Lack of adhesion molecules in testicular diffuse centroblastic and immunoblastic B cell lymphomas as a contributory factor in malignant behaviour

Diffuse large B-cell lymphoma of the testis is a rare tumour, often with disseminated disease. According to the Kiel Classification, these lymphomas are of centroblastic or immunoblastic type, corresponding in the Working Formulation to malignant lymphoma, large cell non-cleaved and large cell immunoblastic, respectively. Adhesive cell-cell and cell-matrix interactions are generally assumed to play an important part in the metastatic process, and to find clues to the highly malignant biological behaviour of this tumour we examined expression of integrins and other adhesion molecules on the tumour cells and the presence of matrix proteins. Few adhesion molecules appeared to be expressed. CD44 was expressed in 10/12 lymphomas, CD49f/VLA-6 was positive in 5/12 cases, and CD49d/VLA-4, CD54 and CD62L were detectable in a small number (2–3) of lymphomas. All other adhesion molecules were lacking. This expression pattern is suggestive of a high metastatic potential: the tumour cells seem to be poorly attached to the extracellular matrix, to each other and to other cells (CD54-, CD11a-, CD58-). The adhesion molecules expressed, CD44, CD49f/VLA-6 and CD49d/VLA-4, have been reported to play a part in dissemination, mediating intravasation (CD49f/VLA-6) and extravasation (CD44, CD49d/VLA-4). This profile of adhesion molecules may explain, at least in part, the specific biological behaviour of these lymphomas with early and rapid dissemination.     

Venular endothelium binding molecules CD44 and LECAM-1 in normal and malignant B-cell populations. A comparative study

Summary Lymphocytes leave the blood via post-capillary venules by binding initially to their specialized endothelium. CD44 is a 80–90 kDa hyaluronate-binding glycoprotein involved in binding to endothelium of high endothelial venules (HEV). LECAM-1 is a 75–85 kDa glycoprotein with lectin activity interacting with human peripheral lymph node vascular addressin (PNAd) on HEV. This immunohistochemical study shows that CD44 and LECAM-1 are essentially coordinately expressed on B-lymphocytes. The mode and level of CD44/ LECAM-1 expression dissect the peripheral B-cell development into stages that are closely linked to morphologically defined B-cell compartments. Although statistically correlated in B-cell leukaemias (p<0.0009) and extranodal B-cell lymphomas (p<0.003), expression of both molecules was less stringently coordinated in 127 B-cell neoplasms examined. B-cell chronic lymphocytic leukaemia, hairy cell leukaemia and mantle zone lymphoma were CD44/LECAM-1 positive, thus corresponding to their reactive counterparts. Correspondingly, follicular centre cell-derived lymphomas were devoid of both markers. Conversely, CD44 and LEC-AM-1 were infrequently detectable in extranodal malignant B-cell neoplasms, irrespective of their maturational state. Presence versus absence of CD44 and LECAM-1, alone or together, determined neither the leukaemic versus aleukaemic state nor the nodal versus extranodal tumour-forming phenotype of a B-cell tumour.     

Human intrathymic T cell differentiation

The human thymus develops early on in fetal gestation with morphologic maturity reached by the beginning of the second trimester. Endodermal epithelial tissue from the third pharyngeal pouch gives rise to TE3+ cortical thymic epithelium while ectodermal epithelial tissue from the third pharyngeal cleft invaginates and splits during development to give rise to A2B5/TE4+ medullary and subcapsular cortical thymic epithelium. Fetal liver CD7+ T cell precursors begin to colonize the thymus between 7 and 8 weeks of fetal gestation, followed by rapid expression on thymocytes of other T lineage surface molecules. Human thymic epithelial cells grown in vitro bind to mature and immature thymocytes via CD2 and CD11a/CD18 (LFA-1) molecules on thymocytes and by CD58 (LFA-3) and CD54 (ICAM-1) molecules on thymic epithelial cells. Thymic epithelial cells produce numerous cytokines including IL1, IL6, G-CSF, M-CSF, and GM-CSF--molecules that likely are important in various stages of thymocyte activation and differentiation. Thymocytes can be activated via several cell surface molecules including CD2, CD3/TCR, and CD28 molecules. Finally, CD7+ CD4-CD8- CD3- thymocytes give rise to T cells of both the TCRab+ and TCR gd+ lineages.     

Modulation of intercellular adhesion molecule 1 (ICAM-1) expression on the human mast-cell line (HMC)-1 by inflammatory mediators

The effect of inflammatory mediators on the expression of several surface adhesion molecules on the human mast-cell line (HMC)-1 was studied. By flow cytometry, it could be shown that among several surface adhesion molecules (ICAM-UCDS4, VLA-4/CD49d, Mac-UCD11b, LFA-1/CD11a, LFA-2/CD2, LFA-3/CDS8, VCAM-1), only the constitutively expressed immunoglobulin family member intercellular adhesion molecule-1 (ICAM-1) is modulated by proinflammatory cytokines on HMC-1 mast cells. Stimulation with tumor necrosis factor-a (TNF-α) and interferon-γ (IFN-γ) resulted, in addition to interleukin-(lL-)4, in selective upregulation of ICAM-1 expression. Costimulation of either IL-4 or IFN-γ with TNF-α further increased the ICAM-1 expression as compared to the stimuli alone. In contrast, stem-cell factor (SCF), granulocyte/macrophage colonystimulating factor (GM-CSF), IL-10, IL-8, monocyte chemotactic and activating factor (MCAF), and the complement split product C5a failed to modulate the expression of any adhesion molecule examined. The levels of cytoplasmic free calcium in HMC-1 mast cells were not altered by cross-linking surface ICAM-1, suggesting linkage of other intracellular signaling pathways. This cytokine-induced upregulation of ICAM-1 expression might reveal a putative regulatory mechanism of mast-cell interaction with effector cells bearing the counterparts of ICAM-1 (CD54), the molecules Mac-1 (CD11b/CD18) and leukosialin (CD43), and the principal ligand LFA-1 (CD11a/CD18).     

Differential expression of cell adhesion molecules in the functional compartments of lymph nodes and tonsils

Aims—To analyse the topographical distribution of adhesion molecules involved in lymphocyte recirculation in human lymph nodes and tonsils. The study focused on the expression of LECAM-1 (CD62L), VLA-α4 (CD49d), VLA-β1 (CD29), LFA-1 αL (CD11a), LFA-β2 (CD18), VCAM-1 (CD106), ICAM-1 (CD54), and H-CAM (CD44).     

Contribution of CD11a/CD18, CD11b/CD18, ICAM-1 (CD54) and −2 (CD102) to human monocyte migration through endothelium and connective tissue fibroblast barriers

Recently we reported that monocyte migration through a barrier of human synovial fibroblasts (HSF) is mediated by the CD11/CD18 (β₂) integrins, and the β₁ integrins VLA-4 and VLA-5 on monocytes. Here we investigated in parallel the role of β₂ integrin family members, LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) on monocytes, and the immunoglobulin supergene family members, ICAM-1 and ICAM-2 on HSF and on human umbilical vein endothelial cells (HUVEC), in monocyte migration through HSF and HUVEC monolayers. Using function blocking monoclonal antibodies (mAb), when both VLA-4 and VLA-5 on monocytes were blocked, treatment of monocytes with mAb to both LFA-1 and to Mac-1 completely inhibited monocyte migration across HSF barriers, although blocking either of these β₂ integrins alone had no effect on migration, even when VLA-4 and VLA-5 were blocked. This indicates that optimal β₂ integrin-dependent monocyte migration in synovial connective tissue may be mediated by either LFA-1 or Mac-1. Both ICAM-1 and ICAM-2 were constitutively expressed on HSF and on HUVEC, although ICAM-2 was only minimally expressed on HSF. Based on results of mAb blockade, ICAM-1 appeared to be the major ligand for LFA-1-dependent migration through the HSF. In contrast, both ICAM-1 and ICAM-2 mediated LFA-1-dependent monocyte migration through HUVEC. However, neither ICAM-1 nor ICAM-2 was required for Mac-1-dependent monocyte migration through either cell barrier, indicating that Mac-1 can utilize ligands distinct from ICAM-1 and ICAM-2 on HSF and on HUVEC during monocyte transmigration.     

Integrins and other adhesion molecules on lymphocytes from synovial fluid and peripheral blood of rheumatoid arthritis patients.

Cell and matrix adhesion of lymphocytes participates in homing, migration and accumulation of these cells in inflamed tissues as well as in the generation of immune and inflammatory responses. In inflamed joints of rheumatoid arthritis (RA) patients, lymphocytes accumulate in the synovial membrane and the synovial fluid. In the present study we have analyzed the expression of integrins and other adhesion molecules in synovial fluid lymphocytes (RA-SFL) and paired peripheral blood lymphocytes (RA-PBL) from 21 RA patients by immunofluorescence flow cytometry. We have also investigated the expression of these adhesion molecules on peripheral blood lymphocytes obtained from 13 sex- and age-matched healthy controls (CO-PBL). RA-SFL, which consisted mostly of T cells, showed higher expression of the integrin subunits beta 1 (CD29), VLA-1 alpha, -3 alpha, -4 alpha, -5 alpha and -6 alpha when compared to RA-PBL. In turn, RA-PBL showed lower expression of these molecules than CO-PBL. The expression of the immunoglobulin-related molecules CD2, CD54 (ICAM-1) and CD58 (LFA-3) was higher on RA-SFL when compared to RA-PBL or CO-PBL, and similar results were obtained with the beta 2 integrin subunits CD11a and CD18. In contrast, L-selectin (LECAM-1) and ICAM-2 were expressed at much lower levels on RA-SFL than on RA-PBL or CO-PBL. CD44, a receptor for hyaluronic acid and collagen, was expressed by most RA-SFL, RA-PBL and CO-PBL cells but at higher density on RA-SFL. The results indicate that RA-SFL express a distinct array of adhesion molecules, similar to the one of memory T lymphocytes. This characteristic phenotype may contribute to the lymphocytic infiltration of the synovium and to the pathogenesis of RA.     

Monoclonal antibodies to the murine VLA-6 alpha-chain trigger homotypic lymphocyte aggregation.

Very Late Antigen-6 (VLA-6) is a laminin receptor found on T cells, macrophages and platelets and may function as an activation antigen. Here we describe that two monoclonal antibodies (mAb) targeting the VLA-6 alpha-chain are capable of inducing homotypic aggregation of murine T-cell lines (3A9 and C10 cells). 3A9 and C10 cells are of the memory phenotype (CD4+, CD8-, CD44+, CD45+) and express VLA-6 abundantly. The VLA-6-induced aggregation is temperature dependent, energy requiring, and involves the cytoskeleton. In addition, divalent cations (Ca2+ and Mg2+) are also necessary for aggregation. The VLA-6-induced aggregation is not inhibited with mAb targeting the LFA-1/ICAM-1, VLA-4/VCAM-1 and CD2/LFA-3 adhesion pairs. We conclude that VLA-6 has a broader function and can serve as an activation molecule, triggering homotypic aggregation of T-cell subsets.     

Distribution of LCA protein subspecies and the cellular adhesion molecules LFA-1, ICAM-1 and p150,95 within human foetal thymus

The distribution of leucocyte common antigen (LCA) protein subspecies and the cellular adhesion molecules LFA-1 (CD11a), ICAM-1 (CD54) and p150,95 (CD11c) has been established within frozen sections of human foetal thymus. Whereas over 95% of foetal cortical thymocytes and approximately 85% of medullary thymocytes were CD45RO positive, CD45RA was only expressed by approximately 29% of medullary thymocytes. The majority of foetal thymocytes also expressed CD11a, whereas CD54 was expressed by thymic epithelial and accessory cells and also apparently by some cortical thymocytes adjacent to epithelial cells. The distribution of CD54 and the major histocompatibility complex (MHC) class II molecule HLA-DR, demonstrated with a monoclonal antibody to a monomorphic determinant, was similar. The CD11c molecule was present on a population of dendritic-type accessory cells, but was absent from the large, scavenger, KiM8-positive macrophages occurring throughout the thymic cortex.     

Only dull CD3+ thymocytes bind to thymic epithelial cells. The binding is elicited by both CD2/LFA-3 and LFA-1/ICAM-1 interactions

In view of the necessity for thymocytes to interact with thymic epithelial cells to differentiate into mature T cells, this study analyzed the binding between human thymocytes, cultured thymic epithelial cells (CTEC) and the required adhesion molecules. Immediately after separation, thymic epithelial cells (TEC) readily expressed ICAM-1, which is one of the ligands of LFA-1 cell adhesion molecules. However, the ICAM-1 expression was gradually lost upon culture of TEC. IFN-gamma re-induced ICAM-1 on the CTEC, and the ability of CTEC to bind to thymocytes was also increased by IFN-gamma treatment. The increase in binding seemed to be caused by the LFA-1/ICAM-1 interaction, since it was inhibited by anti-ICAM-1 monoclonal antibody (mAb) and anti-LFA-1 mAb. This suggests that the LFA-1/ICAM-1 interaction is also involved in vivo with the binding of thymocytes to TEC, which have been shown to express ICAM-1. To better understand the nature of the cells involved in binding, thymocytes were sorted into CD3-, CD3dull+, and CD3bright+ subsets (which are supposed to represent the immature, intermediate and mature stages of differentiation, respectively), and were examined for their binding to IFN-gamma-treated CTEC. The result showed that only the CD3dull+ subset bound to CTEC. CD3-, CD3bright+ cells and peripheral blood T lymphocytes did not bind, but they were induced to bind by neuramidase treatment All these bindings were inhibited by anti-LFA-1 mAb and anti-CD2 mAb. These findings indicate that CD3dull+ cells can bind to TEC via CD2/LFA-3 and LFA-1/ICAM-1 interactions. Other cells seemed not to bind to TEC because of sialylation.     

Role of LFA-1, ICAM-1, VLA-4 and VCAM-1 in lymphocyte migration across retinal pigment epithelial monolayers in vitro.

The blood-retinal barrier (BRB), which is composed of the retinal pigment epithelium (RPE) and retinal vascular endothelium, normally restricts the traffic of lymphocytes into the retina. During ocular inflammatory conditions such as posterior uveitis there is a large increase in lymphocyte migration across the BRB. The differential role played by the two barrier sites, however, remains unclear. To evaluate the role of the posterior BRB, the migration of CD4+ antigen-specific T-cell line through rat RPE cell monolayers was investigated in vitro using time-lapse videomicroscopy. The adhesion molecules involved in controlling transepithelial migration across normal and interferon-gamma (IFN-gamma)-activated RPE was assessed with monoclonal antibodies directed against cell adhesion molecules. Lymphocytes were treated with antibodies specific for CD11a (alpha L subunit of LFA-1), CD18 (beta 2 subnit of the leucam family) and CD49 d (alpha 4 subnit of very late activation antigen-4, VLA-4), and the RPE with antibodies specific for CD54 (intracellular adhesion molecule-1, ICAM-1) and CD 106 (vascular cell adhesion molecule-1, VCAM-1). Migration across unstimulated RPE was inhibited by antibodies to ICAM-1 (48.6 +/- 3.5% reduction), leucocyte functional antigen-1 (LFA-1) alpha (61 +/- 5.2%) and LFA-1 beta (63.2 +/- 4.7%), but not by antibodies to VLA-4. VCAM-1 was not expressed on untreated RPE. Following activation of the RPE monolayers for 72 hr with IFN-gamma, antibodies to LFA-1 alpha, LFA-1 beta and ICAM-1 inhibited migration by 49.9 +/- 9.4%, 63.6 +/- 5.5% and 47.7 +/- 4.2% respectively. Antibodies to VLA-4 and VCAM-1 blocked migration by 21.5 +/- 8.4% and 32.3 +/- 6.2%, respectively, which correlated with the induction of VCAM-1 expression on RPE and increased migration. Under these conditions blocking both VCAM-1 and ICAM-1 reduced migration by 70.9 +/- 2.3%, which was greater than the effect of blocking either of these molecules alone. These results demonstrate that the posterior barrier of the BRB utilizes the same principle receptor-ligand pairings in controlling lymphocyte traffic into the retina as the vascular endothelium of the anterior BRB.     

Identical expression of ELAM-1, VCAM-1, and ICAM-1 in sarcoidosis and usual interstitial pneumonitis

Extravasation of leucocytes in tissues is mediated by leucocyte—endothelial cell interactions in which adhesion molecules play an important role. Until now, two pathways have been unravelled, i.e., the LFA-1/ICAM-1 and the VLA-4/VCAM-1 pathways. ELAM-1 has been shown to be involved in granulocyte accumulation and recently also in lymphocyte migration. The role of HECA-452 is under investigation. In this study we have investigated the expression of the above-mentioned adhesion molecules in lung tissue of patients with pulmonary sarcoidosis and usual interstitial pneumonitis (UIP), and in mediastinal lymph nodes of patients with sarcoidosis. ICAM-1 (CD54) was broadly distributed on the endothelium of all the vessels found in sarcoidosis and UIP. VCAM-1 was present on the endothelium of the venules, capillaries, and arterioles in both sarcoidosis and UIP. ELAM-1 reacted with endothelial cells lining venules and capillaries in chronic progressive sarcoidosis and in the active phase of UIP but not in the stationary phases of both diseases. HECA-452 activity could be detected only on high endothelial venules within sarcoid lymph nodes. In lung tissues, macrophages bearing the ICAM-1 antigen were present in sarcoid tissue but not in the interstitium and alveolar space of UIP. LFA-1 (CD11a/CD18) and VLA-4 (CD49d/CD29) were present on all leucocytes found but seemed to be more highly expressed on lymphocytes in sarcoidosis. These findings suggest that the LFA-1/ICAM-1 and VLA-4/VCAM-1 pathways are involved in leucocyte migration in both types of lung disease, while in the active phases of sarcoidosis and UIP, ELAM-1 is also involved.     

Interactions between epithelial cells and T lymphocytes: role of adhesion molecules

Cell-cell interaction is critical for normal T cell development and function. A number of adhesion molecules important in T cell interactions with other cell types have been defined. This paper reviews the role of two adhesion pathways, CD2/LFA-3 and LFA-1/ICAM-1, in T cell interactions with epithelial cells of the thymus and skin. While thymic epithelium-T cell interactions are mediated by both the LFA-1/ICAM-1 pathway and the CD2/LFA-3 pathway, epidermal-T cell interactions are mediated primarily by the LFA-1/ICAM-1 pathway. Although ICAM-1 is not expressed in vivo on epidermal keratinocytes in normal skin, ICAM-1 is expressed by epidermal keratinocytes at the site of T cell infiltration in inflammatory dermatitis. ICAM-1 is expressed in vivo on thymic epithelium. These antigen independent adhesion molecules play an important role in the cell-cell interactions associated with T cell differentiation and function.     

T-lymphocyte responsiveness in murine schistosomiasis mansoni is dependent upon the adhesion molecules intercellular adhesion molecule-1, lymphocyte function-associated antigen-1, and very late antigen-4.

Granuloma formation in murine schistosomiasis is dependent on CD4+ Th lymphocytes and requires recruitment and accumulation of inflammatory cells at the site of egg deposition. The present study examined the role of three adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), lymphocyte function-associated antigen-1 (LFA-1), and very late antigen-4 (VLA-4), that participate in cellular recruitment, interaction, and lymphocyte activation during in vitro activation of acutely and chronically infected spleen and liver granuloma lymphocytes. Blockade of ICAM-1, LFA-1, or VLA-4 by rat monoclonal antibody inhibited spleen and granuloma lymphocyte interleukin-2 (IL-2) and IL-4 production as well as lymphoproliferative responses at similar levels (66 to 87%). The down-modulated cytokine and proliferative responses of chronically infected lymphocytes were inhibited to the same extent as their acutely infected counterparts. Cell sorting analysis demonstrated that acutely and chronically infected splenic and granuloma lymphocytes expressed similar levels of LFA-1, ICAM-1, and VLA-4 and that more ICAM-1 was expressed on infected than on uninfected mouse lymphocytes. By exposure of cells to paired monoclonal antibodies at suboptimal doses, it was determined that whereas all three adhesion molecules may participate, only ICAM-1 and LFA-1 showed synergistic interactions in determining lymphocyte responsiveness. These data suggest that spleen and liver granuloma lymphocytes are equally well armed with functional adhesion receptors. Thus, ICAM-1, LFA-1, and VLA-4 play an important accessory role in inflammatory cytokine production and lymphocyte proliferation, and therefore these adhesion molecules may participate in the initiation and maintenance of the granulomatous inflammation.     

Adhesion molecules utilized in binding of intraepithelial lymphocytes to human enterocytes

The expression of adhesion molecules by human duodenal intraepithelial lymphocytes (IEL) was examined by two-color flow cytometry. Resting IEL expressed LFA-1, HML-1, CD44. Stimulation with phytohemagglutinin (PHA) resulted in down-regulation of expression of these molecules with induction of expression of ICAM-1 and VLA-4. VLA-4 expression was also found on non-activated IEL from patients with celiac disease. In addition, IEL expressed an antigen recognized by a novel monoclonal antibody D2.1. The molecular mass of D2.1 is heterogenous: 82 kDa in peripheral blood lymphocytes and 44 kDa in an IEL line. Expression of this antigen was also up-regulated by PHA. To determine the involvement of these antigens in binding of IEL to human enterocytes, we developed a system based on adherence of an IEL cell line to the I407 fetal intestinal cell line. Monoclonal antibodies VLA-4, D2.1 and to a lesser extent ICAM-1 blocked adherence of IEL to I407 cells. These data suggest that VLA-4 and D2.1 may be involved in adherence of IEL to human enterocytes or secreted matrix molecules in vivo.     

Role of β2 Integrins in the Binding of Thymocytes to Rat Thymic Macrophages

A role of β2 integrins and one of their ligands, ICAM-1, in thymic macrophage (TMF)/thymocyte interactions was studied. TMF were isolated as adherent cells from 4-day old culture of thymic-cell suspensions either from normal or hydrocortisone-treated rats. Adherent cells were 94-98% positive with ED1 (a pan-macrophage marker). The majority of them (75-95%) expressed the CD11b and CD18 molecules, and 60-70% expressed CD54 (ICAM-1). A low proportion of TMF (10-20%) expressed CDlla (LFA-1). The expression of all these antigens was upregulated by IFN-α and TNF-α. The effect of these mAbs on TMF/thymocyte binding was studied using a simple rosette assay by incubating unstimulated or IFN-γ or TNF-α stimulated TMF, grown on microscopic slides with resting or ConA +IL-2 activated thymocytes. It was found that LFA-1/CD18 and ICAM-1 play a significant role in the TMF/thymocyte adhesion. In addition, a LFA-l-dependent/ICAM- 1-independent adhesion pathway was observed, suggesting that LFA-1 might use another ligand. The inhibitory effect of anti-CD18 mAb (WT-3) was higher than the effect of anti-LFA-1 mAb (WT-1) and was a consequence of blocking the CD18 chain both on thymocytes and TMF. No significant difference in the expression and function of adhesion molecules was found between TMF obtained from normal or hydrocortisone-treated rats. The involvement of CD1 1b in these processes was of lesser importance than the role of the CD11a molecule. By using mAbs to different epitopes of the CD11b molecule, such as OX-42 (anti-CD11b/CD11c), ED7, and ED8 (anti-CD11b), it was found that they were either slightly or moderately inhibitory under certain experimental conditions or did not significantly modulate TMF/thymocyte binding. Oχ-42 was slightly stimulatory in some experiments. Cumulatively, these results show that 2 integrins play a significant role in TMF/thymocyte interactions and probably contribute to T-cell development in vivo.     

Adhesion receptors involved in clustering of blood dendritic cells and T lymphocytes.

The relationship of dendritic cells (DC) isolated from the peripheral blood to those of lymphoid tissue is, in terms of maturation and function, incompletely understood. In our present study, we have explored the molecular basis of adhesion of T cells to blood DC. Analysis of the expression of adhesion receptors on the cell surface of blood DC revealed that these cells express lymphocyte function-associated antigen (LFA)-1 (CD11a/18), ICAM-1 (CD54), LFA-3 (CD58) and CD44, but are very late antigen (VLA)-4 (CD49d) and vascular cell-adhesion molecule (VCAM)-1 negative. The LFA-1 pathway was found to play a key role in T cells-blood DC adhesion; monoclonal antibodies (mAb) against both LFA-1 and ICAM-1 strongly inhibited adhesion between those cells. Moreover, a T cell clone from an LFA-1-deficient patient showed poor binding to blood DC. The important role of LFA-1 in T cell-blood DC adhesion was also supported by the metabolic energy and divalent cation dependence of the interaction. mAb against LFA-3 and CD2 did not inhibit T cell-blood DC binding. In contrast to the strong inhibition by antibodies to LFA-1 and ICAM-1, antibodies to CD44 enhanced conjugate formation between T cells and blood DC. Together, our results show that the LFA-1/ICAM-1 pathway plays a central role in T cell-blood DC adhesion, a situation like that in T cell adhesion to lymphoid DC. However, unlike lymphoid DC, blood DC do not express VCAM-1 nor use LFA-3 for T cell binding.     

Role of beta 1-integrins in epidermotropism of malignant T cells.

To better understand the molecular mechanisms of epidermotropism, we immunohistochemically analyzed the expression pattern of adhesion molecules belonging to the integrin and immunoglobulin superfamilies in cases of mycosis fungoides (MF) (n = 15), pleomorphic T cell lymphoma (n = 10), and high-grade T cell lymphoma (n = 7). The cutaneous T cell lymphomas (CTCLs) investigated were categorized into cases with or without epidermotropism. Focal neoexpression of ICAM-1 on keratinocytes was restricted to epidermotropic lymphomas. Both LFA-1 and LFA-3 were expressed on infiltrating cells in all cases investigated. In contrast, beta 1-integrins showed differential expression, most prominent in the case of VLA-1 and VLA-6: These molecules were present on infiltrating cells in most cases with epidermotropic MF and absent in most other CTCLs. We conclude that the phenomenon of epidermotropism might involve different sets of adhesion molecules in different entities of CTCL, with VLA-1 being the most influential beta 1-integrin in the case of MF.     

Role of leukocyte adhesion molecules in lung and dermal vascular injury after thermal trauma of skin.

Acute second degree thermal injury of rat skin involving 25 to 30% total body surface of anesthetized rats results at 4 hours in evidence of vascular injury both locally (in skin) and remotely (involving lung). The neutrophil dependency for both types of injury has now been established. Monoclonal antibodies to various adhesion molecules have been used to define the requirements for these molecules in the development of vascular injury. In dermal vascular injury, a requirement for Mac-1 (CD11b/CD18) but not for leukocyte function-associated antigen-1 (LFA-1, CD11a/CD18) has been established. In this model requirements have also been demonstrated for intercellular adhesion molecule-1 (ICAM-1) and E- and L-selectin but not for very late arising antigen-4 (VLA-4) or P-selectin. With respect to lung vascular injury, dual requirements for both leukocyte function-associated antigen-1 and Mac-1 were found as well as for ICAM-1 and E- and L-selectin but not for VLA-4 and P-selectin. In the lung, there was a close correlation between neutrophil content of the tissue (as assessed by myeloperoxidase) and the effects of protective interventions (directed against blocking of adhesion molecules). These data emphasize the roles of beta 2 integrins, selectins (L and E), and ICAM-1 in events that lead to neutrophil-mediated vascular injury of dermis and lung after thermal trauma to skin.