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At least 559 records · Page 31Linked to original sources
PubMed2006

A scoring system based on the expression of six surface molecules allows the identification of three prognostic risk groups in B-cell chronic lymphocytic leukemia.

We have previously identified 12 surface antigens whose differential expression represented the signature of B-cell chronic lymphocytic leukemia (B-CLL) subsets with different prognosis. In the present study, expression data for these antigens, as determined in 137 B-CLL cases, all with survivals, were utilized to devise a comprehensive immunophenotypic scoring system of prognostic relevance for B-CLL patients. In particular, univariate z score was employed to identify the markers with greater prognostic impact, while maximally selected log-rank statistics were chosen to define the optimal cut-off points capable to split patients into two groups with different survivals. A weighted immunophenotypic scoring system was developed by integrating results from these analyses. Six antigens were selected: three positive prognosticators (CD62L, CD54, CD49c) and three negative prognosticators (CD49d, CD38, CD79b), with cut-off values ranging from 30% to 50% of positive cells. By weighing the expression of each marker according to its statistical power, a complete scoring system, with point values comprised between 0 (complete absence of phenotypic conditions associated with good prognosis) and 9 (all the phenotypic conditions associated with good prognosis fulfilled), allowed to split the whole set of B-CLL patients, into three distinctive prognostic groups (P = 4.78 x 10(-11)) with high- (score 0-3), intermediate- (score 4-6), and low- (score 7-9) risk of death. The three risk groups showed different distribution of cases as for Rai's stages, IgVH mutations, and ZAP-70 expression. The proposed immunophenotypic scoring system may be an additional useful tool in routine diagnostic/prognostic procedures for B-CLL.

ADP-ribosyl Cyclase 1↗
PubMed2000

Homing and adhesion molecules in autoimmune gastritis.

The pathogenesis of autoimmune gastritis is the result of lymphocyte infiltration of the gastric mucosa, however, the events leading to the selective extravasation of autoreactive lymphocytes are unclear. Here we have examined the expression of adhesion molecules in the gastric mucosa of BALB/c mice with neonatal thymectomy-induced gastritis. The overall area of vascular endothelium was not significantly different between gastritic and non-gastritic mice. However, a significant increase in the area of mucosal endothelium expressing MAdCAM-1 in gastritic mice was observed. Treatment of neonatally thymectomized BALB/c mice with a MAdCAM-1 specific monoclonal antibody (MECA 367) reduced the incidence of autoimmune gastritis from 80 to 26%. Treatment with a monoclonal antibody (R1-2) directed to the MAdCAM-1 ligand, alpha4beta7, also resulted in a reduction in the incidence of gastritis to 40%. These findings identify the alpha4beta7/MAdCAM-I interaction as a pivotal event in the initiation of autoimmune gastritis.

Animals↗
PubMedDate not supplied

A monoclonal antibody to alpha 4-integrin reverses the MR-detectable signs of experimental allergic encephalomyelitis in the guinea pig.

Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the CNS characterized by blood-brain barrier breakdown, cerebral edema formation, lymphocyte infiltration, and demyelination, and is used as an animal model of multiple sclerosis (MS). MR imaging is important for the diagnosis of MS and for the evaluation of potential new therapies. In this study, T2-weighted and T1-weighted contrast-enhanced MR imaging was used to evaluate the effectiveness of an antiadhesion therapy in EAE. Leukocyte-endothelial adhesion at the blood-brain barrier is considered an essential step in the mediation of CNS leukocyte infiltration in EAE. AN100226m, a monoclonal antibody to alpha 4 integrin has been previously shown to reverse the clinical and histologic signs of EAE by blocking this interaction. In the present study, AN100226m treatment in acute EAE significantly decreased contrast enhancement of the CNS parenchyma indicating closure of the blood-brain barrier. The percentage of pixels due to leakage of contrast material in T1-weighted images decreased to < 4% in AN100226m-treated animals whereas it was increased to 15% in control animals (P < .05, Mann-Whitney rank sum test). A decrease in CNS abnormalities associated with cerebral edema and inflammation was also observed on T2-weighted images (P < .05, Mann-Whitney rank sum test). Thus, an antibody to alpha 4 integrin reversed the blood-brain barrier permeability changes characteristic of acute EAE. In addition, the further accumulation of inflammatory edema was prevented and preexisting edema was resolved.

Animals↗
PubMed1995

A regulatory element in the 5'UTR directs cell-specific expression of the mouse alpha 4 gene.

Transfection experiments showed that the mouse alpha 4 promoter contains a downstream element in its 5'UTR which is essential for efficient promoter activity. DNaseI footprinting and electrophoretic mobility shift assays (EMSA) demonstrated that the region from nt +113 to +148 can bind a cell type-specific factor (MIII-3) present in the alpha 4m expressing cell line L1210 but not in the non-expressing cell lines A9 and LMTK. Two consensus SP1 sites in this 5'UTR were recognised in L1210, A9 and LMTK, and with extracts from A9 and LMTK, an AP2-like protein was shown to bind a downstream AP2 site. Thus both ubiquitous and cell type-specific factors regulate the expression of alpha 4m.

Animals↗
PubMed1998

Differential regulation of rejection of small intestinal and skin allografts in rats by injection of antibodies to ICAM-1 or the integrins alpha 4, alpha L, or beta 2.

Female Lewis (LEW) rats received orthotopic small intestinal transplantation (SIT), or tail skin grafts from female (Lewis x Brown Norway)F1 (LBNF1) rats, along with peritransplant portal venous (pv) infusion of LBNF1 bone marrow-derived dendritic cells derived from male donors. All animals received im injection with cyclosporin A (5 mg/kg) for 3 consecutive days following transplantation. In some cases rats received intravenous injections, at 2-day intervals, with 1 mg of monoclonal antibodies to ICAM-1 or the integrins alpha 4, alpha L, or beta 2, or combinations of these reagents. Cells were harvested from the recipient rats at different times posttransplantation, and single cell suspensions were analyzed by FACS for expression of CD3+, CD4+, CD8+, alpha beta TcR+, and gamma delta TcR+ cells. Other tissue samples were used for histopathological assessment of rejection. We also investigated donor-specific and third-party (Wistar-Furth, Wi) restimulation of host lymphocytes from MLN, PLN, and PP for production of different cytokines in vitro. Of the various antibodies tested, only anti-alpha 4, but not anti-alpha L, -beta 2, nor -ICAM-1 led to further increased graft survival of LBNF1 SIT beyond that seen with pv-infused cells alone (30 days vs 19 days), while the combination of anti-alpha L (or beta 2) and ICAM-1 produced further significantly increased survival of skin grafts (30 days vs 21 days). For both SIT and skin-grafted animals increased graft survival was associated with decreased production of IL-2 and IFN-gamma and increased production of IL-4 and IL-10 from tissues local to the graft (PP and draining LN, respectively), with less significant alterations in tissues distant to the graft (PLN for SIT, and MLN for skin grafts). While, as reported previously, pv-immunized SIT rats showed increased gamma delta TCR+ cells within the SIT in association with increased graft survival, treatment with anti-alpha 4 diminished this increase in gamma delta TCR+ cells, while simultaneously increasing SIT survival. Nevertheless, the bias toward increased IL-10 production, and decreased IFN-gamma production, from cells of animals showing increased survival was maintained. These data suggest that local graft infiltration with gamma delta TCR+ cells following pv immunization is not necessary for prolongation of survival in this model system, although functional changes in the local cytokines milieu may be important.

Animals↗
PubMed1997

Different patterns of gamma delta and alpha beta T cell redistribution in the mouse after partial gastrectomy.

BACKGROUND: Stress, including surgical trauma, results in different dysfunctions of the body. In our former experiments on posttraumatic modification of immune response of gastrectomized mice we observed a significant suppression of contact sensitivity. This could be transferred by lymph nodes and spleen T lymphocytes of mice which underwent surgery. MATERIALS AND METHODS: We studied changes in gammadelta and alphabeta T cell numbers in peripheral blood, Peyer's patches, and mesenteric lymph nodes after partial gastrectomy (major operation) and after sham gastrectomy (laparotomy-minor operation) in mice. The number of gammadelta and alphabeta T cells was counted on the FACSTAR cell sorter before and 1, 2, 3, 7, and 14 days after surgery. RESULTS: In our observations there was a significant increase of percentage of gammadelta T cells both in Peyer's patches (1.9 +/- 0.5 to 10.5 +/- 0.3) and in mesenteric lymph nodes (2.7 +/- 0.7 to 8.8 +/- 3.5) on the third day after partial gastrectomy (546 and 322% of control values, respectively). In contrast in gastrectomized mice the number of alphabeta T cells in Peyer's patches (38.4 +/- 6.8 to 21.2 +/- 6.2) and lymph nodes (56.7 +/- 15 to 40.4 +/- 17) was decreased on day 3 (55 and 71% of control values, respectively). There was a decline in both alphabeta (18.1 +/- 8 to 8.2 +/- 1.7) and gammadelta (6.7 +/- 2.8 to 3.9 +/- 2) T cell numbers in peripheral blood on days 1, 3, and 7 (45 and 58% of normal values, respectively). Sham operation had no significant influence on alphabeta and gammadelta T cell numbers. We observed that after leg amputation the number of gammadelta T cells in mesenteric lymph nodes was significantly increased on day 3 (0.8 +/- 0.2 to 7.7 +/- 0.3), 770% of normal. In contrast to this, leg amputation had a negligible effect on T cell counts in Peyer's patches during all periods of observation. CONCLUSIONS: We suggest that the major surgical stress (partial gastrectomy) may disturb the normal cell traffic selectively with increased gammadelta T cell homing in intestinal Peyer's patches and lymph nodes (GALT) and with the cell displacement from peripheral blood to lymphatic organs. The severity and localization of stress may be crucial.

Animals↗
PubMed1998

The roles of alpha 4-integrins in the development of insulin-dependent diabetes mellitus.

Lymphocyte/endothelial adhesion followed by transendothelial migration is a key event in the development of organ-specific autoimmunity. Selective interactions of cell surface AM regulate lymphocyte migration under normal as well as pathologic inflammatory conditions. NOD mice are an ideal model for investigating the roles of AM in regulation of lymphocyte migration to target organs in autoimmune diseases such as IDDM. Both in vitro and in vivo studies in NOD mice strongly suggest that the mucosal (alpha 4 beta 7/MAdCAM-1) adhesion system and alpha 4-integrin/VCAM-1 appear to be prominent pathways for insulitis development. In contrast, alpha 4-mediated interactions in NOD inflamed salivary and lacrimal gland and in the inflamed CNS of rodents with EAE seem to be dominated by alpha 4-integrins and VCAM-1. The fact that blocking alpha 4-integrin pathways in NOD mice leads to successful interruption of the diabetogenic process suggests that AM provide a potential therapeutic target for human IDDM. Further studies on IDDM patients will prove helpful for understanding IDDM pathogenesis and in providing a basis for designing AM-based therapeutic approaches.

Animals↗
PubMed1998

alpha 4 integrins and tumor metastasis.

Taken together, alpha 4 integrins may influence metastatic process at various stages (Fig. 1). The detachment of tumor cells from the primary tumor and the invasion of the surrounding tissue represent the onset of tumor metastasis. There is good experimental evidence that at the primary tumor site expression of alpha 4 integrins inhibits the ability of melanoma cells to break loose. This could be achieved either by strengthening of homotypic adhesion to adjacent tumor cells or by down regulation of matrix metalloproteases that are required for tumor cell migration through the extracellular matrix. After entering the blood circulation, alpha 4 integrins on tumor cells derived from melanomas, sarcomas or lymphomas rather promote than inhibit accumulation of disseminated cells in distant organs. The positive effects of alpha 4 integrins at this stage of metastasis formation appear to depend on alpha 4 integrin interactions with ligands expressed on the surface of endothelial cells. While VCAM-1 is expressed on endothelial cells exposed to inflammatory cytokines, MAdCAM-1 is constitutively expressed on mucosal endothelium. In addition, it is conceivable that tumor cell aggregates trapped in the microcirculation may trigger local inflammatory reactions that result in VCAM-1 up-regulation. Tumor cell-bound alpha 4 integrins may strengthen adhesion to endothelium and promote trans-endothelial migration (HAUZENBERGER et al. 1997; MEERSCHAERT and FURIE 1994). Successful formation of new tumor colonies in distant organs is the final step in the metastatic cascade. Interestingly, alpha 4 integrin dependent mechanisms may either promote or inhibit this process. Thus, it was observed that alpha 4 integrins may direct cancer cells like CHO and lymphoma cells to organ compartments, where ligands for alpha 4 integrins are expressed (e.g., bone marrow). Depending on the tumor type this event may result in enhanced metastasis formation. However, as was documented for murine lymphoma cells alpha 4 integrins may also inhibit tumor cell growth either by inducing apoptosis or by reducing the proliferation rate. Based on numerous studies on human cancers and experimental tumor models, alpha 4 integrins may represent attractive target molecules for therapeutic manipulation of tumor cell behavior. To this end, however, it will be of great importance to precisely define the molecular basis for the adverse effects of alpha 4 integrins on metastasis formation.

Animals↗
PubMed1999

Effect of ligustrazine on expression of adherent molecule CD49d and cyclin D2 in hematopoietic cells in acute radiation injured mice.

After irradiation by 8.0 Gy gamma-ray, each mouse was stomach-fed by 4 mg ligustrazine injection twice a day. On the 7th day after irradiation, CD49d expression in ligustrazine-treated group was significantly higher than that in control group (P < 0.01), and showed no difference from that in normal group (P > 0.05). On the 14th day after irradiation. CD49d expression was increased in control group, but decreased significantly in ligustrazine-treated group (P < 0.01). The expression of Cyclin D2 in spleen mononuclear cells (MNC) in ligustrazine-treated group was significantly higher than that in control group, but the ratio of G0 + G1 phase cells was significantly lower in ligustrazine-treated group (P < 0.01). This finding indicated that ligustrazine could increase the expression of adherent molecule on bone marrow hematopoietic cells and Cyclin D2 in spleen MNC, thereby promoting the growth of hematopoietic cells.

Animals↗
PubMed1999

Expression of adherent molecule and cyclin by ligustrazine in bone marrow of mice with immune-induced aplastic anemia.

Mice with immune-induced aplastic anemia (AA) were given 5 mg ligustrazine intraperitoneally twice a day. On the 14th day, the expression of CD49d, CD49c, cyclinD2 in bone marrow mononuclear cells (MNC) was examined by flow cytometry, and VCAM-1 on stromal cells was immunohistochemically measured by Strept Avidin-Biotin Complex (SABC). The expression of CD49d, CD49c, VCAM-1 and cyclinD2 in ligustrazine-treated group was significantly higher than that in AA group (P < 0.01), but the ratio of G0 + G1 phase cells was significantly lower than that in AA group (P < 0.01). The results showed that ligustrazine could improve the expression of adherent molecule and cyclin D2 in the bone marrow of mice with immune-induced aplastic anemia, thereby promoting the growth of hematopoietic cells.

Anemia, Aplastic↗
PubMed2001

Differential cell adhesion molecule expression and lymphocyte mobilisation during prolonged aerobic exercise.

This study was undertaken to determine the cell adhesion molecule profile of CD4+, CD8hi and CD56+ lymphocytes, which are mobilised to and from the peripheral blood during and after prolonged aerobic exercise. Ten healthy males (21-35 years old) were tested on two occasions, separated by at least 14 days. On the first occasion, subjects were examined in a rested state but did not exercise. On the second occasion, the same subjects were examined at the same time of day before, during and after 2 h of exercise at 65% of peak oxygen consumption. Blood samples obtained at rest (t0), during (at 0.5, 1, 1.5 and 2 h, t0.5, t1, t1.5 and t2, respectively) and after (at 4 and 24 h, t4 and t24, respectively) exercise were analysed by two-colour flow cytometry for CD4+, CD8hi and CD56+ cell surface expression, and density of CD62L, CD49d and CD11a. At t2, circulating concentrations of CD56+, CD8hi and CD4+ lymphocytes had increased (P < 0.05) by 330%, 105% and 30%, respectively. The majority of CD4+, CD8hi and CD56+ lymphocytes mobilised to the blood at t2 were CD62L- and CD11ahi, although populations of CD4+ and CD56+ cells that expressed CD62L+ and CD11alo were also mobilised. Changes in subset concentrations at t0.5 were positively associated (r = 0.63; P < 0.01) with their corresponding mean surface density of CD11a at t0. Our findings suggest that the differential mobilisation of lymphocytes during prolonged aerobic exercise is linked to the surface expression of CD11a (i.e. lymphocyte-function-associated antigen-1). However, mechanisms unrelated to CD11a expression also appear to be involved.

Adult↗
PubMed2001

Comparison of processing four and five times the patients' blood volume during peripheral blood stem cell collection and analysis of CD34+38--and CD34+49d+ subsets during apheresis.

PURPOSE: We investigated whether increasing the patients' processed blood volume (BV) during peripheral blood stem cell collection (PBSCC) from four to five times leads to a greater yield of CD34+ cells. We also studied the kinetics of CD34+38- and CD34+49d+ subsets and compared the amount of transfused cells with engraftment. METHODS: All patients ( n=20) received chemotherapy followed by G-CSF for PBSC mobilization. Samples from the patients' peripheral blood and the PBSC harvests were taken after processing 1-, 4-, and 5 times the patients' calculated BV. RESULTS: The mean total yields of CD34+, CD34+38-, and CD34+49d+ cells were 15.69-, 1.13- and 4.17 x 10(6)/kg body weight, respectively. The mean increase for these subsets between 4- and 5 BV was 10%, 8%, and 21%, respectively. Based on the mean number of 2.25 (range 2-3) planned courses of high-dose chemotherapy (HDC) per patient, the mean yield of CD34+ cells per kg body weight and intended course of HDC after 4- and 5 BV was 6.31- and 6.97 x 10(6) ( P=0.014). Twenty HDC were evaluable for engraftment. There was some correlation between the number of transfused CD34+ and CD34+38- cells and WBC engraftment ( r = -0.66 and --0.69; P<0.01) and CD34+ cells and platelet engraftment ( r = -0.56; P= 0.013). No toxicity occurred during PBSCC, although the mean platelet count dropped by 50% which must be kept in mind regarding the additional application of anti-coagulants and the fact that most patients had large indwelling catheters. CONCLUSION: Processing 4 BV is sufficient to collect >5 x 10(6) CD34+ cells/kg body weight and intended course of HDC in most patients, although extension to 5 BV further increases the total yield of CD34+ cells.

ADP-ribosyl Cyclase↗
PubMed1999

Selective upregulation of MHC class I expression in metastatic colonies derived from tumor clones of a murine fibrosarcoma.

Eighteen metastatic nodes derived from the wild-type (GR9) and from 4 different clones (G2, D8, B10, and B9) obtained from a fibrosarcoma were analyzed for H-2 class I and II expression, as well as for adhesion molecules (CD44, CDIIb, CD18, CD49, and CD54). When metastatic nodes were cultured, typed for H-2 antigens, and compared with the H-2 expression of the inducing tumor cell, H-2 Kd and Dd class I expression was greater in most nodes analyzed. In contrast, the Ld molecule remained negative, or showed a minor increase. Class II expression was negative in the wild-type and the tumor clones, and remained so in the metastatic colonies. Analysis of the adhesion molecules revealed no differences between the inducing tumor cells and the metastatic nodes. The only molecule expressed was CD44, which was present in all cells studied and was also inducible by interferon-gamma. The increase in H-2K and H-2D expression was associated with resistance to natural killer cytotoxicity, as observed in the G2 tumor clone and some autologous metastases, such as B9MP2, G2MK2, and G2MLI. In three independent clones of this tumor system (D8, BIOMP6, and B9MP6) we found that tumor cells treated with interferon-gamma had the same altered phenotype, i.e., a selective lack of response of the Ld molecule to induction. These findings add a cautionary note to the well-established idea that tumor cells may lose all class I antigens during tumor progression, and suggest that sometimes this may not be the case. The selective downregulation of Ld and upregulation of Kd and Dd class I expression may give some tumor cells means of escaping both cytotoxic lymphocyte and natural killer immune surveillance.

Animals↗