Chemokines and Chemokine Receptors

Chemokines form a large family composed primarily of small secreted cytokine proteins that coordinate leukocyte trafficking by binding to seven-transmembrane (7TM) domain receptors. Chemokines mediate normal host defense and tissue repair; however, they may also support pathological immune responses, including chronic inflammation, autoimmunity, and cancer. The chemokine system is also a major target for immune system evasion or exploitation by pathogens (e.g., human immunodeficiency virus [HIV] and Plasmodium vivax). Increasingly, additional immunological and nonimmunological chemokine functions are being recognized. The nonimmunological functions can be beneficial, as in embryogenesis, or harmful, as in cancer. WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is the only known mendelian condition caused by mutations in a chemokine or chemokine receptor (the receptor CXCR4). Two chemokine receptor antagonists have been approved by the U.S. Food and Drug Administration (FDA) so far: maraviroc, a CCR5 antagonist, used in the treatment of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), and plerixafor, a CXCR4 antagonist, approved for hematopoietic stem cell mobilization for transplantation in cancer. This chapter will expand on these and other basic principles and clinical correlates of chemokine regulation of the immune system.