µl of human globulin at 4°C for 5 min and stained with 0.5
µg of anti-cytokine Abs at 4°C for 30 min. Cells were washed
with permeabilization buffer and finally resuspended in 200 µl of
staining buffer. FACScan and CELLQuest computer software (Becton
Dickinson, Mountain View, CA) were utilized for fluorescent signal
detection and data analysis. Fifty thousand events were evaluated.
Lymphocytes were gated on forward and side scatter image, and the
proportion of cytokine-positive, CD8+, and
CD8- cells was calculated.
Culture condition of PBL
Frozen PBL were thawed, washed twice, and resuspended. The
viability of the cells was over 90% by trypan blue staining. One
million cells were transferred to a 96-well round-bottom plate in 200
µl of RPMI 1640 (Life Technologies, Gaithersburg, MD) containing 5%
heat-inactivated human serum, 2.8 mM L-glutamine, 14 mM
HEPES buffer, 40 U/ml penicillin, and 40 µg/ml streptomycin. To
optimize the detection of intracellular cytokines, conditions were
initially established in which PBL were cultured for various periods (4
h to 48 h) of time before the addition of brefeldin A (BFA) (10
µg/ml) (Sigma, St. Louis, MO). BFA inhibits protein transportation
from the Golgi apparatus to the cell surface, resulting in accumulation
of protein in the Golgi (33). CD8+ and
CD8- cell populations from PBL of HAM/TSP patients and
healthy controls were gated and analyzed for intracellular expression
of IFN-, IL-2, and TNF-. For the kinetic study of cytokine
production, PHA was added to cells at a concentration of 1 µg/ml.
Based on these results, the culture conditions were optimized in which
PBL were cultured in the absence of exogenous stimuli for 4 h
before a 10-h incubation with BFA. These conditions were chosen for the
following reasons: 1) the IFN- secretion appeared specific for
HTLV-I-infected individuals; 2) detection of this cytokine,
particularly in the absence of exogenous stimuli, may reflect dynamic
events of cytokine production in T cell subsets in vivo; and 3) the
percentage of cytokine-positive cells appeared high in HAM/TSP PBL,
which facilitated further analysis. HLA-A2-binding peptide, HTLV-I tax
11–19 peptide (LLFGYPVYV), CMV gB peptide (IAGNSAYEYV), and influenza
virus M1 peptide (GILGFVFTL) were used at the indicated
concentration (34).
Blocking of IFN- production by anti-HLA Abs
To determine whether antigenic stimulation is involved in the
elevated cytokine production in CD8+ cells from HAM/TSP
patients, it was initially determined whether the expression of IFN-
from CD8+ cells could be inhibited by anti-HLA Abs.
Anti-HLA class I (W6/32) and class II (L243) mAbs were added to PBL
from a HAM/TSP patient at a final concentration of 10 µg/ml or 40
µg/ml at the start of culture and the proportion of
IFN-+ cells in the CD8+ population was
assessed by flow cytometry.
Cell-mixing experiment for IFN- production
To investigate if HAM/TSP CD4+ cells could induce
cytokine expression from autologous CD8+ lymphocytes,
cell-mixing experiments were performed. PBL from a HLA-A2 HAM/TSP
patient were positively selected for CD8+ and
CD4+ cells by immunomagnetic beads according to the
manufacturer’s instructions (Dynal, Lake Success, NY). The purity was
greater than 96% in each cell population by flow cytometric analysis.
Purified CD8+ cells (5 x 105) were
cocultured for 4 h with autologous or allogenic CD4+
cells at CD4:CD8 ratios of 0.04, 0.2, and 1. BFA was then added and
cells were cultured for an additional 10 h. Allogenic
CD4+ cells were obtained from an HLA-A2-matched,
HTLV-I-noninfected individual. In addition, Hmy-A2 cells (an
HLA-A2-transfected B cell line) were pulsed with HTLV-I tax 11–19
peptide or influenza virus M1 peptide for 2 h at 37°C at the
indicated concentration, and washed twice (34).
Peptide-prepulsed Hmy-A2 cells (5 x 105) were added
to 5 x 105 purified CD8+ cells and
cultured for 4 h before culture with BFA (10 µg/ml) for an
additional 10 h. The portion of IFN-+ cells in the
CD8+ population was assessed by flow cytometry.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In Figure 1
A,
CD8+ cells from a HAM/TSP patient, in the absence of
exogenous stimulation, produced IFN-, IL-2, and TNF- at an
optimal incubation time of 4 h preculture before the addition of a
10-h culture period in the presence of BFA. In the CD8-
population, an incubation time of 12 to 24 h preculture before the
addition of BFA was required for maximal production of IFN-, IL-2,
and TNF- (Fig. 1B).
|
,
IL-2, and TNF- in the CD8+ population from a HAM/TSP
patient, expression of these cytokines was barely detectable from
CD8+ or CD8- cells from a healthy control
(Fig. 1
, C and D). Incubation with 1 µg/ml of
PHA in both the CD8+ and CD8- cell populations
from healthy controls increased the expression of all three cytokines
although the kinetics of expression were different in these T cell
subgroups (Fig. 1, E and F).
CD8+ cells from HAM/TSP express both TNF- and
IFN-
To determine whether there was an increase in the number of
CD8+ cells from HAM/TSP patients that expressed IFN- and
TNF-, PBL were doubly stained with anti-cytokine Abs and Abs to
CD8. As shown in a representative experiment in Figure 2, IFN-- and TNF--positive cells
were detected at 14.0% and 11.5% in the CD8+ population,
respectively (Fig. 2B and 2C). Importantly, 81%
of the TNF--positive cells stained for IFN-, strongly suggesting
that the TNF-+ CD8+ population in HAM/TSP
PBL also produced IFN- (Fig. 2D).
|
production by CD8+ cells in PBL of HAM/TSP,
asymptomatic carriers, and healthy controls
The proportion of CD8+ cells that express IFN- in
PBL from HAM/TSP patients, HTLV-I seropositive asymptomatic carriers,
and healthy controls were analyzed to determine whether the increased
number of IFN-+ CD8+ cells was related to
infection with HTLV-I or the clinical status of the patient. Figure 3A is a representative flow
cytometric analysis of IFN--producing CD8+ cells from
PBL of HAM/TSP patients, asymptomatic carriers, and healthy controls. A
distinct subset of CD8+ cells that express IFN- could
clearly be detected in PBL from HAM/TSP patients, while no comparable
population was observed in healthy controls or HTLV-I asymptomatic
carriers (Fig. 3A). In a survey of eight patients with
HAM/TSP, nine asymptomatic carriers, and seven healthy controls, the
percentage of IFN--expressing cells in the CD8+
population was 4.9%, 0.4%, and 0.3%, respectively (Fig. 3B). The IFN- producing CD8+ cells was
significantly greater in HAM/TSP patients compared with HTLV-I
asymptomatic carriers or healthy controls. Indeed, in one HAM/TSP
patient, as high as 14% of CD8+ cells expressed
IFN-.
|
production in CD8+ cells by
anti-HLA Abs
It was determined if the increased number of IFN-+
CD8+ cells in HAM/TSP patients could be inhibited by
anti-HLA Abs. As shown in Figure 4,
only the anti-HLA class I but not HLA class II Ab suppressed the
IFN- production in CD8+ cells.
|
by CD8+ cells is HTLV-I tax
peptide dependent
The ability of the immunodominant HTLV-I tax 11–19 peptide to
induce IFN- expression in CD8+ cells from a HAM/TSP
patient was examined. As shown in Figure 5, culture conditions were chosen in
which the expression of IFN- from CD8+ cells was
dramatically reduced when BFA was added at the start of the culture
period (Fig. 5; 0 h time point precultivation without BFA). Upon
addition of the HTLV-I tax 11–19 peptide to HAM/TSP PBL, there was a
dramatic induction of IFN-+ CD8+ cells
(8.1%), comparable (if not greater) than the optimal PBL culture
condition for the induction of IFN- from CD8+ cells
(Fig. 5, 4-h time point precultivation without BFA). A control CMV
peptide, known to bind HLA A2, did not induce IFN- cytokine
expression in CD8+ cells (Fig. 5).
|
Since we have shown that an immunodominant HTLV-I tax
peptide could induce the expression of IFN- in CD8+
cells from HAM/TSP PBL, it was of interest to determine whether
autologous CD4+ cells, known to harbor HTLV-I in
HTLV-I-infected individuals (31), could also induce
cytokine expression. As shown in Figure 6, the addition of purified
CD4+ cells from a HAM/TSP patient to purified HAM/TSP
CD8+ cells resulted in a dose-dependent increase in the
intracellular IFN- expression to the level observed from unseparated
PBL from this patient. In contrast, the addition of purified
CD4+ cells from an HLA-A2-matched HTLV-I seronegative donor
to purified HAM/TSP CD8+ cells did not increase the
expression of IFN- in these CD8+ cells (Fig. 6).
|
in HAM/TSP
CD8+ cells was HTLV-I tax peptide specific, Hmy-A2 cells (a
B cell line transfected with HLA-A2) prepulsed with the HTLV-I tax
11–19 peptide were added to purified CD8+ cells.
Increasing concentrations of HTLV-I tax 11–19 peptide-pulsed Hmy-A2
cells induced the expression of IFN- in purified HAM/TSP
CD8+ cells, but not from purified CD8+ cells of
an HLA-A2-matched HTLV-I seronegative donor (Fig. 7). As controls, Hmy-A2 cells prepulsed
with influenza virus M1 peptide did not induce the expression of
IFN- either from purified HAM/TSP CD8+ cells or from
CD8+ cells of an HLA-A2-matched HTLV-I seronegative donor
(Fig. 7).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, TNF-, and IL-2. Moreover,
the proportion of these cytokine-expressing HTLV-I-specific
CD8+ cells in total CD8+ cells was
extraordinarily high. On average, 4.9% of HAM/TSP CD8+
cells expressed IFN- (which was as high as 14% in one patient).
This is in marked contrast to the proportion of cytokine-expressing
CD8+ cells that can be demonstrated in the peripheral blood
of HTLV-I seropositive asymptomatic carriers (0.4%), a level
comparable in PBL of normal healthy controls (0.3%). The ability to
detect an increased frequency of cytokine-expressing CD8+
cells, particularly in patients with HAM/TSP, suggests that these
CD8+ cells may play a role in the pathogenesis of
HAM/TSP.
HTLV-I contains a unique pX gene coding for the HTLV-I tax
protein, which is known to be a strong transactivator of many host
genes (30). In vitro, cells infected with HTLV-I or
transfected with HTLV-I tax constructs constitutively produce many
cytokines including IL-1, IL-2, IL-6, TNF-, TNF-ß, IFN-, and
granulocyte macrophage-CSF (30). However, it has not been
determined which cells from HTLV-I-infected individuals in vivo produce
these cytokines. In this report, CD8+ cells from PBL of
HAM/TSP patients were shown to preferentially express IFN- and
TNF-, although we cannot exclude the possibility that
HTLV-I-infected CD4 lymphocytes or other cell types such as macrophages
may also express these cytokines. Because anti-HLA class I Abs were
able to suppress the production of these cytokines from HAM/TSP
CD8+ cells (Fig. 4) that are not infected with HTLV-I in
vivo (31), it suggests that the expression of cytokines
from CD8+ cells is a consequence of a virus-induced
inflammatory process rather than trans-activation by the
HTLV-I pX gene.
The inhibition of IFN- production from HAM/TSP
CD8+ cells by HLA class I Ab suggests that cytokine
expression may be associated with an interaction of the TCR/Ag/HLA
trimolecular complex. The addition of purified CD4+ cells
from a HAM/TSP patient to autologous CD8+ cells resulted in
a dose-dependent increase in the intracellular IFN- expression to
the level observed from unseparated PBL. The addition of
CD4+ cells from a HTLV-I-noninfected individual did not
induce IFN- production from HAM/TSP CD8+ cells (Fig. 6).
This indicates that the CD8+ cells produced IFN- by
recognition of some HTLV-I Ags on the infected CD4+ cells,
the main reservoir of HTLV-I in vivo (31). Moreover, the
production of IFN- in CD8+ cells from an HLA-A2 HAM/TSP
patient was up-regulated by the addition of the HTLV-I tax 11–19
peptide (Figs. 5 and 7). We have demonstrated previously that CTL in
HLA-A2 HAM/TSP patients recognized this same immunodominant HTLV-I tax
11–19 peptide in strong association with HLA-A2 (12).
Similarly, results in this study demonstrate that the production of
IFN- in CD8+ cells from an HLA-A2 HAM/TSP patient can be
up-regulated by the addition of the HTLV-I tax 11–19 peptide.
Recent molecular biologic studies provide evidence that the HTLV-I
genome and its transcripts are present in the CNS of HAM/TSP patients
(17, 18, 19, 20, 21). If HTLV-I-specific CD8+ cells in the
affected lesions (16) recognize immunodominant HTLV-I
peptides, this may lead to the production of proinflammatory cytokines
such as IL-2, IFN-, and TNF-. The expression of TNF- by
CD8+ lymphocytes from HAM/TSP patients is of considerable
interest since TNF- has been reported to be cytotoxic to
oligodendrocytes in culture and induces demyelination
(35). Moreover, in a disease like multiple sclerosis which
is clinically similar to HAM/TSP, mRNA levels of TNF- in PBL have
been shown to correlate with the disease progression
(36).
In HAM/TSP, there is a large body of information on HTLV-I pathology, disease association, and cellular immune reactivity, which allows for a number of hypothetical models of HAM/TSP pathogenesis. Three major models have been proposed: 1) recognition of HTLV-I gene products in the CNS by Ag-specific CD8+ effector CTL that result in lysis of glial elements and cytokine release (37), 2) an autoimmune process in which HTLV-I infection leads to activation of autoreactive T cells (19, 38), and 3) an autoaggressive bystander model mediated by immunocompetent virus-specific T cells releasing a cascade of cytokines that result in CNS damage (39). In all these models, HTLV-I-specific CD8+ lymphocytes are considered to play a crucial role in the pathogenesis of HAM/TSP, although it remains to be determined which cells in the CNS are preferential targets for these cells (18, 19, 20, 21). Importantly, if HTLV-I-specific CD8+ lymphocytes play a central role in the development of HAM/TSP, immunotherapeutic strategies targeted to eliminate or inactivate these high levels of circulating HTLV-I-specific CD8+ cells expressing proinflammatory cytokines may be clinically beneficial in this disease.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Steven Jacobson, NINDS, National Institutes of Health, Building 10, Room 5B-16, Bethesda, MD 20892. E-mail address:
3 Abbreviations used in this paper: HTLV-1, human T lymphotropic virus type I; HAM/TSP, HTLV-I-associated myelopathy/tropical spastic parapareis; BFA, brefeldin A; PE, phycoerythrin; CNS, central nervous system.
Received for publication October 9, 1997. Accepted for publication February 27, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-positive cells in cerebrospinal fluid of patients with HTLV-I-associated myelopathy. J. Neuroimmunol. 42:127.[Medline]
and disease progression in patients with multiple sclerosis. N. Engl. J. Med. 325:467.[Abstract]
This article has been cited by other articles:
|
|
 |
|
  T. Kattan, A. MacNamara, A. G. Rowan, H. Nose, A. J. Mosley, Y. Tanaka, G. P. Taylor, B. Asquith, and C. R. M. Bangham The Avidity and Lytic Efficiency of the CTL Response to HTLV-1 J. Immunol., May 1, 2009; 182(9): 5723 - 5729. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. Sabouri, K. Usuku, D. Hayashi, S. Izumo, Y. Ohara, M. Osame, and M. Saito Impaired function of human T-lymphotropic virus type 1 (HTLV-1)-specific CD8+ T cells in HTLV-1-associated neurologic disease Blood, September 15, 2008; 112(6): 2411 - 2420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Enose-Akahata, U. Oh, C. Grant, and S. Jacobson Retrovirally induced CTL degranulation mediated by IL-15 expression and infection of mononuclear phagocytes in patients with HTLV-I-associated neurologic disease Blood, September 15, 2008; 112(6): 2400 - 2410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kozako, N. Arima, S. Toji, I. Masamoto, M. Akimoto, H. Hamada, X.-F. Che, H. Fujiwara, K. Matsushita, M. Tokunaga, et al. Reduced Frequency, Diversity, and Function of Human T Cell Leukemia Virus Type 1-Specific CD8+ T Cell in Adult T Cell Leukemia Patients J. Immunol., October 15, 2006; 177(8): 5718 - 5726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mitra-Kaushik, J. Harding, J. Hess, R. Schreiber, and L. Ratner Enhanced tumorigenesis in HTLV-1 Tax-transgenic mice deficient in interferon-gamma Blood, November 15, 2004; 104(10): 3305 - 3311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. E. A. Brito-Melo, J. G. Souza, E. F. Barbosa-Stancioli, A. B. F. Carneiro-Proietti, B. Catalan-Soares, J. G. Ribas, G. W. Thorum, R. D. R. Rocha, O. A. Martins-Filho, and Grupo Interdisciplinar de Pesquisas em HTLV Establishing Phenotypic Features Associated with Morbidity in Human T-Cell Lymphotropic Virus Type 1 Infection Clin. Vaccine Immunol., November 1, 2004; 11(6): 1105 - 1110. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yamano, C. J. Cohen, N. Takenouchi, K. Yao, U. Tomaru, H.-C. Li, Y. Reiter, and S. Jacobson Increased Expression of Human T Lymphocyte Virus Type I (HTLV-I) Tax11-19 Peptide-Human Histocompatibility Leukocyte Antigen A*201 Complexes on CD4+ CD25+ T Cells Detected by Peptide-specific, Major Histocompatibility Complex-restricted Antibodies in Patients with HTLV-I-associated Neurologic Disease J. Exp. Med., May 17, 2004; 199(10): 1367 - 1377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Saito, V. M. Braud, P. Goon, E. Hanon, G. P. Taylor, A. Saito, N. Eiraku, Y. Tanaka, K. Usuku, J. N. Weber, et al. Low frequency of CD94/NKG2A+ T lymphocytes in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis, but not in asymptomatic carriers Blood, July 15, 2003; 102(2): 577 - 584. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kubota, Y. Furukawa, S. Izumo, K. Usuku, and M. Osame Degenerate specificity of HTLV-1-specific CD8+ T cells during viral replication in patients with HTLV-1-associated myelopathy (HAM/TSP) Blood, April 15, 2003; 101(8): 3074 - 3081. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Muraro, K.-P. Wandinger, B. Bielekova, B. Gran, A. Marques, U. Utz, H. F. McFarland, S. Jacobson, and R. Martin Molecular tracking of antigen-specific T cell clones in neurological immune-mediated disorders Brain, January 1, 2002; 126(1): 20 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Hanon, P. Goon, G. P. Taylor, H. Hasegawa, Y. Tanaka, J. N. Weber, and C. R. M. Bangham High production of interferon {gamma} but not interleukin-2 by human T-lymphotropic virus type I-infected peripheral blood mononuclear cells Blood, August 1, 2001; 98(3): 721 - 726. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Saito, G. P. Taylor, A. Saito, Y. Furukawa, K. Usuku, J. N. Weber, M. Osame, and C. R. M. Bangham In Vivo Selection of T-Cell Receptor Junctional Region Sequences by HLA-A2 Human T-Cell Lymphotropic Virus Type 1 Tax11-19 Peptide Complexes J. Virol., January 15, 2001; 75(2): 1065 - 1071. [Abstract] [Full Text]
|
|
|
|
|
|
K. J. M. Jeffery, A. A. Siddiqui, M. Bunce, A. L. Lloyd, A. M. Vine, A. D. Witkover, S. Izumo, K. Usuku, K. I. Welsh, M. Osame, et al. The Influence of HLA Class I Alleles and Heterozygosity on the Outcome of Human T Cell Lymphotropic Virus Type I Infection J. Immunol., December 15, 2000; 165(12): 7278 - 7284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Hanon, S. Hall, G. P. Taylor, M. Saito, R. Davis, Y. Tanaka, K. Usuku, M. Osame, J. N. Weber, and C. R. M. Bangham Abundant Tax protein expression in CD4+ T cells infected with human T-cell lymphotropic virus type I (HTLV-I) is prevented by cytotoxic T lymphocytes Blood, February 15, 2000; 95(4): 1386 - 1392. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Pique, A. Ureta-Vidal, A. Gessain, B. Chancerel, O. Gout, R. Tamouza, F. Agis, and M.-C. Dokhelar Evidence for the Chronic In Vivo Production of Human T Cell Leukemia Virus Type I Rof and Tof Proteins from Cytotoxic T Lymphocytes Directed against Viral Peptides J. Exp. Med., February 7, 2000; 191(3): 567 - 572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. M. Jeffery, K. Usuku, S. E. Hall, W. Matsumoto, G. P. Taylor, J. Procter, M. Bunce, G. S. Ogg, K. I. Welsh, J. N. Weber, et al. HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy PNAS, March 30, 1999; 96(7): 3848 - 3853. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
