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At least 307 records · Page 17Linked to original sources
PubMed2003

The CD44 receptor is a molecular predictor of survival in ovarian cancer.

PURPOSE: CD44 is a cell surface receptor implicated in cancer progression and metastases. Malignant tumors may show a loss of CD44 splice control mechanisms. We investigated the role of CD44 splice variant expression in ovarian tumors and metastases, and its association with survival. EXPERIMENTAL DESIGN: We tested CD44 expression in 142 cases of epithelial carcinoma of the ovary and 265 metastatic sites by immunohistochemistry. RESULTS: Survival analysis showed that the expression of CD44s, CD44-v4, -v5, -v6, -v9, and -v10 are significant predictors for survival in univariate analysis. After stage, the expression of CD44-v10 in metastases was the strongest predictor of decreased survival in multivariate analysis (p = 0.0009). Conversely, CD44-v10 expression in the primary tumor was an independent predictor of improved survival in multivariate analysis (p = 0.0002). The expression of CD44s in the tumor/stroma interface of the primary tumor was associated with improved survival (p < 0.0001). CONCLUSIONS: CD44 variant expression is a molecular prognostic maker for epithelial ovarian carcinomas. CD44-v10 expression is an independent prognostic indicator and the site of expression determines a positive or negative influence in survival. Our results also indicate that CD44 may be involved in important tumor/stroma interactions.

Adenocarcinoma, Mucinous↗
PubMed2005

Protection against renal ischemia reperfusion injury by CD44 disruption.

Inflammation contributes to renal ischemia reperfusion (I/R) injury, potentially causing renal dysfunction. The inflammatory infiltrate mainly consists of neutrophils, which are deleterious for the renal tissue. Because CD44 is expressed by neutrophils and is rapidly upregulated by capillary endothelial cells after I/R injury, it was hypothesized that CD44 might play an important role in the development of I/R injury. This study showed that rapid CD44 upregulation on renal capillary endothelial cells mediates neutrophil recruitment to the postischemic tissue. Hence, CD44 deficiency led to decreased influx of neutrophils regardless of comparable levels in chemotactic factors expressed in the kidney. The reduced influx of neutrophils was associated with preserved renal function and morphology. Adoptive transfer experiments of labeled neutrophils revealed that endothelial CD44 rather than neutrophil CD44 mediates neutrophil migration. Activation of neutrophils increased cell-surface expression of hyaluronic acid (HA). Altogether, a novel mechanism in the recruitment of neutrophils that involves interaction of endothelial CD44 and neutrophil HA was found. Either blocking endothelial CD44 or removal of neutrophil HA decreased rolling and adhesion of neutrophils. Administration of anti-CD44 to mice reduced the influx of neutrophils into the postischemic tissue, associated with renal function preservation. Therefore, anti-CD44-based therapies may contribute to prevent or reduce renal I/R injury.

Animals↗
PubMed1999

Serum CD44 in non-Hodgkin's lymphoma.

CD44 molecule is a cell surface glycoprotein involved in several cell-cell and cell-matrix interactions. It has been linked to the growth and spread of malignancies. The majority of non-Hodgkin's lymphomas (NHL) express CD44 reflecting the CD44 expression of the normal lymphocytic counterparts. Cell surface CD44 has been suggested to be involved in hematogenous distribution of NHL, and elevated levels of serum CD44 (s-CD44) have been detected in various malignant diseases. Circulating s-CD44 has been found to be functionally active according to several functional studies. In patients with NHL increased s-CD44 levels have been detected at the time of diagnosis and at progression of the disease and s-CD44 levels change in parallel with response to therapy. Moreover, a high s-CD44 level at diagnosis is associated with a high tumor burden, poor response to treatment and unfavorable outcome in NHL.

Biomarkers, Tumor↗
PubMed1999

Methylation of the CD44 metastasis suppressor gene in human prostate cancer.

Previous studies demonstrated that CD44 is a metastasis suppressor gene for prostate cancer and that the expression of CD44 both at mRNA and protein levels is down-regulated during prostate cancer progression, with down-regulation being correlated with higher tumor grade, aneuploidy, and distant metastasis. In this study, we evaluated DNA hypermethylation as a potential mechanism accompanying this decreased CD44 expression in human prostate cancer. Nucleotide sequence analysis revealed a CpG island in the CD44 transcriptional regulatory region. We found that cytosine methylation of CD44 promoter occurs in CD44-negative prostate cancer cell line (i.e., LNCaP) but not in prostate cancer cell lines (i.e., TSU, PC3, and DU145) expressing this gene. In addition, we examined methylation status of CD44 in 84 matched normal and cancer prostate specimens. Hypermethylation of the 5' CpG island of CD44 gene was observed in 31 of 40 primary prostate cancer specimens, 3 of 4 distant organ site metastases obtained at autopsy from men who died of prostate cancer, and 4 of the 40 matched normal tissues. These results demonstrated that methylation of the 5' CpG island of CD44 gene is closely associated with transcriptional inactivation, resulting in a decreased expression of CD44 in human prostate cancer.

Adenocarcinoma↗
PubMed2002

Expression of CD44 in human neoplastic and normal hyaline cartilage.

Although low-grade cartilage neoplasms typically consist of hyaline-like cartilage, most of them also contain some fibrocartilaginous regions. CD44, a cell surface receptor for hyaluronan, has been identified in cartilage. A family of alternatively spliced mRNA containing the variant 6 (v6) exon sequence of CD44 has been linked to several types of neoplasms. We hypothesized that expressions of v6-containing CD44 species are associated with fibrocartilaginous regions of low-grade cartilage neoplasms. To test this hypothesis we performed reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemical analysis on eight samples: four from normal articular cartilage, one from a synovial chondromatosis, and three chondrosarcomas which were graded as I and I/II. The standard CD44s and a unique v6-containing CD44 species (CD44v6-10) were identified in all tissue samples by RT-PCR analysis. Immunohistochemically, using an antibody that cross-reacted with all CD44 species, CD44 was localized to the cell surface, lacuna wall and intracellular compartment of the chondrocytes in the middle and deep zone of normal cartilage, as well as with cells throughout the neoplastic masses. Utilizing an antibody specific for v6-containing CD44 species, the variant species was identified throughout cells of the middle and deep zone of normal cartilage, and localized selectively to intracellular positions. In neoplastic masses, v6-containing CD44 species were found associated only with cells in the hyaline-like cartilage, but not in the fibrocartilaginous regions. Thus a differential expression of the v6-containing CD44 species in the neoplastic masses containing both hyaline-like cartilage and fibrocartilaginous regions was observed when compared to its homogenous expression in normal hyaline cartilage. An involvement between the lack of the variant CD44 (v6-containing) and altered tissue phenotype (e.g., fibrocartilaginous) is suggested.

Bone Neoplasms↗
PubMed1992

Mechanism of peripheral T cell activation by coengagement of CD44 and CD2.

A number of CD44 antibodies are known to augment peripheral T cell proliferation stimulated with suboptimal concentrations of activating pairs of CD2 mAb. These findings have implicated the CD44 adhesion receptor in the activation of peripheral T cells via CD2. We have investigated early events after CD44 and CD2 coengagement on peripheral T cells. CD44 and CD2 coengagement resulted in enhanced [Ca2+]i mobilization. However, the increase in [Ca2+]i mobilization did not occur until at least 3 min after CD2 and CD44 coengagement, suggesting that other events precede the elevation in [Ca2+]i. Using a T cell/fibroblast adhesion assay, we could demonstrate a dramatic increase in T cell adhesiveness after about 1 min after CD44 and CD2 coengagement. The increase in T cell adhesiveness was comparable to that induced by PMA. In the absence of antibodies or treatment with mAb directed to other T cell surface Ag, there was little if any adhesion between unstimulated peripheral T cells and fibroblasts. Enhancement of T cell adhesiveness through CD44 engagement was not mediated by a direct effect on lymphocyte-function associated Ag-3, the known ligand of CD2. However, cross-linking of CD44 resulted in epitopic modulation of CD2 as demonstrated by the increased expression of the T11(3) activation epitope. Furthermore, anti-CD44 could substitute for anti-T11(2) in the activation of peripheral T cells via CD2. These results suggest that CD44 ligation has profound effects on CD2-mediated events by inducing epitopic modulation of CD2.

Antigens, CD↗
PubMedDate not supplied

Evaluation of CD44 variant 6 expression and clinicopathological factors in pulmonary metastases from colon carcinoma.

Although relatively little is known about the molecular mechanisms underlying tumor progression, recently CD44 glycoproteins and the c-Met receptor tyrosine kinase have been identified as potentially important components of the metastatic cascade. CD44 is a family of transmembrane receptors generated from a single gene by alternative splicing and differential glycosylation. Important biological processes involving CD44 glycoproteins include cell adhesion, lymphocyte homing, hematopoiesis, tumor progression and metastasis. The precise mechanism via which CD44 promotes tumorigenesis have not yet been elucidated. We evaluated the expression of adhesion molecule CD44 variant 6 in pulmonary metastases from colorectal carcinomas and its correlation with clinicopathological parameters. Twenty patients were randomly selected from the patients who had undergone a resection of pulmonary metastasis from colorectal cancer. Formalin-fixed, paraffin-embedded archival specimens of tumor tissues and adjacent normal mucosa from these patients were the subjects of the present study. Immunoreactivity for CD44 was quantified. Specimens were considered positive if almost 25% of the neoplastic cells were stained. CD44 v6 expression was related to the interval between colon resection and metastases diagnosis, the number of pulmonary metastases, and the survival after lung resection. No statistical correlation was found between CD44 v6 positivity and disease-free interval after colon resection, number of metastases or 2-year survival after lung resection. Probably CD44 v6 is necessary and sufficient to confer metastatic potential to carcinoma cells increasing the migration capacity and participating in invasion via changes in adhesion to the extracellular ligands, but is not necessary to modify the clinical history of the metastases. Therefore the evaluation of CD44 v6 expression in lung metastases does not influence the therapeutic scheme.

Aged↗
PubMed2003

CD44 expression indicates favorable prognosis in epithelial ovarian cancer.

PURPOSE: The purpose of this study was to investigate the expression and prognostic significance of CD44 in epithelial ovarian cancer. EXPERIMENTAL DESIGN: We analyzed the expression of CD44 by immunohistochemistry in 307 epithelial ovarian cancers and evaluated its relation to hyaluronan, clinicopathological factors, and prognosis. RESULTS: Fifty-one percent of the tumors had a high proportion of CD44-positive cells (i.e., >/==" BORDER="0">10%), and this high CD44 expression was significantly associated with cancer cell-associated hyaluronan, well-differentiated tumor, mucinous histological type, and early stage of the tumor. High CD44 expression predicted better 5-year overall survival (50% versus 22%) and recurrence-free survival (70% versus 34%) in the univariate analyses (P < 0.00005 for both). In the Cox multivariate analyses, the independent predictors of overall survival at 5 years were primary residual tumor (P < 0.0005), International Federation of Gynecologists and Obstetricians (FIGO) stage (P = 0.001), histological grade (P = 0.014), adjuvant chemotherapy (P = 0.004), and stromal hyaluronan level (P < 0.0005), but not CD44. However, the expression of CD44 (P = 0.04) and stromal hyaluronan (P = 0.005) were both independent predictors of recurrence-free survival at 5 years, together with the size of the primary residual tumor (P < 0.0005) and histological type (P = 0.043). CONCLUSIONS: The relatively frequent ectopic expression of CD44 on ovarian cancer cells is thus related to well-differentiated, early-stage tumor and long survival of the patients. Thus, whereas CD44-expressing cancer cells may adhere and implant to the hyaluronan-positive mesothelium, at least in model systems, high expression of CD44 in the tumor does not bring about an unfavorable prognosis.

Adenocarcinoma, Mucinous↗
PubMed1989

Dual role of the CD44 molecule in T cell adhesion and activation.

Studies of T cell adhesion and activation reveal two new functions of the CD44 molecule, a molecule now recognized to be identical to three molecules of functional interest: Pgp-1, Hermes, and extracellular matrix receptor type III (ECMRIII). By screening for mAb which inhibit T cell adhesion to E, we have identified a functionally unique CD44-specific mAb, NIH44-1, which partially inhibits T cell rosetting by binding to CD44 on the E. NIH44-1, which immunoprecipitates a protein of 85 to 110 kDa with broad tissue distribution, was determined to be specific for CD44 based on comparison of its tissue distribution with multiple CD44-specific reference mAb and sequential immunoprecipitation with such mAb. Anticipating a role for many adhesion molecules in signal transduction, we studied the effect of CD44 mAb on T cell activation and observed that CD44 mAb dramatically augments T cell proliferation induced by CD3- and CD2-receptor-mediated activation. The augmentation of the response to immobilized CD3 mAb by exhaustively monocyte-depleted T cells indicates that augmentation can be mediated by binding to the T cell. Thus, our studies demonstrate specific new roles for CD44 in T cell adhesion and activation. Furthermore, we suggest that: 1) CD44 has a role in adhesion of cells of multiple lineages; and 2) CD44 may participate in adhesion not (only) by functioning as an adhesion receptor but rather by serving as an anchorage site for other adhesion molecules.

Adjuvants, Immunologic↗
PubMed1993

Alternatively spliced CD44 transcripts in diffuse large-cell lymphomas: characterization and comparison with normal activated B cells and epithelial malignancies.

CD44 exists in a variety of alternatively spliced isoforms that include variable numbers of additional exons from the membrane proximal domain (exons 6-14). Lymphocytes express high levels of a "hematopoietic" isoform (CD44H) with no additional variable exons. CD44H binds lymphocytes to postcapillary venules and promotes lymphocyte extravasation into nodal areas. Epithelial carcinomas also express CD44 variants, including exon 10-containing isoforms associated with metastasis in a rat model. An exon 10-containing CD44 isoform is also transiently expressed by normal activated lymphocytes, suggesting that the protein may function in the trafficking of both normal lymphocytes and metastatic tumors. To identify the specific CD44 transcripts in tumors from patients with primary nodal, extranodal, and disseminated large-cell lymphomas (LCLs) and compare them with CD44 mRNAs in normal Ig-activated splenic B cells and epithelial cells, we used a semiquantitative RNA-based polymerase chain reaction. Specific CD44 variants were identified by size, hybridization with exon-specific probes, and sequence analysis. In comparison to primary nodal LCLs, extranodal and disseminated LCLs had increased levels of CD44H and additional isoforms, including a directly spliced (exon 5-->exon 10-->exon 15) exon 10-containing CD44 variant. The CD44 transcripts in extranodal and advanced-stage LCLs were similar to those in normal Ig-activated splenic B cells, whereas epithelial malignancies contained decreased CD44H and increased amounts of larger CD44 variants with additional exons from the membrane proximal domain. The regulated expression of specific CD44 variants is likely to influence the trafficking of lymphoid and epithelial malignancies.

Alternative Splicing↗
PubMed1994

Serum CD44 in malignant lymphoma: an association with treatment response.

CD44, a cell surface glycoprotein, is involved in lymphocyte trafficking from the blood to lymphatic tissues, and is of importance in dissemination of lymphoma. A variant form of CD44 that has additional amino acids in the common protein backbone (CD44v6) also seems to play a role in the metastatic dissemination of malignancies. We measured serum CD44 and CD44v6 in 34 patients with lymphoma and in healthy controls by dot blot assay. Small amounts of both CD44 (range, 10 to 80 ng/mL) and CD44v6 could be detected in sera of all controls. Serum CD44 was elevated in all patients with lymphoma before treatment (range, 70 to > 2,000 ng/mL, P < .0001), and CD44v6 was also slightly elevated. Serum CD44 levels correlated with response to treatment. Patients with complete response achieved similar CD44 levels as the controls, whereas those with progressive disease had increased serum CD44 levels. We conclude that both the standard and the variant form of CD44 are detectable in sera of healthy individuals, and that serum CD44 may be useful in monitoring treatment response in patients with lymphoma.

Adolescent↗
PubMed1995

CD44 isoforms correlate with cellular differentiation but not with prognosis in human breast cancer.

CD44 is a transmembrane glycoprotein occurring in several isoforms with different extracellular regions. The various transcripts are encoded by one gene locus containing 20 exons, of which at least 10 can be alternatively spliced in nascent RNA. Isoforms encoded by the variant exons (termed CD44v) are highly restricted in their distribution in nonmalignant tissue as opposed to the standard form of CD44 (CD44s) abundant in many tissues. Specific variant isoforms containing exon 6v have been shown to render nonmetastatic rat tumor cells metastatic. Based on the prominent role in rat metastasis formation, CD44v isoforms were suggested to be involved in human tumor progression. Correlations between prognosis and expression of CD44v have been reported for gastric and colon carcinoma, for non-Hodgkin's lymphoma, and recently for breast carcinoma. We evaluated the expression of CD44 isoforms in node-positive (n = 119) and node-negative (n = 108) cases of breast carcinoma by immunohistochemistry using CD44v exon-specific mAbs. In a subset of 43 cases of high-risk patients, reverse transcription-PCR was used to determine the exon composition of the transcripts. Protein and RNA expression data were probed statistically for their correlation to survival of the patients and clinical risk factors. In contrast to recently published data (M. Kaufmann et al., Lancet, 345: 615-619, 1995), in our cohort disease-free and overall survival data did not indicate significant correlations with the expression of the analyzed isoforms in univariate and multivariate analyses. Comparison of CD44 protein expression with established clinical risk factors for survival such as tumor size (pT1+pT2) and histological grading revealed correlations with the presence of CD44s (P = 0.02 and P = 0.03, respectively) and CD44-9v (P = 0.05 for histological grading). Carcinoma tissues with elevated estrogen and progesterone receptor levels showed positive correlation with CD44-6v (P = 0.001), while a trend for significant coexpression of CD44s and CD44-9v isoforms was observed in estrogen receptor-positive tissues (P = 0.08 and 0.06, respectively). In breast cancer, CD44s, CD44-9v, and CD44-6v are apparently markers for cellular differentiation but not for tumor progression. Our data suggest that steroid hormone receptors may be associated with the in vivo expression of CD44-6v-containing isoforms in human mammary carcinoma.

Adult↗
PubMed1993

Glycoprotein CD44 expression and its association with survival in breast cancer.

To investigate the clinical significance of CD44 expression (lymphocyte-homing receptor) in adenocarcinoma, deparaffinized sections from 198 female breast carcinomas were stained with Hermes-3 MoAb for CD44 glycoprotein. In 16% of the cancers most (> or = 90%) of the cancer cells stained positively for CD44, whereas the rest of the cancers were either heterogenous (46%) or negative (38%) in CD44 staining. Cancers with > 50% CD44 positive cells were more often poorly differentiated (grade 3) than those with < or = 50% positive cells (38 vs. 19%, P = 0.006), they had higher mitotic counts (P = 0.04), and were more often estrogen receptor negative (52 vs. 31%, P = 0.01). Among ductal not otherwise specified cancers and node-positive cancers strong CD44 expression was associated with poor outcome (P = 0.05 and 0.02, respectively). However, CD44 expression was not an independent prognostic factor in these subgroups in a multivariate analysis. Unlike in lymphomas the unfavorable prognosis associated with CD44 expression may not be explained by the greater metastatic potential of CD44-positive cells, because the difference in mortality between the groups appeared to diminish with time, and CD44 positivity was associated with aggressive histological features.

Adenocarcinoma↗
PubMed1993

Isolation and characterization of the soluble and membrane-bound porcine CD44 molecules.

Porcine CD44 was identified by the cross-reactive anti-human CD44 monoclonal antibody (mAb) Hermes-1. Material which inhibited the Hermes-1 mAb binding to porcine lymphocytes was found in porcine intestinal efferent lymph and demonstrated to be a soluble form of porcine CD44. A protocol using non-affinity techniques was established to isolate this material from porcine lymph. The isolated soluble CD44 molecule consists of a single peptide with an apparent MW of about 50,000, containing the Hermes-1 epitope. The soluble and membrane-bound forms of porcine CD44 were also affinity purified and characterized. The soluble CD44 preparation comprised a major component of 48,000-70,000 MW peptide and a minor band of 120,000 MW. The membrane-bound CD44 preparation contained a 90,000 MW major and a 120,000 MW minor component. Both the major components of the soluble and membrane-bound forms of porcine CD44 contained N-linked glycosylation. The 48,000-70,000 MW component of the soluble CD44 molecules consisted of two subsets discriminated by their binding capacity for lentil lectin and a slight difference in molecular weights. Soluble CD44 molecules were also identified in the sera of sheep, goats, horses, dogs and humans. Like the porcine counterpart, these molecules could be enriched by anion-exchange chromatography, suggesting that they have similar biochemical properties.

Amino Acids↗
PubMed1996

In vitro culture of human peripheral blood monocytes induces hyaluronan binding and up-regulates monocyte variant CD44 isoform expression.

CD44 is a cell surface proteoglycan homologous to cartilage link protein that serves as a receptor for hyaluronan (HA). CD44 isoforms include an unspliced 80- to 90-kDa standard form (CD44S) and isoforms derived from alternative splicing of nine CD44 variant exons (CD44V). Ligation of CD44 isoforms on monocytes induces the production of IL-1 and TNF-alpha. In addition, CD44 mAbs and HA inhibit HIV infection of monocytes by monocytotropic HIV, but do not inhibit T cell tropic HIV infectivity of T cells. To determine the ability of PB lymphocytes and monocytes to bind HA and to define and compare CD44 isoforms present on PB monocytes and lymphocytes, we studied PBMC using a panel of CD44 mAbs, HA-FITC, flow cytometry, and Western blot analysis. We found that freshly isolated PB monocytes and lymphocytes did not bind soluble HA. However, in vitro culture of PBMC for 8 to 16 h resulted in CD44-dependent HA-FITC binding to monocytes, but not to lymphocytes. Western blot and flow cytometry analyses using CD44 mAbs demonstrated selective expression of high m.w. CD44V isoforms on cultured monocytes, but not on lymphocytes. Finally, tissue macrophages and multinucleated giant cells from patients with inflammatory lesions expressed CD44V6- and CD44V9-containing CD44 isoforms in vivo, suggesting that CD44V expression is associated with differentiation of monocytes to tissue macrophages in vivo in inflammatory sites. Taken together, our data demonstrate that PB monocytes, but not T or B lymphocytes, acquire the ability to bind HA and up-regulate CD44V expression after in vitro culture.

CD3 Complex↗
PubMed1997

Phorbol myristate acetate stimulates the dimerization of CD44 involving a cysteine in the transmembrane domain.

Receptor oligomerization is important for ligand binding and signal transduction. CD44 is a transmembrane protein present on many cell types. One of the ligands for CD44 is hyaluronic acid (HA). HA binding activity of CD44 is linked to cellular activation in some cell types. Clustering of CD44 has been speculated to be important for binding of HA. However, the molecular mechanisms for converting CD44 from an inactive receptor to an active receptor are not known. Here we report that PMA stimulates the binding of CD44 to HA by inducing clustering of CD44 followed by covalent homodimerization of CD44 on the cell surface. Covalent dimerization involves a cysteine (Cys286) in the transmembrane domain of CD44 and is essential for binding of high levels of fluorescein-conjugated HA. Activation-induced clustering followed by disulfide bond-mediated dimerization of CD44 represents an additional signal transduction mechanism for regulating receptor-ligand interactions.

Carcinogens↗
PubMed1997

Cytokine induction of the ability of human monocyte CD44 to bind hyaluronan is mediated primarily by TNF-alpha and is inhibited by IL-4 and IL-13.

Ligation of CD44 by hyaluronan (HA) is a key proinflammatory event that regulates lymphocyte and monocyte adhesion and cytokine production. While most immune cells express CD44, few immune cells constitutively bind HA. We have previously shown that monocyte CD44 acquires the ability to bind HA after in vitro culture of PBMC in human serum and, therefore, we have investigated a series of human cytokines and bacterial LPS for their ability to induce and/or inhibit monocyte CD44 to bind HA. We found that IL-1alpha, IL-1beta, IL-3, granulocyte macrophage (GM)-CSF, and TNF-alpha, as well as bacterial LPS, all directly induced peripheral blood monocytes to bind HA. In contrast, IL-2 and IL-15 up-regulated monocyte CD44 HA-binding in PBMC suspensions, but not in purified monocyte suspensions. An anti-TNF-alpha-neutralizing Ab inhibited IL-1alpha-, IL-1beta-, IL-3-, and GM-CSF-mediated monocyte HA binding. In addition, treatment of IL-2- and IL-15-stimulated PBMC cultures with an anti-TNF-alpha Ab prevented IL-2- and IL-15-induced monocyte HA binding, thus identifying TNF-alpha as a lymphocyte-derived factor that acted on monocytes to induce HA binding. In contrast, IL-4 and IL-13 were potent inhibitors of monocyte CD44-HA binding induced by either human serum or by IL-1alpha, IL-1beta, IL-3, GM-CSF, or TNF-alpha. IL-10 had dual effects on monocyte CD44-HA binding. Alone, IL-10 induced HA binding to PBMC monocyte CD44, while in contrast, IL-10 inhibited IL-1-induced monocyte CD44 binding to HA. Taken together, these studies identify a network of T cell and monocyte-derived cytokines that regulate HA binding to peripheral blood monocyte CD44, primarily through TNF-alpha.

Binding, Competitive↗
PubMed1998

Epitope specificity of CD44 for monoclonal antibody-dependent facilitation of marrow engraftment in a canine model.

Primary graft rejection after marrow transplantation occurs more frequently in patients receiving HLA-haploidentical compared with HLA-identical sibling transplants. Both human and experimental animal data suggest that the cells responsible for this phenomenon are either host natural killer (NK) cells, T cells, or both. To investigate the mechanisms of graft rejection, we have developed a canine model of marrow transplantation, which uses DLA-nonidentical unrelated donors in the absence of postgrafting immunosuppression. In this model most animals rejected their marrow grafts after a preparative regimen of 9.2 Gy total body irradiation (TBI). However, engraftment of DLA-nonidentical marrow can be facilitated when the recipients are pretreated with monoclonal antibody (MoAb) S5, which recognizes CD44. In this report, we extended these observations by first cloning the canine CD44 and, next, mapping the epitope recognized by S5, which was located in a region conserved among human and canine CD44 and was distinct from the hyaluronan binding domain. However, in vitro binding of S5 caused a conformational change in CD44, which allowed increased hyaluronan binding. Then, we reexamined the in vivo model of marrow transplantation and compared results with MoAb S5 to those with two other anti-CD44 MoAbs, IM7 and S3. Only MoAb S5 significantly increased the engraftment rate of DLA-nonidentical unrelated marrow, whereas the two other anti-CD44 MoAbs were ineffective. The enhanced in vivo effect was not related to differences in the MoAbs' avidities, since both S5 and IM7 had equivalent binding to CD44, but most likely related to the specific epitope that S5 recognizes. Thus, this study shows that the effect of the anti-CD44 MoAb S5 in facilitating engraftment is epitope specific and if one is to use an anti-CD44 to facilitate engraftment of marrow in humans, one cannot assume that any anti-CD44 would work.

Amino Acid Sequence↗