Current Medicinal Chemistry- Anti- Inflammatory & Anti- Allergy Agents, Vol. 3, No. 4, 2004
Contents
Chemokines
Guest Editor:
Chang H. Kim
Stromal Cell Derived
Factor-1/CXCL12, CXCR4 and CD26 in the Mobilization and Homing of Hematopoietic
Stem and Progenitor Cells Pp.303-311
H.E. Broxmeyer and K.W. Christopherson II
Migration of T Cell Progenitors
in the Thymus Pp.313-319
Shoji Uehara, Joshua M. Farber
and Paul E. Love
Trafficking Potentials of
Unconventional T Cell Subsets Pp.321-330
Chang H. Kim and Robert Johnson
Lymphocyte Homing to the Liver Pp.331-339
Tohru Sato, Henrik Thorlacius
and Eugene Butcher
Chemokines and Autoimmune
Diseases Pp.341-350
Tomoya Katakai and Akira
Shimizu
Chemokines in Allergic
Inflammation: Human Disease and Animal Models Pp.351-361
Harm HogenEsch
Small-Molecule Chemokine Receptor
Antagonists: Potential Targets for Inflammatory and Allergic Disorders Pp.363-375
Toshihiko Saeki
Abstracts
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Stromal Cell Derived Factor-1/CXCL12, CXCR4 and CD26 in the Mobilization and Homing
of Hematopoietic Stem and Progenitor Cells
H.E. Broxmeyer and K.W. Christopherson II
Hematopoietic Stem (HSC) and Progenitor (HPC) cells are rare and give rise to all blood forming cells. In many malignant and non-malignant disorders, a transplant of HSC/HPC is the only curative regiment available for these disorders. Transplants of HSC/HPC are done through intravenous injection of donor cells into conditioned recipients where the cells home to and engraft in the bone marrow. The majority of HSC/HPC transplants are currently performed with these cells after they are mobilized from the marrow to circulating blood where they are then collected for transplantation. Chemokines are recognized for their chemoattractant/chemotactic capabilities of many different cell types. Stromal Cell Derived Factor-1 (SDF-1/CXCL12) and its receptor, CXCR4 have been implicated by us and others in the migration in vitro and in vivo of HSC/HPC. This paper reviews the role and practical implications of the SDF- 1/CXCL12-CXCR4 axis in the homing, engraftment and mobilization of HSC, and the modulation of these events by the cell surface component CD26, which manifests Dipeptidylpeptidase IV (DPPIV) activity that truncates SDF-1/CXCL12 and changes its activity, and by AMD3100, a specific antagonist of SDF-1/CXCL12 binding to CXCR4. Inhibition or deletion of CD26 has been used to enhance the homing and engrafting capabilities of murine HSC, while AMD3100 has been used to induce mobilization of murine and human HSC and HPC, and to enhance this mobilization induced by Granulocyte-Colony Stimulating Factor. Further efforts in understanding the SDF-1/CXCL12-CXCR4 axis, and CD26 and their mechanisms of actions and modulation should yield information of clinical relevance and utility.
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Migration of T Cell Progenitors in the Thymus
Shoji Uehara, Joshua M. Farber and Paul E. Love
T cell development begins during late gestation
and continues well into adulthood. A special property of T lymphopoiesis is
that it involves the periodic migration of progenitor cells from their site of
production (fetal liver or adult bone marrow) to the thymus where they complete
their development. As thymocytes progress through distinct stages of maturation
they migrate into and between different thymus microenvironments where they are
exposed to growth factors and receive specialized signals that are required for
their development. Chemokines are a group of small, structurally related
molecules that regulate trafficking of leukocytes through interactions with a
subset of seven-transmembrane, G protein-coupled receptors. Several different
chemokines are produced in the thymus and expression of the receptors for these
chemokines on thymocyte subpopulations is developmentally regulated. The recent
generation of chemokine/chemokine receptor deficient mice has revealed
important functions for these molecules in regulating movement of cells into
and through the thymus. In this review, we discuss current data relating to the
role of chemokines and chemokine receptors in T cell development.
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Trafficking Potentials of Unconventional T Cell Subsets
Chang H. Kim and Robert Johnson
Conventional TCR-ab T cells dramatically change the expression pattern of homing receptors at least twice during their development to effector T cells. The first change to emigrate out of the thymus and into secondary lymphoid tissues occurs in the thymus. The second change from naïve type to memory type occurs during T cell priming with antigens in secondary lymphoid tissues. Antigen presenting cells and cytokines play critical roles in the switch of homing behavior. However, the two unconventional T cell subsets, CD1d-restricted NKT cells and gd T cells, are very different from conventional T cells in this respect. NKT cells and gd T cells display the memory type migration phenotype as soon as they emigrate out of the thymus. This implies that these unconventional T cells do not need to migrate to secondary lymphoid tissues in order to acquire the migratory capacity to non-lymphoid tissues. In this regard, most CD1d-restricted NKT cells and gd T cells are somewhat similar to polarized conventional effector T cells such as T helper 1 cells and NK cells in their migratory capacity. CD4+CD25+ regulatory T cells, however, are heterogeneous in their homing capacity in a manner similar to the conventional TCR-ab T cells. Some CD4+CD25+ T cells have the migratory behavior of naïve T cells, while others have the homing capacity of memory T cells. The importance of these migration behaviors of unconventional T cells is discussed in this review.
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Lymphocyte Homing to the Liver
Tohru Sato, Henrik Thorlacius and Eugene Butcher
The liver has a large population of resident lymphocytes that survey the liver under normal conditions but can be rapidly expanded through recruitment and proliferation in response to various insults. The tissue-specific homing molecules for tissues such as intestine and skin are well characterized, but liver-specific homing molecules are still not known. The molecules that have been implicated in liver homing are also selectins, integrins, and chemokines, as in other tissues, however, the unique flow conditions, architecture, and specialized cell populations allow different molecules to play prominent roles in various microenvironments within the liver. In this review, we take a closer look at adhesion molecules (selectins, a4b7, a4b1, aLb2, and vascular adhesion protein-1) and “inflammatory” chemokine receptors (CXCR3, CCR5, and CXCR6) under various inflammatory conditions and compartments within the liver. Their prominent roles in accumulating lymphocytes to inflamed liver suggest its importance as possible therapeutic targets for human liver diseases.
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Chemokines and Autoimmune Diseases
Tomoya Katakai and Akira Shimizu
Autoimmune diseases are caused by a
misdirection of the host immune system against the self. After the triggering
of self-reactivity, two successive phases, i.e. the acute/deterioration phase
and subsequent chronic phase are observed during the course of manifestation
and maintenance of autoimmune symptoms. Not only inflammatory chemokines but
also homeostatic chemokines are involved in effector cells’ migration and the
development of tertiary lymphoid tissue in the target tissue. In the
acute/deterioration phase, Th1-associated chemokines and a vicious cycle of
type 1 immune responses are crucial for the destruction of the tissue.
Subsequently, homeostatic chemokines play important roles in organizing ectopic
lymphoid tissue for sustaining autoreactivity in the chronic phase. If they are
only correctly directed toward invasive pathogens, immune responses are,
essentially, an evolutionally acquired function of the adaptive immune system,
which is quite efficient for eradicating non-self. However, if self-components
accidentally happen to become the target of the host immune system, a serious
situation ensues. For clinical treatment, both inflammatory and homeostatic
chemokines would be promising targets in the different phases of autoimmune
diseases.
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Chemokines in Allergic Inflammation: Human Disease and Animal Models
Harm HogenEsch
The prevalence of allergic diseases has
increased dramatically in the past 30 years. Inflammation, characterized by
accumulation of eosinophils and T cells, and mast cell degranulation, plays a
critical role in the pathogenesis of these diseases. Chemokines and their
receptors are important in the control of leukocyte migration and are potential
targets for therapeutic intervention. A large body of literature documents the
increased presence of various chemokines and chemokine receptors in tissue
samples collected from patients with allergic diseases, but the role of
individual chemokines and chemokine receptors in the pathogenesis of allergic
inflammation is often uncertain. Some progress has been made through the use of
animal models of allergic disease, in which chemokines or chemokine receptors
can be selective blocked with specific antibodies or genetically deleted. This
review discusses the immunopathology of allergic inflammation in asthma,
allergic rhinitis and atopic dermatitis in human patients and in mouse models
of allergic inflammation of the airway and skin. The role of chemokine
receptors and their ligands is reviewed by comparing the expression of these
molecules in human tissue samples and animal models, and by a discussion of the
effect of selective manipulation of chemokines and chemokine receptors in
animal models. Human and mouse studies corroborate a critical
role for CCR3 and its ligands in allergic
inflammation, in particular in the infiltration of eosinophils. The role of
chemokines and chemokine receptors in the accumulation of T cells and the
migration and activation of mast cells is less clear and the delineation of
their role may depend on the development and use of improved mouse models of
chronic allergic inflammation.
[Back to top] Small-Molecule Chemokine Receptor
Antagonists: Potential Targets for Inflammatory and Allergic Disorders
Toshihiko Saeki
A substantial body of evidence suggests that
blockade of chemokine-chemokine receptor interaction with potent small-molecule
receptor antagonists may be a promising therapeutic intervention for
inflammatory and allergic disorders in humans. A number of pharmaceutical
companies have disclosed patents and journals regarding chemokine receptor
antagonists with their pharmacological activities. Recently, some chemokine
receptor antagonists have successfully progressed to clinical trials, and
preliminary results have suggested effectiveness in treating in human
disorders. This section highlights some representative and promising chemokine
receptor antagonists targeting inflammatory and allergic disorders, and “proof
of concept” studies in inflammatory and allergic disorders in animals and
humans.