Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents - Volume 3, Issue 4, 2004

The chemokine network in our bodies is composed of ∼40 chemokines and 18 chemokine receptors. The primary function of chemokines is to attract and retain hematopoietic cells within tissue microenvironments, thereby facilitating cell-cell interaction necessary for hematopoiesis, development and effector function. Each tissue site expresses unique combinations of chemokines to ensure the recruitment of blood cell subsets expressing appropriate chemokine receptors. This journal issue contains seven review articles reviewing the up-to-date findings on the roles of chemokines and their receptors in the migration of blood cells at various developmental and functional stages from stem and progenitor cells in the bone marrow and the thymus to functionally mature effector cells at sites of inflammation. Hematopoiesis, which is to make all blood cells, occurs in the bone marrow in adults. Retention of stem and progenitor cells in the bone marrow and emigration of mature leukocytes out of the bone marrow are regulated by chemokines. SDF-1 / CXCL12 is the major player in this aspect. The article by Drs. Broxmeyer and Christopherson entitled “Stromal cell derived factor- 1 / CXCL12, CXCR4 and CD26 in the mobilization and homing of hematopoietic stem and progenitor cells” reviews the role and practical implications of the SDF-1 / CXCR4 axis in the homing, engraftment and mobilization of hematopoietic stem cells. Some stem and progenitor cells migrate to the thymus to generate functional T cells that protect our bodies from pathogens. T cells undergo maturation and selection processes in the thymus to become naïve T cells that recognize foreign, but not self, antigens. The review by Drs. Uehara, Farber and Love at NIH entitled “Migration of T cell Progenitors in the Thymus” reviews the recent progress in thymocyte migration into, within and out of the thymus. Recently, significant progress has been made in the characterization of unconventional T cells such as NKT cells, γδ T cells and CD4+CD25+ regulatory T cells. The next article, entitled “Trafficking Potentials of Unconventional T cells” by Robert Johnson and myself, reviews the recent progress in research in the migration of NKT cells, γδ T cells and regulatory T cells. These T cells are unconventional in their function, which are well reflected in their unconventional patterns of migration. Functional maturation of naïve T cells to become memory / effector cells occurs in secondary lymphoid tissues. Many of these memory / effector cells migrate to the liver, an organ that has peculiar characteristics in terms of lymphocyte migration. Drs. Sato, Thorlacius and Butcher at Stanford University School of Medicine review the recent progress in this area in their article entitled “Lymphocyte Migration to the Liver.” Although immune cells have been evolved to protect our bodies from pathogens, sometimes they recognize self antigens and attack our own tissues or organs. The review entitled “Chemokines and Autoimmune diseases” by Drs. Tomoya Katakai and Akira Shimizu discusses the onset and progression of autoimmune diseases, and the roles of chemokines in the migration of effector T cells and the development of ectopic lymphoid tissues in inflamed tissues of autoimmune diseases. While most autoimmune responses are Th1 diseases, there are some diseases that are of Th2 type and are mediated, in part, by a specialized group of chemokines. The review article entitled “Chemokines in Allergic Inflammation. Human Disease and Animal Models” by Dr Harm HogenEsch at Purdue University provides an extensive review on the involvement of chemokines in allergic and Th2 type diseases. In order to suppress the autoimmune diseases and allergic diseases, it is important to regulate the migration of self-reactive immune cells to lymphoid and non-lymphoid tissues. The article by Dr. Toshihiko Saeki entitled “Small-Molecule Chemokine Receptor Antagonists: Potential Targets for Inflammatory and Allergic Disorders” reviews the small molecule antagonists developed so far to block interactions between various chemokine receptors and their chemokine ligands. Some of these antagonists are in clinical trials for treatments of inflammatory and allergic disorders in animals and human. I would like to thank all the authors for their contribution of the interesting review articles, and thank the editorial board members and staffs for their help in publication of this special journal issue.

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.

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.

Conventional TCR-αβ 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 γδ T cells, are very different from conventional T cells in this respect. NKT cells and γδ 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 γδ 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-αβ 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.

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, α4β7, α4β1, αLβ2, 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.

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.

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.

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.