Celtaxsys - Biology in Reverse

Chemotaxis

Chemorepulsion

Chemoattraction

Background

All cells possess the ability to survey their environment through the detection of external stimuli. Cells can also perceive their own physiological state, which acts as an internal stimulus. To detect these stimuli, chemosensory systems are present in most cell types and a number have been described for both prokaryotic and eukaryotic organisms. For external stimuli, chemosensory systems rely on receptor proteins with pronounced stimulus specificity. Typically, the receptor is presented on the cell surface and stimulation corresponds to the binding or dissociation of a stimulant to or from the receptor. Following receptor ligation, a series of biochemical events are initiated inside the cell to elicit a biochemical response. In many instances, the stimulus results in chemotaxis, which may be defined as the purposeful movement of cells toward, or away, from a chemical or biological agent. The consequence of a chemotactic stimulus is to induce cellular polarization and movement (Figure 1).

Figure 1: Chemotaxis and cell polarization in attractive mode for the soil amoeboid Dityostelium discoidium (left) and a human neutrophil (right). As might be apparent from the similarities in cell morphology, the pathways governing cell polarization and induction of chemoattractive chemotaxis are related in the soil amoeba and a migratory human leukocyte. Below each micrograph is an illustration of the major pathways governing cell polarization in response to a chemokine stimulus. Image courtesy of Carole A. Parent, Laboratory of Cellular and Molecular Biology, National Cancer Institute.

Chemokines

Around 1980, a family of proteinaceous stimuli were defined, the chemokines, whose biological role was linked to the trafficking of leukocytes crucial to the initiation of normal, disease-fighting inflammatory responses (Figure 2). The chemokines bind G-protein coupled receptors (GPCRs) displayed on the surface of immune cells. Chemokines and their receptors are key players in host defense, based on their potent activity in leukocyte migration and recruitment. The chemokine/GPCR interaction has long been thought to represent the principal mechanism by which immune cells can be induced to migrate toward a chemical or biological agent.

Figure 2: Leukocytes must under go four adhesion steps to accumulate in a blood vessel: Tethering, Rolling, Activation and Adhesion. The predominant leukocyte-expressed trafficking molecules that participate in each step and their endothelial counter-receptors are indicated. Arrows indicate interactions of individual molecules with one or more binding partners. Leukocytes in the blood stream tether to endothelial cell ligands and roll slowly downstream. Tethering is mediated mainly by leukocyte receptors on tips of surface microvilli (L-selectin, PSGL-1 and α4 integrins). L-selectin recognizes sulfated sialyl-Lewis X (sLeX)-like sugars as well as PSGL-1 on adherent leukocytes (broken arrows). E-selectin can also interact with PSGL-1 and other sialyl-Lewis X-bearing glycoconjugates, commonly called \'CLA\'. E-selectin and the α4 integrins can stabilize rolling mediated by L- and P-selectin and reduce rolling velocities. When a GPCR on a rolling cell becomes engaged by a specific chemoattractant (often a chemokine), the activating signal (red square) is transmitted intracellularly to induce rapid activation of β2 and/or α4 integrins, which assume extended conformations and bind tightly to endothelial immunoglobulin superfamily members. Prolonged ligation of L-selectin or ligands for E- and P-selectin can act in synergy with or even substitute for GPCR signals to activate β2 integrins in some settings. Image and description courtesy of Ulrich von Andrian of Harvard Medical School, a member of the Scientific Advisory Board.

New technology and therapeutic focus

Celtaxsys has developed a high-throughput assay system which has identified a large number of chemotactic agents of protein and non-protein origin. Mechanistic investigation of these newly defined chemosensory agents demonstrates that cell migration stimulants are not merely linked to GPCR function and many are not chemokine or cytokine related. Thus, Celtaxsys may have discovered new biology and is characterizing these pathways for application in human disease therapies. The ability of our portfolio of agents to induce immune cell chemorepulsion can be appreciated from a time-lapse video of T cells repelled by one of our proprietary agents (Figure 3).

Figure 3: The technology developed by Celtaxsys is presently being applied to four therapeutic areas, each of which can be viewed from a perspective of defective immune cell migration. The therapeutic resolution of these diseases is achieved by introduction or removal of a cell migration agent, as indicated.