Stem cell homing and repopulation are not well understood. The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 were found to be critical for murine bone marrow engraftment by human severe combined immunodeficient (SCID) repopulating stem cells. Treatment of human cells with antibodies to CXCR4 prevented engraftment. In vitro CXCR4-dependent migration to SDF-1 of CD34+CD38-/low cells correlated with in vivo engraftment and stem cell function. Stem cell factor and interleukin-6 induced CXCR4 expression on CD34+ cells, which potentiated migration to SDF-1 and engraftment in primary and secondary transplanted mice. Thus, up-regulation of CXCR4 expression may be useful for improving engraftment of repopulating stem cells in clinical transplantation.

The burgeoning field of leukocyte trafficking has created new and exciting opportunities in the clinic. Trafficking signals are being defined that finely control the movement of distinct subsets of immune cells into and out of specific tissues. Because the accumulation of leukocytes in tissues contributes to a wide variety of diseases, these 'molecular codes' have provided new targets for inhibiting tissue-specific inflammation, which have been confirmed in the clinic. However, immune cell migration is also critically important for the delivery of protective immune responses to tissues. Thus, the challenge for the future will be to identify the trafficking molecules that will most specifically inhibit the key subsets of cells that drive disease processes without affecting the migration and function of leukocytes required for protective immunity.

Leukocyte migration through activated venular walls is a fundamental immune response that is prerequisite to the entry of effector cells such as neutrophils, monocytes, and effector T cells to sites of infection, injury, and stress within the interstitium. Stimulation of leukocytes is instrumental in this process with enhanced temporally controlled leukocyte adhesiveness and shape-changes promoting leukocyte attachment to the inner wall of blood vessels under hydrodynamic forces. This initiates polarized motility of leukocytes within and through venular walls and transient barrier disruption facilitated sequentially by stimulated vascular cells, i.e., endothelial cells and their associated pericytes. Perivascular cells such as macrophages and mast cells that act as tissue inflammatory sentinels can also directly and indirectly regulate the exit of leukocytes from the vascular lumen. In this review, we discuss current knowledge and open questions regarding the mechanisms involved in the interactions of different effector leukocytes with peripheral vessels in extralymphoid organs.

In vivo, leukocyte transendothelial migration (TEM) occurs at endothelial cell junctions (paracellular) and nonjunctional (transcellular) locations, whereas in vitro models report that TEM is mostly paracellular. The mechanisms that control the route of leukocyte TEM remain unknown. IntroductionLeukocyte transendothelial migration (TEM) is a key step in their recruitment to sites of inflammation, injury, and immune reactions. Leukocyte recruitment involves a multistep cascade consisting of leukocyte rolling, firm adhesion, and, ultimately, transmigration. 1 These steps are regulated by shear flow, apical chemokines, and inducible adhesion molecules expressed by endothelium. 2 The actual path of leukocyte egress (paracellular versus transcellular) has been examined in several models (reviewed in Muller, 3 Kvietys and Sandig, 4 and Engelhardt and Wolburg 5 ). Experiments carried out in several animal models of inflammation found that leukocyte TEM can occur at both paracellular and transcellular locations. [6][7][8][9][10][11][12] In contrast, most in vitro studies have reported that leukocyte TEM occurs primarily at paracellular locations. 3,[13][14][15] As a result, in vitro models of polymorphonuclear leukocyte (PMN) transcellular TEM do not exist, and the factors that dictate whether leukocytes use a transcellular or paracellular route and the mechanisms underlying transcellular TEM are unknown.Intercellular adhesion molecule-1 (ICAM-1) interacting with its leukocyte counterreceptors lymphocyte function-associated antigen-1 (LFA-1) and macrophage antigen-1 (Mac-1) is key for leukocyte adhesion and TEM. [16][17][18][19] ICAM-1 is a transmembrane glycoprotein with 5 extracellular immunoglobulin G (IgG)-like domains and a short cytoplasmic tail that associates with multiple cytoskeletal linker proteins (reviewed in Springer 1 ). Vascular endothelium expresses low levels of ICAM-1, and inflammatory stimuli can markedly increase ICAM-1 surface expression. 20,21 In acute and chronic inflammatory diseases, endothelial cells become activated and express high levels of ICAM-1, in addition to vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. [22][23][24][25] ICAM-1 has been shown to signal in endothelium during leukocyte adhesion or when cross-linked by anti-ICAM-1 antibodies. ICAM-1 occupancy triggers elevations in intracellular free Ca 2ϩ and myosin contractility, 26 activation of p38 kinase, 27 and the small guanosine triphosphatases (GTPases), in particular, members of the Rho family 28,29 and the tyrosine kinase p60 Src . 30 Activation of these signaling pathways results in extensive cytoskeletal remodeling events that alter endothelial cell contractility and function, 27 possibly facilitating leukocyte diapedesis. Recently, we have shown that neutrophil LFA-1 rapidly redistributes to form a ringlike structure that coclusters with endothelial ICAM-1 during PMN transmigration at cell junctions. 31 Others have reported that ICAM-1-enriched projections engulf leukocytes during their firm adhesion and locomot...