Silvano Sozzani

Chemokines: A superfamily of chemotactic cytokines

Chemokines are a bipartite family of chemotactic proteins that bear the structural hallmark of four cysteine residues, the first two of which are in tandem. The spectrum of action of chemokines encompasses a large number of leukocyte populations, including monocytes, granulocytes, lymphocytes, NK and dendritic cells. Although the spectrum of action of chemokines largely overlaps, clear differences are still present. Chemokines play an important role in the recruitment of leukocytes at the site of inflammation, allergic reaction and tumors. Available information on receptor usage by MCP-1 and related chemokines and signal transduction pathways is reviewed. The better understanding of signaling mechanisms will provide a new basis for the development of therapeutic strategies.

CHAPTER 15 – Dendritic cells and chemokines

Dendritic cells (DCs) respond to chemoattractants representative of different classes of chemotactic agonists, including lipid attractants, formyl peptides, and C5a generated by the complement cascade. Immature DCs, generated in vitro from monocytes, express a unique repertoire of inflammatory chemokine receptors. These receptors bind a pattern of “inflammatory” chemokines, including RANTES, MCP-3, MIP-1α, MIP-1β, and MIP-5. Langerhans cells (LCs) purified from skin or generated in vitro from CD34 precursors are characterized by the expression of CCR6, the receptor for MIP-3α, also known as LARC or exodus, in addition to the receptors expressed by monocyte DCs. The ability of precursor cells and immature DCs to migrate in response to a pattern of chemotactic signals is relevant for the accumulation of immature DCs into nonlymphoid tissues in normal conditions and during the early phase of inflammation, when local production of chemokines is strongly induced.

CHAPTER 47 – CC chemokines

This chapter focuses on CC chemokines, which are a complex system of molecules that affect a variety of hematopoietic and non-hematopoietic cell types. Validation as pharmacological targets includes gene targeting, usage of antibodies or antagonists, whose expression in human pathology is discussed in the chapter. CC chemokine receptor antagonists have been developed, and are at various stages of preclinical or clinical development. CC chemokines are the most numerous, and diversified family of the four subgroups defined, based on the Cys motif (CC, CXC, C, CX3C). In humans, it includes at least 25 members interacting with at least 11 signaling receptors. CC chemokines have been discovered following different pathways, ranging from biological, and biochemical identification to direct cDNA cloning to, more recently, in silico cloning by gene bank mining. The development of efficacious CC chemokine antagonists remains a “holy grail” for the general field of cytokine pharmacology. The chemokines role in the transition from innate to acquired immunity, and in amplification of polarized responses on selected molecules, and pathologies are used as a paradigm.

Tumors as a Paradigm for the In Vivo Role of Chemokines in Leukocyte Recruitment

Ever since the first description by Virchow in 1863, histopathologists have recognized the occurrence of host leukocytes in tumor tissues and/or at their periphery. Interestingly, Virchow felt that the frequent presence of a lymphoreticular infiltrate in human neoplasms reflected the origin of cancer at sites of previous chronic inflammation. In 1907 Hardley reported that normal cell infiltration in malignant melanoma indicated a “regressive process.” This observation marked a complete change in the general opinion as to the significance of the “lymphoreticular infiltrate,” a change reflected by a number of reports on pathology and prognosis. These opposite ways of looking at the relationship between leukocyte infiltration and malignancy have polarized views in the field but, indeed, reflect the pleiotropic, ambivalent functions of infiltrating cells.

Molecules Involved in the Recruitment and Regulation of Tumor-Associated Macrophages

Recirculation and accumulation of leukocytes in tissues are crucial aspects of physiological processes. However, selective accumulation of one or more leukocyte subpopulations is the hallmark of pathological conditions including allergic and inflammatory reactions and tumors.

Chemokines: Attraction of dendritic cells and role in tumor immunobiology

In this chapter we will discuss selected aspects of the structure and function of chemokines, with emphasis on monocyte chemotactic proteins (MCPs) as prototypic CC chemokine. Among functions, we will emphasize recent results on molecules which attract dendritic cells of obvious relevance for skin immunobiology and emphasize potential relevance for tumor therapy.

Regulation of Inflammatory Cytokine Receptor Expression by Pro- and Anti-Inflammatory Molecules

Publisher Summary Inflammatory cytokines act in cascades. One can recognize schematically primary inflammatory cytokines, the prototype of which is IL-1, and secondary effector molecules, among which chemokines play an important role in recruitment. Pro- and anti-inflammatory signals regulate the production of primary and secondary inflammatory cytokines, sometimes in unexpected ways. Primary and secondary inflammatory cytokines are highly regulated by diverse signals. Emphasis has largely been on how pro- and anti-inflammatory molecules affect cytokine production. The possibility that micro environmental signals regulate the action of pro-inflammatory cytokines by acting at the receptor level has been less extensively studied.

Cytokine Regulation of Tumor-Associated Macrophages: Therapeutic Implications

Macrophages are a major component of the lymphoreticular infiltrate of tumors. Tumor-derived cytokines play an important role in the regulation of the recruitment and function of tumor-associated macrophages (TAM). TAM have pleiotropic functions that influence various aspects of the immunobiology of neoplastic tissues including vascularization, stroma formation and dissolution, and growth rate. These cells, strategically located at the interface between tumor and host, have the potential to destroy neoplastic tissues and hence are a target for therapeutic Intervention. Recent clinical results in ovarian cancer encourage efforts along this line.

Biological Significance and Therapeutic Potential of Tumor-Associated Leukocytes

Macrophages are a major component of the lymphoreticular infiltrate of rodent and human tumors (Mantovani et al 1992a). Since these cells are situated at the very interface between tumor and host, they may represent a strategically located target for therapeutic intervention. Interest in these cells is stimulated by the knowledge that macrophages have the potential to kill neoplastic cells including drug-resistant variants surviving conventional chemotherapy (Allavena et al 1987).