Marked Suppression of T Cells by a Benzothiophene
Derivative in Patients with Human T-Lymphotropic Virus Type
I-Associated Myelopathy/Tropical Spastic Paraparesis |
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Authors: | Masahiko Makino Miyuki Azuma Shin-Ichi Wakamatsu Yukio Suruga Shuji Izumo Mitchel M Yokoyama Masanori Baba |
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Affiliation: | Division of Human Retroviruses1. and Division of Molecular Pathology,3. Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University, Kagoshima, and Department of Allergy and Immunology, National Children’s Medical Research Center, Setagaya-ku, Tokyo,2. Japan |
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Abstract: | In a search for new anti-autoimmune agents that selectively
suppress activation of autoreactive T cells, one such agent,
5-methyl-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide
(CI-959-A), was found to be effective. This compound, which is known to
suppress tumor necrosis factor alpha (TNF-α)-induced CD54 expression,
inhibited the primary proliferative response of the T cell to antigen
(Ag)-presenting cells (APCs) including allogenic dendritic cells (DCs),
autologous Epstein-Barr virus-infected B cells, and human T
lymphotropic virus type I (HTLV-I)-infected T cells. Autoreactive T
cells from patients with HTLV-I-associated myelopathy/tropical spastic
paraparesis (HAM/TSP) spontaneously proliferate in vitro, and their
activation is reported to be associated with CD54 expression. The
spontaneous proliferation of T cells from patients with HAM/TSP was
entirely blocked by CI-959-A. However, in this study, the T-cell
proliferation in 15 patients with HAM/TSP was found to depend more
extensively on major histocompatibility complex (MHC) class II and CD86
than on CD54 Ags. Since most important APCs for the development of
HAM/TSP are DCs and HTLV-I-infected T cells, the effect of CI-959-A on
DC generation and on the expression of surface molecules on activated T
cells is examined. CI-959-A suppressed recombinant
granulocyte-macrophage colony stimulating factor (GM-CSF)- and
recombinant interleukin-4-dependent differentiation of DCs from
monocytes and inhibited the expression of CD54 and, more extensively,
MHC class II and CD86 Ags. CI-959-A showed little toxicity toward
lymphoma or HTLV-I-infected T-cell lines or toward monocytes and
cultured DCs. These results suggest that CI-959-A might be a potent
anti-HAM/TSP agent.Human T lymphotropic virus type I
(HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP)
is thought to be an autoimmune disease induced by HTLV-I infection
(8, 9, 24). The T lymphocytes obtained from patients with
HAM/TSP patients produce interleukin-2 (IL-2) in vivo and proliferate
spontaneously in vitro without any additional stimuli or cytokines
(35). This spontaneous proliferation of T lymphocytes (SPL)
depends on the interaction of T cells with antigen (Ag)-presenting
cells (APCs) such as dendritic cells (DCs) (17, 25) and
HTLV-I-infected CD4+ T cells (15, 32). The DCs
localized in the blood and nonlymphoid organs are considered to be
functionally immature, in that they are optimized for the uptake and
processing of Ag but not for the initiation of primary T-cell
responses. However, after the uptake of Ag and exposure to inflammatory
agents including tumor necrosis factor alpha (TNF-α) and IL-1, the
DCs undergo a process of maturation and gain the ability to present Ag
to T cells for their priming (22, 26). In addition to DCs,
HTLV-I-infected CD4+ T cells directly stimulate autologous
CD4+ T cells in a major histocompatibility complex (MHC)
class II- and CD86 molecule-dependent fashion (32). Among
the T cells stimulated with these APCs, some might cross-react with
self Ags and closely associate with the development of HAM/TSP.We have been searching for compounds that inhibit the cellular
interaction between APCs and T cells to suppress the activation of
autoreactive and Ag-specific T cells. The molecules associated with the
APC-T cell interaction may provide an effective target for therapy for
autoimmune diseases. Binding of APCs and T cells is initiated by
contact of adhesion molecules, such as CD54 and CD11a/CD18, expressed
on both cells, and induction of sustained proliferation of T cells
requires two independent signals provided by APCs: a T-cell
receptor-mediated Ag-specific signal and a signal mediated by
costimulatory molecules (CSMs) (10, 20) including CD86 and
CD58 Ags (1, 11, 31). Blocking of their tight binding
through adhesion molecules or interaction of the CSMs with CSM ligands
effectively suppressed the abnormal expansion of disease-associated T
cells in vivo and in vitro (19, 30, 32) and sometimes
effectively induced a long-term unresponsiveness of T cells to recall
stimuli.5-Methyl-3-(1-methylethoxy)benzo[b]thiophene-2-carbox-amide
(CI-959-A) is known to inhibit CD54 expression, and its derivative is
reported to inhibit casein kinase II (4). In the present
study, we found that CI-959-A markedly suppressed SPL in patients with
HAM/TSP. Furthermore, the compound suppressed the primary T-cell
proliferative response to stimuli provided by various APCs, the
differentiation of immature DCs from monocytes and their subsequent
maturation, and the induction of expression of MHC class II, CD54, and
CD86 Ags on activated CD4+ T cells. |
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