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PubMed2001

Structural elements of the osteopontin SVVYGLR motif important for the interaction with alpha(4) integrins.

The osteopontin SVVYGLR motif binds the integrins alpha(4)beta(1) and alpha(9)beta(1). We show that alpha(4)beta(7) also interacts with this motif and that an SVVYGLR-OH peptide antagonises the alpha(4)beta(7) MAdCAM interaction. The important elements of this motif required to bind alpha(4)beta(1) and alpha(4)beta(7) were probed using a series of mutated peptides based around SVVYGLR. Leu167 is important for the interaction with alpha(4) integrins, as is the C-terminal carboxylic acid of Arg168 exposed by thrombin cleavage. The importance of the acidic group means that SVVYGLR has structural elements in common with other alpha(4) integrin-binding motifs and suggests why thrombin cleavage activates this motif.

Amino Acid Motifs↗
PubMed2000

Adhesion molecules on peripheral blood lymphocyte subpopulations in the elderly.

Adhesion molecules, such as CD49d, CD50 and CD62L, have important roles in many adhesive interactions involving cells of the immune system. Since it has been shown that many immunological alterations are present in aged subjects, we studied, by means of triple colour whole blood immunostaining and multiparametric flow cytometry, the expression and intensity level (MFI) of these molecules on peripheral blood lymphocyte subpopulations from 23 healthy elderly subjects and 13 young controls. In the elderly a decrease in total peripheral blood lymphocytes bearing CD62L antigen was observed (39 +/- 13% vs 63 +/- 6% and 745 +/- 312/mm3 vs 1,393 +/- 407/mm3; p<0.001), whereas the numbers of lymphocytes expressing CD49d and CD50 antigens were comparable in aged and young subjects. In addition, CD50 and CD62L MFI values on total peripheral blood lymphocytes were higher in elderly than in young subjects (5.23 +/- 1.03 vs 4.18 +/- 0.44, p = 0.001 and 2.60 +/- 0.35 vs 2.21 +/- 0.40, p = 0.005 respectively) while the intensity expression of CD49d was unchanged. The percentages and absolute numbers of T and B lymphocytes expressing CD62L were decreased in elderly compared to young subjects (CD62L+CD3+: 43 +/- 15% vs 66 +/- 9% and 581 +/- 257/mm3 vs 1,028 +/- 418/mm3, p<0.001; CD62L+CD19+: 78 +/- 12% vs 90 +/- 4%, p < 0.005 and 103 +/- 64/mm3 vs 207 +/- 98, p < 0.001). A decrease in the proportion of CD62L bearing NK cells was also observed in the elderly (25 +/- 14% vs 46 +/- 24%, p<0.005), although their absolute number was unchanged. No significant differences were detected in the proportion of T, B and NK lymphocytes expressing CD49d and CD50 antigens and only the absolute numbers of B cells expressing these adhesion molecules were lower in elderly (CD49d+CD19+: 121 +/- 71/mm3 and CD50+CD19+: 107 +/- 73/mm3) compared to young donors (CD49d+CD19+: 248 +/- 112/mm3 and CD50+CD19+: 235 +/- 120/mm3, p < 0.001). Moreover, the intensity of adhesion molecule expression was differentially modulated in the elderly depending on the specific lymphocyte cell population considered. The densities of CD49d, CD50 and CD62L antigens on B and NK lymphocytes from the two age groups were not different; on the contrary, T lymphocytes from elderly donors exhibited increased CD49d (1.69 +/- 0.09 vs 1.62 +/- 0.07, p < 0.05), CD50 (4.98 +/- 1.16 vs 3.77 +/- 0.46, p < 0.001) and CD62L (2.26 +/- 0.38 vs 1.99 +/- 0.37, p < 0.05) MFI values compared to young donors.

Adult↗
PubMed1996

VCAM-1/alpha 4-integrin adhesion pathway: therapeutic target for allergic inflammatory disorders.

Lymphocyte recirculation and leukocyte extravasation involve a multistep process that is central to immune surveillance and the rapid response of white blood cells to sites of injury or infection. Interaction of vascular adhesion molecules (VCAM-1, ICAM-1, and selectins) with ligands on the leukocyte surface (integrins, carbohydrates, and mucin-like molecules) regulate diapedesis. The nature of an inflammatory stimulus ultimately determines the pattern of endothelial adhesion molecule expression and the avidity state of their counterreceptors, thus dictating to a large extent whether a subclass of leukocytes will play a dominant role in the immune response. Immunoglobulin superfamily member VCAM-1 recognizes alpha 4 beta 1 integrin, expressed on all leukocytes except neutrophils. Blockade or inhibition of VCAM-1/alpha 4 beta 1 interaction is expected to have therapeutic potential in treating various inflammatory disorders and autoimmune diseases since this adhesion pathway has a major influence on eosinophil, lymphocyte, and monocyte trafficking. This review summarizes some of the strategies that are currently used to selectively inhibit the VCAM-1/alpha 4 integrin pathway, including soluble VCAM-Ig fusion protein, peptide antagonists, antisense oligonucleotides, natural products, and neutralizing antibodies to VCAM-1 or alpha 4 integrin.

Animals↗
PubMed1999

A single backmutation in the human kIV framework of a previously unsuccessfully humanized antibody restores the binding activity and increases the secretion in cos cells.

Humanization of rodent mAbs by CDR-grafting (also called "reshaping") is now a standard procedure for reducing immunogenicity and recruiting human effector functions. However, the design of the humanized mAb can sometimes prove circuitous. Attempts were made to humanize L-25, a mouse antibody against the human alpha-4 integrin subunit using the usual protocols. Despite reaching eight backmutations in the light chain, it was not possible to recover the binding activity to the level of the chimeric. In an effort to restore the binding activity, an analysis of the human kappa IV acceptor frameworks was undertaken. This analysis highlighted the Asp at position 9 in framework 1, which although a common amino acid in human kappa IV frameworks, was an unusual residue in mouse kappa frameworks. Backmutating this position to the mouse amino acid completely restored the binding of the humanized antibody and as a by-product also increased the secretion levels in cos cells. Mutating position 9 to the consensus residue for human kappa I also restored the binding and secretion levels although not to the same extent. The resulting humanized antibody had a light chain with only a single backmutation to the mouse sequence.

Amino Acid Sequence↗
PubMed2000

Lymphocyte-endothelial cell adhesive interactions in lung immunity: lessons from the murine response to particulate antigen.

The adhesive interaction between lymphocytes and lung endothelial cells presents an attractive arena for the development of novel therapeutic agents to modify pathologic pulmonary immune responses. The conceptual basis for choosing molecular targets to modulate this adhesive interaction derives, in large part, from results of murine experimental model systems of the pulmonary immune response. This article reviews one such model, the response of primed C57BL/6 mice to the particulate antigen sheep erythrocytes. Novel data are presented on the effect of a blocking anti-alpha(4) integrin monoclonal antibody on lung leukocyte and lymphocyte subset accumulation after intratracheal (IT) antigen challenge. Results from this model system have indicated that lymphocytes may use either the endothelial selectins or alpha(4) integrin as independent pathways to initiate recruitment into the lungs.

Animals↗
PubMed2002

Age-related accumulation of memory cells in mouse Peyer's patches.

The development of memory cells seems to take place in the germinal centres, which are chronically present in Peyer's patches (PPs). We report here age-associated changes in the lymphocyte compartment and in the number of PPs of unimmunised mice. Mice 4 weeks old do not exhibit well constituted germinal centres, but just only 1 week later, the mice develop a normal germinal centre reaction, which is maintained until late ages (mice 30 weeks old), to decrease thereafter in older mice. In addition, we also show that memory cells accumulate in PPs in old mice, being the main population CD44(+) CD62L(-) CD49d(+) CD40(+) CD25(-) B cells. These data suggest that memory B cells tend to accumulate in PPs in ageing mice, even when the GC reaction has already decreased.

Aging↗
PubMed1999

Differentiation of a human eosinophilic leukemic cell line, EoL-1: characterization by the expression of cytokine receptors, adhesion molecules, CD95 and eosinophilic cationic protein (ECP).

Purification of enough eosinophils for the study of allergic inflammation is difficult because eosinophils comprise only a small percentage of circulating leucocytes. A human eosinophilic leukemic cell line, EoL-1, has been considered to be an in vitro eosinophilic model. In the present study, the suitability of EoL-1 cells as an eosinophilic model was further investigated. EoL-1 cells were induced to differentiate by dibutyryl cyclic AMP (dbcAMP). The expression of cell surface cytokines (IL-3, IL-5, GM-CSF) receptors, adhesion molecules (CD49d, CD11b), and CD95 (Fas) was investigated by flow cytometry. Expression of eosinophilic cationic protein (ECP) was determined by fluorescence enzyme immunoassay (FEIA) and reverse transcription-polymerase chain reaction (RT-PCR). EoL-1 cells could be differentiated into eosinophilic vacuole-containing cells by dbcAMP. They were found to express cell surface IL-3 and GM-CSF receptors, CD95 and CD49d. Treatment with dbcAMP could induce the expression of CD11b but decrease the expression of CD95. Anti-CD95 antibody could induce their apoptosis. The differentiation of EoL-1 cells was accompanied by increase in release of ECP into the supernatant and total ECP synthesis. Differentiation of EoL-1 cells also up-regulated the expression of mRNA for ECP and its level was parallel to the total amount of ECP synthesis. By virtue of their expression of haematopoietic cytokines receptors, adhesion molecules, CD95, synthesis and release of ECP, EoL-1 cells are suitable as an in vitro eosinophilic model for studying eosinophilic functions.

Antigens, CD↗
PubMed2000

CD4(+)CD45RO(+)CD49d(high) cells are involved in the pathogenesis of relapsing-remitting multiple sclerosis.

In the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis, encephalitogenic T cells differ from the non-encephalitogenic ones in their expression of CD49d. The disease-inducing CD49d(high) and not the CD49d(low) cells enter the brain parenchyma. In this context, we characterized CD4(+)(CD45RO(+))CD49d(high) cells in relapsing-remitting multiple sclerosis (RR-MS) patients. These cells, showing characteristics of activated cells able to produce pro-inflammatory cytokines, were found to be increased in peripheral blood during relapses and present in high numbers in cerebrospinal fluid. These results suggest that the CD4(+)CD45RO(+)CD49d(high) subpopulation in RR-MS patients includes autoreactive cells and may be target for immunotherapy.

Acute Disease↗
PubMed2001

CD1 expression is differentially regulated by microglia, macrophages and T cells in the central nervous system upon inflammation and demyelination.

Expression of CD1 by microglia, macrophages and T cells was investigated ex vivo. In the healthy central nervous system (CNS), resident microglia, macrophages and T cells express levels of CD1 significantly lower than that expressed by splenic macrophages and T cells. During experimental autoimmune encephalomyelitis (EAE), CD1 expression by microglia and the number of CD1+ microglia increase. Macrophages and T cells strongly upregulate CD1 expression in the CNS, but not in the spleen. Whereas the function of CD1 expressed by T cells remains unclear, the expression by microglia and macrophages provides the CNS with a (glyco)lipidic-presenting molecule in an inflammatory and demyelinating environment.

Animals↗
PubMed2003

Innate immune responses following emergency vaccination against foot-and-mouth disease virus in pigs.

Inactivated "emergency" foot-and-mouth disease virus (FMDV) vaccine of high potency will induce early protection against the disease, implying a critical role for innate immune defences. At 3 and 6 days post-vaccination (dpv), there was no evidence of vaccine-induced specific anti-FMDV antibodies (Abs), nor enhanced uptake and destruction of opsonised virus by macrophages. Sera from vaccinates and control animals showed similar capacity to neutralise the virus, and were not different from the pre-vaccination sera. There were also no distinguishable changes in the distribution of the different peripheral blood leucocyte (PBL) subpopulations. Nor was any vaccine-induced increase in production of acute phase proteins noted. In contrast, chemotaxis assays identified an increase in PBL migratory activity which was vaccine-related. Furthermore, sera from 3 days post-vaccination contained elevated chemotactic potential. These results demonstrate that enhanced chemotaxis of cells of the innate immune defences, could play an important role during the early protection induced by emergency FMDV vaccines.

Acute-Phase Proteins↗
PubMed1996

Hematopoiesis: wandering progenitor cells.

The generation of mice that are chimeric for expression of alpha 4 integrin has revealed a critical role for this adhesion molecule, specifically in postnatal lymphopoiesis.

Animals↗
PubMed2003

C5 is required for CD49d expression on neutrophils and VCAM expression on vascular endothelial cells following mesenteric ischemia/reperfusion.

Complement activation is critical in the development of local mucosal damage and inflammation as well as of remote organ injury after mesenteric ischemia/reperfusion. To further define the role of C5 activation in local and remote tissue injury, C5 deficient (C5(-/-)) and wild-type control (C5(+/+)) mice treated with an anti-C5 mAb were subjected to sham or ischemia followed by up to 4 h of reperfusion. The development of local (intestinal) and remote (lung) injury was associated with the expression of CD49d on the surface of circulating blood neutrophils and with VCAM on the endothelial cells of intestinal and lung vessels. Because CD49d heterodimerizes with integrin beta1 on the surface of neutrophils and can bind VCAM on the endothelium, we propose that complement activation causes organ damage by upregulating molecules that lead to inappropriate homing of neutrophils.

Animals↗
PubMed2003

C5a causes limited, polymorphonuclear cell-independent, mesenteric ischemia/reperfusion-induced injury.

C5 is critical in the development of local mucosal damage and inflammation as well as in the development of remote organ injury after mesenteric ischemia/reperfusion (IR). To define the role of C5a in tissue injury, we treated wild-type mice with a cyclic hexapeptide C5a receptor antagonist (C5aRa) and administered recombinant C5a to C5 deficient (C5(-/-)) mice subjected to mesenteric IR. We demonstrate that at 2-h postreperfusion, C5a administered to C5-/- mice during IR induces limited intestinal mucosal injury but failed to cause remote lung injury despite the fact that it upregulated adhesion molecule expression. C5aRa treatment of C5+/+ mice undergoing IR limited local injury and prevented distant organ injury. We conclude that although C5a can trigger certain components of the IR induced injury, other mediators such as C5b-9 and local factors are needed for the complete expression of IR tissue damage.

Animals↗
PubMed2002

Functional effects of eotaxin are selectively upregulated on IL-5 transgenic mouse eosinophils.

Synergistic interactions between cytokines, chemokines and adhesion molecules may facilitate the selective recruitment of eosinophils into sites of allergic inflammation. Ovalbumin-sensitized IL5TG mice responded to antigen challenge with robust airway eosinophilia 24 and 72 hr post-exposure. Adhesion molecule expression and functional responsiveness of immune cells derived from IL5TG mice to various inflammatory mediators were evaluated. IL5TG-derived eosinophils, but not neutrophils, expressed higher levels of CD49d and CD11b relative to WT. Functional responsiveness to eotaxin was increased in IL5TG eosinophils as demonstrated by a 10x increase in its potency in producing actin polymerization and 3x increase in CD11b upregulation relative to WT. These data are consistent with increased CCR3 expression on IL5TG eosinophils. Responsiveness of eosinophils to LTB4 or MIP-1alpha was similar between WT and IL-5TG mice. These data provide evidence of synergy between eosinophil-specific cytokines and chemokines that may promote accumulation of this cell type under conditions of allergic inflammation in vivo.

Adjuvants, Immunologic↗
PubMed2001

alpha(4) integrin-dependent eosinophil recruitment in allergic but not non-allergic inflammation.

1. Although anti-alpha(4) integrin mAbs reduce eosinophil accumulation in several models of allergic inflammation, it is not clear whether this occurs via a direct action to block eosinophil alpha(4) integrins or indirectly on another cell type. The role of alpha(4) integrins on the accumulation of (111)In-labelled eosinophils in allergic and non-allergic inflammation in guinea-pig skin was therefore investigated. 2. Intradermal injection of antigen in sensitized skin sites induced accumulation of (111)In-eosinophils that was reduced up to 70% by two anti-alpha(4) integrin mAbs. In contrast, accumulation of (111)In-eosinophils to intradermal chemoattractants was unaffected by the same mAbs. 3. Accumulation of (111)In-eosinophils in allergic and non-allergic conditions was partly inhibited by a low dose of an anti-beta(2) integrin mAb. In combination with anti-alpha(4) integrin mAb, responses were not further reduced suggesting that these adhesion pathways are not additive or synergic. 4. Pretreating skin sites with antiserum or contaminating LPS did not reveal an alpha(4) integrin dependent pathway for chemoattractant-induced (111)In-eosinophil accumulation. These data suggest that alpha(4) integrins are involved in the response to antigen in sensitized skin sites. 5. Pretreating (111)In-eosinophil with alpha(4) integrin mAb blocked their adhesion to fibronectin in vitro but did not inhibit their accumulation in allergic inflammation suggesting that the blocking effect in vivo was eosinophil independent. 6. These data support the concept that targeting alpha(4) integrins on cells other than eosinophils could control eosinophil accumulation and have therapeutic potential in allergic diseases such as asthma and atopic dermatitis.

Animals↗