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.

Oral administration of myelin basic protein (MBP) is an effective way of suppressing experimental autoimmune encephalomyelitis (EAE). We have previously shown that such suppression is mediated by CD8' T cells, which adoptively transfer protection and suppress immune responses in vitro. In the present study we have found that modulator cells from animals orally tolerized to MBP produce a suppressor factor upon stimulation with MBP in vitro that is specifically inhibited by anti-transforming growth factor (3 (TGF-fl) neutralizing antibodies. No effect was observed with antibodies to y interferon, tumor necrosis factor a/fl, or indomethacin. In addition, the active form of the type 1 isoform of TGF-fl1 can be directly demonstrated in the supernatants of cells from animals orally tolerized to MBP or ovalbumin after antigen stimulation in vitro. Antiserum specific for TGF-Pf administered in vivo abrogated the protective effect of oral tolerization to MBP in EAE. Furthermore, injection of anti-TGF-fl1 serum to nontolerized EAE animals resulted in an increase in severity and duration of disease. These results suggest that immunomodulation of EAE induced by oral tolerization to MBP and natural recovery mechanisms use a common immunoregulatory pathway that is dependent on TGF-f81. Implications of such an association are of therapeutic relevance to human autoimmune diseases and may help to explain one of the mechanisms involved in the mediation of active suppression by T cells.

SummarySuppression of experimental autoimmune encephalomyelitis (EAE) in Lewis rats by the oral administration of myelin basic protein (MBP) is mediated by CD8 + T cells that can be isolated from the spleens of MBP-fed animals. These cells adoptively transfer protection to naive animals subsequently immunized with MBP and complete Freund's adjuvant (CFA) and suppress in vitro MBP proliferative responses. Using a transwell system in which the modulator spleen cells from MBP-fed animals are separated by a semipermeable membrane from responder cells, MBP, or OVA-specific T cell lines, we have found that cell contact is not required for in vitro suppression to occur. In vitro suppression is dependent, however, upon antigen-specific triggering of modulator T cells. Once antigen-specific triggering occurs, suppression across the transwell is mediated by an antigen-nonspecific soluble factor that equally suppresses an MBP line or an ovalbumin (OVA) line. This phenomenon of antigen-driven bystander suppression was also demonstrated in vivo. Specifically, Lewis rats fed OVA which were then immunized with MBP/CFA plus OVA given separately subcutaneously were protected from EAE. Animals fed OVA and then immunized with MBP/CFA without OVA given subcutaneously were not protected. The protective effect of feeding OVA could be adoptively transferred by CD8 + T cells from OVA-fed animals into MBP/CFA plus OVA-injected animals. Feeding bovine serum albumin (BSA) or keyhole limpet hemocyanin did not suppress EAE in animals immunized with MBP/CFA plus OVA. EAE was suppressed, however, if BSA was fed and animals then immunized with MBP/CFA plus BSA given subcutaneously. Antigen-driven bystander suppression appears to be an important mechanism by which antigen-driven peripheral tolerance after oral administration of antigen is mediated, and presumably occurs in the microenvironment accounting for the antigen specificity of suppression generated by oral tolerization to antigens.A variety of mechanisms have been described for the maintenance of self-tolerance in the host. These include clonal deletion (1), clonal anergy (2, 3), and active suppression (4; and reviewed in reference 5). We have been studying antigen-driven active suppression after oral administration of antigens as a tolerance mechanism and as a method to downregulate autoimmune diseases in experimental animals (6-11). In the experimental autoimmune encephalomyelitis (EAE) 1 model, oral administration of myelin basic protein (MBP) suppresses clinical, histologic, and immune parameters of the disease (6, 12). This effect is mediated by CD8 + T cells, which can adoptively transfer protection and suppress in vitro proliferative responses (7). Although various mechanisms of active suppression have been demonstrated (5, 13), the precise mechanism(s) by which T cells mediate suppression re1Abbreviations used in this paper: DTH, delayed-type hypersensitivity; EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; PPD, purified protein derivative. 791 mains t...

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Hematopoietic stem cell homing and engraftment require several adhesion interactions, which are not fully understood. Engraftment of nonobese/severe combined immunodeficiency (NOD/SCID) mice by human stem cells is dependent on the major integrins very late activation antigen–4 (VLA-4); VLA-5; and to a lesser degree, lymphocyte function associated antigen–1 (LFA-1). Treatment of human CD34+cells with antibodies to either VLA-4 or VLA-5 prevented engraftment, and treatment with anti–LFA-1 antibodies significantly reduced the levels of engraftment. Activation of CD34+ cells, which bear the chemokine receptor CXCR4, with stromal derived factor 1 (SDF-1) led to firm adhesion and transendothelial migration, which was dependent on LFA-1/ICAM-1 (intracellular adhesion molecule–1) and VLA-4/VCAM-1 (vascular adhesion molecule–1). Furthermore, SDF-1–induced polarization and extravasation of CD34+/CXCR4+ cells through the extracellular matrix underlining the endothelium was dependent on both VLA-4 and VLA-5. Our results demonstrate that repopulating human stem cells functionally express LFA-1, VLA-4, and VLA-5. Furthermore, this study implies a novel approach to further advance clinical transplantation.

These findings suggest that TLR4 mutations, but not the CD14/-159 polymorphism, are associated with an increased risk of severe RSV bronchiolitis in previously healthy infants.

Tissue injury caused by infection or physical damage evokes inflammatory reactions and events that are necessary for regaining homeostasis. Central to these events is the translocation of leukocytes, including monocytes, neutrophils, and T lymphocytes, from the vascular system, through endothelium, and into the extracellular matrix (ECM) surrounding the injured tissue. This transition from the vasculature into the site of inflammation elicits remarkable changes in leukocyte behavior as cells adhere to and migrate across ECM before carrying out their effector functions. Growing evidence suggests that, through its interactions with cytokines and degradative enzymes, the ECM microenvironment has a specialized role in providing intrinsic signals for coordinating leukocyte actions. Recent advances also reveal that enzymatic modifications to ECM moieties and cytokines induce distinctive cellular responses, and are likely part of the mechanism regulating the perpetuation or arrest of inflammation. This article reviews the findings that have elucidated the dynamic relationships among these factors and how they communicate with immune cells during inflammation. J. Leukoc. Biol. 67: 149-159; 2000.

Elevated extracellular K+ ([K+]o), in the absence of “classical” immunological stimulatory signals, was found to itself be a sufficient stimulus to activate T cell β1 integrin moieties, and to induce integrin-mediated adhesion and migration. Gating of T cell voltage-gated K+ channels (Kv1.3) appears to be the crucial “decision-making” step, through which various physiological factors, including elevated [K+]o levels, affect the T cell β1 integrin function: opening of the channel leads to function, whereas its blockage prevents it. In support of this notion, we found that the proadhesive effects of the chemokine macrophage-inflammatory protein 1β, the neuropeptide calcitonin gene–related peptide (CGRP), as well as elevated [K+]o levels, are blocked by specific Kv1.3 channel blockers, and that the unique physiological ability of substance P to inhibit T cell adhesion correlates with Kv1.3 inhibition. Interestingly, the Kv1.3 channels and the β1 integrins coimmunoprecipitate, suggesting that their physical association underlies their functional cooperation on the T cell surface. This study shows that T cells can be activated and driven to integrin function by a pathway that does not involve any of its specific receptors (i.e., by elevated [K+]o). In addition, our results suggest that undesired T cell integrin function in a series of pathological conditions can be arrested by molecules that block the Kv1.3 channels.