Biomedical subjects

Margot Zöller

Publications and source records attributed to Margot Zöller.

At least 19 recordsLinked to original sources

PubMed2006

GSK-3 mediates differentiation and activation of proinflammatory dendritic cells.

The key components of the intracellular molecular network required for the expression of a specific function of dendritic cells (DCs) are as yet undefined. Using an in vitro model of human monocyte-derived DC differentiation, this study investigates the role of glycogen synthase kinase 3 (GSK-3), a multifunctional enzyme critical for cellular differentiation, apoptosis, self-renewal, and motility, in this context. We demonstrate that GSK-3 (1) inhibits macrophage development during differentiation of DCs, (2) is constitutively active in immature DCs and suppresses spontaneous maturation, and (3) acquires a proinflammatory functional status mediating high levels of IL-12, IL-6, and TNF-alpha secretion, and partially inhibits IL-10 in the context of DC activation. In particular, GSK-3 enhances IL-12p35 mRNA expression and thus the production of the proinflammatory cytokine IL-12p70 by integrating the activities of other kinases priming GSK-3 targets and the inhibitory effects of Akt-1. GSK-3 may therefore act as a key integrator of activating and inhibitory pathways involved in proinflammatory DC differentiation and activation.

Cell Differentiation↗

PubMed2006

Systemic induction of the angiogenesis switch by the tetraspanin D6.1A/CO-029.

Expression of the tetraspanin CO-029 is associated with poor prognosis in patients with gastrointestinal cancer. In a pancreatic tumor line, overexpression of the rat homologue, D6.1A, induces lethally disseminated intravascular coagulation, suggesting D6.1A engagement in angiogenesis. D6.1A-overexpressing tumor cells induce the greatest amount of angiogenesis in vivo, and tumor cells as well as exosomes derived thereof strikingly increase endothelial cell branching in vitro. Tumor cell-derived D6.1A stimulates angiogenic factor transcription, which includes increased matrix metalloproteinase and urokinase-type plasminogen activator secretion, pronounced vascular endothelial growth factor expression in fibroblasts, vascular endothelial growth factor receptor expression, and strong D6.1A up-regulation in sprouting endothelium. Thus, D6.1A initiates an angiogenic loop that, probably due to the abundance of D6.1A in tumor-derived exosomes, reaches organs distant from the tumor. Most importantly, because of the strong D6.1A up-regulation on sprouting capillaries, angiogenesis could be completely inhibited by a D6.1A-specific antibody, irrespective of whether or not the tumor expresses D6.1A. Tetraspanins have been suggested to be involved in morphogenesis. This is the first report that a tetraspanin, CO-029/D6.1A, promotes tumor growth by its capacity to induce systemic angiogenesis that can effectively, and with high selectivity for sprouting endothelium, be blocked by a D6.1A-specific antibody.

Adenocarcinoma↗

PubMed2006

A chronic contact eczema impedes migration of antigen-presenting cells in alopecia areata.

Long-lasting allergen treatment is the most efficient therapy in alopecia areata (AA). The underlying mechanism is unknown. We here asked whether treatment with a contact sensitizer influences leukocyte migration such that dendritic cell (DC) migration or the recruitment of activated T-cells towards the skin become hampered. Allergen treatment of AA mice was not accompanied by a decrease in skin-infiltrating leukocytes or draining lymph node cells (LNC). However, the distribution of leukocyte subsets was changed with a dominance of monocytes in the skin and a reduced percentage of DCs in draining nodes. Chemokine and chemokine receptor expression in skin and draining nodes was strikingly increased and LNC from untreated and allergen-treated AA mice showed high migratory activity in vitro and readily homed in draining nodes and skin after intravenous injection. However, FITC labelling of the skin and subcutaneous transfer of dye-labelled DC revealed that allergen treatment created a chemokine milieu severely hampering DC migration from the skin towards the draining node. An allergic eczema-induced reduction in DC migration and antigen transfer could well contribute to insufficient T-cell activation and the recovery of hair follicle in AA and possibly be of relevance for other skin-related autoimmune diseases.

Alopecia Areata↗

PubMed2006

Serological analysis of human renal cell carcinoma.

Serological analysis of cDNA expression libraries (SEREX) has proven to be a useful technique in the quest to elucidate the repertoire of immunogenic gene products in human cancer. We have applied the SEREX method to human renal cell carcinoma (RCC) in order to identify associated immunogenic gene products. cDNA expression libraries were prepared from a RCC tumor, a RCC cell line and human testis. The 3 libraries were screened with sera from 35 RCC patients and 15 healthy controls. Approximately 4.5 x 10(6) phage plaques were screened resulting in 234 positive clones, which corresponded to 74 different gene products. The seroreactivity toward 49 of these antigens was assessed. Seroreactivity to 21 (43%) of the antigens was similar in RCC patients and healthy controls, 9 antigens (18%) elicited antibodies more frequently and 19 antigens (39%) solely in RCC patients. In the reverse setting, reactivity of RCC patients' sera was tested against a panel of 44 previously identified "tumor-associated" antigens via the SADA (serum antibody detection array) method; 6 antigens reacted with RCC patients' and healthy donors' sera, 8 were reactive only with RCC patients' sera. From the 27 antigens identified by SEREX and SADA, which did not react with sera from healthy controls, 10 antigens reacted with a significant proportion of RCC patients' sera and 77% of RCC patients' sera reacted at least with one of these antigens. Sera from patients with non-malignant renal diseases or an autoimmune disease did not react with these 10 antigens.

Antigens, Neoplasm↗

PubMed2006

In vivo CD44-CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance.

CD44 is involved in leukocyte migration and activation and has recently been reported to contribute to leukocyte extravasation by associating with CD49d. We explored whether similar changes in CD44 activity are seen in vivo using murine alopecia areata (AA) as a chronic, organ-related autoimmune disease model system. Expression of the activated, hyaluronan-binding form of CD44, and of CD49d, was elevated in draining lymph node cells (LNC) of AA-affected mice as compared to control mice. LNC of AA mice displayed increased motility, proliferative activity and apoptosis resistance, which were equally well inhibited by anti-CD44 and anti-CD49d. The latter is the sequelae of the association between CD44 and CD49d that is seen in activated lymphocytes. Significantly, due to CD44-CD49d complex formation, CD44 gains access to focal adhesion kinase and CD49d gains access to CD44-associated lck and ezrin, such that downstream kinases become activated via CD44 or CD49d engagement. Thus, by their association, CD44 and CD49d mutually avail themselves of the partner's signaling pathways and the ligand binding of each one triggers signaling pathways of both. This strongly influences the lymphocytes' activation state and function.

Alopecia Areata↗

PubMed2006

Expression of cytokeratin-20 in pancreatic cancer: an indicator of poor outcome after R0 resection.

BACKGROUND: After complete removal of the neoplasm (R0 resection), approximately 80% of pancreatic cancer patients will die of the disease within 5 years. The expression panel of cytokeratins (CK) is linked closely with cell differentiation. The aim of the study was to investigate the expression of CK-20 in pancreatic cancer tissue and to correlate CK-20 expression with survival in R0-resected pancreatic cancer patients. METHODS: Tissue samples of 63 patients with pancreatic cancer were subjected to CK-20 reverse-transcription polymerase chain reaction. Thirty-four of 63 patients underwent R0 resection and were followed-up for survival statistics. From these 34 patients, 26 (76%) neoplasms were CK-20 positive and 8 (24%) samples were CK-20 negative. The mean follow-up period for the entire group was 17 months (range, 4-36 mo), the follow-up period in censored patients was 23 months (range, 10-36 mo). RESULTS: In the R0-resected group, 3 of 8 (38%) patients with CK-20-negative neoplasms, and 16 of 26 (62%) patients with CK-20-positive neoplasms (P = .15) died of recurrent disease. The median survival time of patients with CK-20-positive neoplasms was 13 months (range, 4-36), the median survival in R0-resected patients with CK-20-negative neoplasm was 26 months (range, 13-35; P = .06). The survival difference observed in patients with CK-20-negative neoplasms could not be attributed to intergroup variations in tumor stage or tumor grade. CONCLUSIONS: A majority of primary ductal pancreatic adenocarcinomas express CK-20. This seems to be associated with poorer survival in R0-resected patients. Our data suggest that ductal pancreatic adenocarcinomas negative for CK-20 constitute a subgroup of patients showing a more favorable disease outcome. The expression of CK-20 in resected pancreatic cancer may be of interest as a prognostic parameter.

Carcinoma, Pancreatic Ductal↗

PubMed2005

Overexpression of the small transmembrane and glycosylated protein SMAGP supports metastasis formation of a rat pancreatic adenocarcinoma line.

Small cell transmembrane and glycosylated protein (SMAGP) was recently identified in the metastasizing rat pancreatic adenocarcinoma line BSp73ASML. SMAGP, an evolutionary conserved transmembrane protein, is expressed on lateral epithelial cell membranes. SMAGP expression was restricted to or was upregulated in several metastasizing as compared to nonmetastasizing human and rat tumor lines. In contrast to nontransformed tissue, SMAGP was mainly expressed in the cytoplasm, as has already been described for high-grade human colorectal cancer. This raised the question on the impact of SMAGP on tumor progression. To answer the question, metastasis formation was evaluated in the nonmetastasizing rat pancreatic adenocarcinoma subline BSp73AS (AS), which was stably transfected with SMAGP cDNA (AS-SMAGP). Cytoplasmic SMAGP expression promoted cell agglomeration, but inhibited tumor cell proliferation, adhesion to and migration toward vitronectin and matrigel invasion, which was accompanied by a failure of actin reorganization. AS-SMAGP clones strongly promoted metastasis formation by dislodgment of normal tissue; 82% of rats developed lymph node metastasis as compared to 22% of rats receiving AS or mock-cDNA-transfected AS cells. The incidence of lung metastasis was increased from 6% in AS to 98% in AS-SMAGP tumor-bearing rats. Thus, SMAGP strongly promotes tumor progression. This likely is due to redistribution from the plasma membrane into the cytoplasm. SMAGP redistribution does not only facilitate tumor cell detachment from neighboring cells and the extracellular matrix, but obviously contributes actively by a not yet defined mechanism to tumor cell agglomeration and capillary plugging.

Adenocarcinoma↗

PubMed2005

Antitumoral activity of non-platinum xanthate complexes.

To establish structure-activity relationships, derivatives of bis(O-alkyldithiocarbonato)platinum(II) complexes were analyzed. Eighteen bis(O-alkyldithiocarbonato) metal complexes were synthesized, and their cytotoxic activity on two human cancer cell lines was compared with the corresponding platinum bis(O-alkyldithiocarbonato) complexes and cisplatin. Complexes were synthesized with palladium, gold, nickel, copper, rhodium, and bismuth. Palladium and bismuth complexes were found to display significant cytotoxic activity. Palladium complexes were most active with up to 10-fold lower IC50 values as compared with the corresponding platinum complexes. The other complexes were only poorly active. Palladium, bismuth, and nickel complexes were more active at pH 6.8 than at pH 7.4. This difference in activity was most pronounced with palladium complexes. A pH of 6.8 and lower has been frequently found in solid tumors. Drugs with such pH dependent activity are supposed to have an improved therapeutic index as compared to drugs that are active irrespective of pH.

Antineoplastic Agents↗

PubMed2005

Generation of RAGE-1 and MAGE-9 peptide-specific cytotoxic T-lymphocyte lines for transfer in patients with renal cell carcinoma.

Renal cell carcinomas (RCCs) are supposed to be immunogenic, and several clinical trials of immunotherapy using tumor lysate-pulsed dendritic cells (DCs) have been performed. We report on the generation of RAGE-1 and MAGE-9 peptide-specific CTL lines. RAGE-1 and MAGE-9 are expressed in 56% and 38% of RCCs. Seven MAGE-9- and 13 RAGE-1-derived peptides were found to be immunogenic in the context of the HLA-A*0201 MHC. CTLs were generated by coculture with peptide-pulsed, activated B cells, which were easily generated in great quantities and displayed functional activity for a prolonged period of time. MAGE-9 and RAGE-1 peptide-specific CTL lines were strictly peptide-specific and displayed high cytotoxic activity not only against peptide-loaded T2 cells but also against HLA-A*0201-positive RCC lines, which naturally express MAGE-9, RAGE-1 or both. Thus, B cells are well suited as APCs for the generation of large numbers of tumor peptide-specific CTLs for adoptive transfer. MAGE-9 as well as RAGE-1 may well provide suitable targets for immunotherapy of RCC.

Adoptive Transfer↗

PubMed2005

The cell-cell adhesion molecule EpCAM interacts directly with the tight junction protein claudin-7.

We recently described that in the metastasizing rat pancreatic carcinoma line BSp73ASML the cell-cell adhesion molecule EpCAM, CD44 variant isoforms and the tetraspanins D6.1A and CD9 form a complex that is located in glycolipid-enriched membrane microdomains. This complex contains, in addition, an undefined 20 kDa protein. As such complex formation influenced cell-cell adhesion and apoptosis resistance, it became of interest to identify the 20 kDa polypeptide. This 20 kDa protein, which co-precipitated with EpCAM in BSp73ASML lysates, was identified as the tight junction protein claudin-7. Correspondingly, an association between EpCAM and claudin-7 was noted in rat and human tumors and in non-transformed tissues of the gastrointestinal tract. Co-localization of the two molecules was most pronounced at basolateral membranes, but was also observed in tight junctions. Evidence for direct protein-protein interactions between EpCAM and claudin-7 was obtained by co-immunoprecipitation after treatment of tumor cells with a membrane-permeable chemical cross-linker. The complex, which is located in glycolipid-enriched membrane microdomains, is not disrupted by partial cholesterol depletion, but claudin-7 phosphorylation is restricted to the localization in glycolipid-enriched membrane microdomains. This is the first report on an association between EpCAM and claudins in both non-transformed tissues and metastasizing tumor cell lines.

Animals↗

PubMed2005

Ly6 family member C4.4A binds laminins 1 and 5, associates with galectin-3 and supports cell migration.

C4.4A is a member of the Ly6 family, with low homology to uPAR. It has been detected mainly on metastasizing carcinoma cells and proposed to be involved in wound healing. So far, C4.4A has been observed as an orphan receptor, and its functional activity has not been explored. Using recombinant rat C4.4A (rrC4.4A) made in a eukaryotic expression system, we demonstrate by immunohistology that C4.4A ligands are strongly expressed in tissues adjacent to squamous epithelia of, e.g., tongue and esophagus, the expression pattern partly overlapping with laminin (LN) and complementing the C4.4A expression that is found predominantly on the basal layers of squamous epithelium. ELISA screening of several components of the extracellular matrix revealed selective binding of rrC4.4A to LN1 and LN5 and that transfection of the BSp73AS tumor line with C4.4A cDNA (BSp73AS-1B1) promoted LN1 and LN5 binding. Binding of BSp73AS-1B1 to LN5 and, less markedly, LN1 induced spreading, lamellipodia formation and migration. C4.4A also associates with galectin-3 in nontransformed tissues and tumor lines. There is evidence that the association of C4.4A with galectin-3 influences LN adhesion. C4.4A was described originally as a metastasis-associated molecule. Our findings that LN1 and LN5 are C4.4A ligands, that galectin-3 associates with C4.4A and that C4.4A ligand binding confers a migratory phenotype are well in line with the supposed metastasis association.

Animals↗

PubMed2005

The tetraspanin D6.1A and its molecular partners on rat carcinoma cells.

Tetraspanins function as molecular organizers of multi-protein complexes by assembling primary complexes of a relatively low mass into extensive networks involved in cellular signalling. In this paper, we summarize our studies performed on the tetraspanin D6.1A/CO-029/TM4SF3 expressed by rat carcinoma cells. Primary complexes of D6.1A are almost indistinguishable from complexes isolated with anti-CD9 antibody. Indeed, both tetraspanins directly associate with each other and with a third tetraspanin, CD81. Moreover, FPRP (prostaglandin F2alpha receptor-regulatory protein)/EWI-F/CD9P-1), an Ig superfamily member that has been described to interact with CD9 and CD81, is also a prominent element in D6.1A complexes. Primary complexes isolated with D6.1A-specific antibody are clearly different from complexes containing the tetraspanin CD151. CD151 is found to interact only with D6.1A if milder conditions, i.e. lysis with LubrolWX instead of Brij96, are applied to disrupt cellular membranes. CD151 probably mediates the interaction of D6.1A primary complexes with alpha3beta1 integrin. In addition, two other molecules were identified to be part of D6.1A complexes at this higher level of association: type II phosphatidylinositol 4-kinase and EpCAM, an epithelial marker protein overexpressed by many carcinomas. The characterization of the D6.1A core complex and additional more indirect interactions will help to elucidate the role in tumour progression and metastasis attributed to D6.1A.

Animals↗

PubMed2005

Stimulation of CD95-induced apoptosis in T-cells by a subtype specific neutral sphingomyelinase inhibitor.

Neutral sphingomyelinase (nSMase) has been supposed to be involved in the activation of anti-apoptotic genes and, thus, could well sustain autoimmune reactions by preventing activation induced death of autoreactive T-cells. When screening cellular extracts for SMase activity in the range between pH 6.5 and 8.5 various murine tissue samples as well as cell lines of murine and human origin displayed peaks of activity, both, at pH 7.0 and 8.0. In contrast, T-cells (human T-cell lymphoma and PHA stimulated murine lymph node cells) and monocytic leukemia cells were lacking SMase activity at pH 8.0. Only one peak of activity was found at pH 7.0. Recently we described an inhibitory compound, C11AG which selectively suppresses nSMase activity. In dose-response assays using cellular extracts the pH 7.0 nSMase turned out to be almost 100-fold more sensitive to the inhibitor than the pH 8.0 nSMase. In Jurkat T-cell lymphoma cells lacking the pH 8.0 nSMase, treatment with C11AG enhanced sensitivity to apoptosis: the concentration of CD95-specific antibody anti-APO1 could be lowered by six-fold in order to induce cell death. Concomitantly the expression of the anti-apoptotic protein A1 was found to be down-regulated. In the joints of arthritic mice, apoptosis of T-cells was stimulated after application of C11AG. Accordingly, C11AG displayed curative effects on experimental arthritis: swelling and inflammation were found to be significantly alleviated.

Animals↗

PubMed2005

Colocalization of the tetraspanins, CO-029 and CD151, with integrins in human pancreatic adenocarcinoma: impact on cell motility.

PURPOSE: Patients with pancreatic adenocarcinoma have a poor prognosis due to the extraordinary high invasive capacity of this tumor. Altered integrin and tetraspanin expression is suggested to be an important factor. We recently reported that after protein kinase C activation, colocalization of alpha6beta4 with the tetraspanin CO-029 strongly supports migration of a rat pancreatic adenocarcinoma. The finding led us to explore whether and which integrin-tetraspanin complexes influence the motility of human pancreatic tumors. EXPERIMENTAL DESIGN: Integrin and tetraspanin expression of pancreatic and colorectal adenocarcinoma was evaluated with emphasis on colocalization and the impact of integrin-tetraspanin associations on tumor cell motility. RESULTS: The majority of pancreatic and colorectal tumors expressed the alpha2, alpha3, alpha6, beta1, and beta4 integrins and the tetraspanins CD9, CD63, CD81, CD151, and CO-029. Expression of alpha6beta4 and CO-029 was restricted to tumor cells, whereas alpha1, alpha2, alpha3, alpha6, beta1, and CD9, CD81, CD151 were also expressed by the surrounding stroma. CD63, CD81, and beta1 expression was observed at comparably high levels in healthy pancreatic tissue. alpha3beta1 frequently colocalized and coimmunoprecipitated with CD9, CD81, and CD151, whereas alpha6beta4 colocalized and coimmunoprecipitated mostly with CD151 and CO-029. Notably, protein kinase C activation strengthened only the colocalization of CD151 and CO-029 with beta4 and was accompanied by internalization of the integrin-tetraspanin complex, decreased laminin 5 adhesion, and increased cell migration. CONCLUSION: alpha6beta4 is selectively up-regulated in pancreatic and colorectal cancer. The association of alpha6beta4 with CD151 and CO-029 correlates with increased tumor cell motility.

Adenocarcinoma↗

PubMed2005

Transfer of CD8(+) cells induces localized hair loss whereas CD4(+)/CD25(-) cells promote systemic alopecia areata and CD4(+)/CD25(+) cells blockade disease onset in the C3H/HeJ mouse model.

Alopecia areata (AA) is a suspected hair follicle specific autoimmune disease. The potential for cell transfer of AA using the C3H/HeJ mouse model was examined. Cells isolated from lymph nodes and spleens of AA-affected mice using magnetic bead conjugated monoclonal antibodies were subcutaneously injected into normal C3H/HeJ recipients. Within 5 wk, all CD8(+) cell-injected mice exhibited localized hair loss exclusively at the site of injection that persisted until necropsy. In contrast, some CD4(+) and CD4(+)/CD25(-) cell-injected mice developed extensive, systemic AA, and a combination of CD8(+) and CD4(+)/CD25(-) cells injected yielded the highest frequency of systemic AA induction. CD4(+)/CD25(+) cells were less able to transfer the disease phenotype, partially blockaded systemic AA induction by CD4(+)/CD25(-) cells, and prevented CD8(+) cell-induced, injection site-localized hair loss. CD11c(+) and CD19(+) cells failed to promote significant phenotype changes. Increases in co-stimulatory ligands CD40 and CD80, plus increased leukocyte apoptosis resistance with reduced CD95, CD95L, and CD120b expression, were associated with successful alopecia induction. The results suggest that CD8(+) cells may be the primary instigators of the hair loss phenotype. However, systemic disease expression fate is, apparently determined by CD4(+)/CD25(-) cells, while CD4(+)/CD25(+) lymphocytes may play a predominantly regulatory role.

Adoptive Transfer↗

PubMed2005

Reduced expression of interleukin-2 decreases the frequency of alopecia areata onset in C3H/HeJ mice.

Alopecia areata (AA) is an autoimmune hair loss disease, that can be transferred between C3H/HeJ mice by skin grafting. We explored whether AA susceptibility is influenced by the availability of interleukin (IL)-2, a cytokine with leukocyte activating and regulatory properties. Mice heterozygous for a targeted deletion of IL-2 from the histocompatible C3.129P2(B6)-Il2(tm1Hor) substrain, that produce reduced levels of IL-2, were examined for AA development after grafting skin from AA-affected C3H/HeJ mice. After grafting, nine of 19 (47%) heterozygous IL-2+/-versus 16 of 18 (88%) IL-2+/+ wild-type littermates developed AA. Although dense follicular leukocyte infiltrates were apparent in AA affected wild-type mice, AA-developing IL-2+/- littermates had a reduced leukocyte infiltration, and AA-resistant IL-2+/- mice had no inflammation. Lymph node cell analysis revealed a reduction in leukocyte activation markers in AA-developing IL-2+/- mice. IL-2+/- mice presented with low level expression of cytokines (IL-4, IL-10, interferon-gamma, transforming growth factor-beta), upregulation of tumor necrosis factor receptors, and increased leukocyte apoptosis susceptibility independent of AA expression. In the skin, CD4+ cells and monocytes were reduced; activation markers were not upregulated and very few CD44v3+ or CD44v10+ leukocytes were recovered. Taken together, our data suggest that AA resistance of IL-2+/- mice is because of the failure of activated leukocyte recruitment, thus pointing toward an involvement of IL-2 in AA pathogenesis.

Alopecia Areata↗

PubMed2004

CD44v6 promotes proliferation by persisting activation of MAP kinases.

CD44v6 is transiently expressed during T cell activation, and constitutively CD44v4-v7 expressing transgenic T cells show accelerated responses towards nominal antigens. The underlying mechanism is unknown. The mouse thymoma EL4 was transfected with CD44 standard isoform (CD44s) or CD44v6 cDNA (EL4-s, EL4-v6). Only EL4-v6 cells proliferated at an over 10-fold higher rate than untransfected cells, displayed up-regulated expression of CD69, CD25, and IL-2, and were protected from apoptosis by CD44v6 cross-linking. In the absence of any stimulus, ERK1/2 was partly phosphorylated, and phosphorylation was significantly increased by CD44v6 cross-linking. The same accounted for JNK, c-jun, and IkappaBalpha. Moreover, NF-kappaB was partly translocated into the nucleus. Instead, CD44s cross-linking induced ERK1/2, JNK, c-jun, and IkappaBalpha phosphorylation only in the context of TCR engagement. No selectively CD44v6 associated transmembrane proteins were uncovered in EL4 cells. However, CD44v6, as opposed to CD44s, did not colocalise with the TCR/CD3 complex after CD3 cross-linking. Furthermore, a CD44-associated 85-kDa protein became hypophosphorylated only after CD44v6 cross-linking. Threonine hypophosphorylation of this protein coincided with the activation of MAP and SAP kinases, which was prohibited in the presence of a phosphatase inhibitor. Thus, CD44v6, distinct to CD44s, stimulates autonomously growth and IL-2 secretion of a thymoma line and rescues cells from apoptosis.

Animals↗

PubMed2004

Potential of human gammadelta T lymphocytes for immunotherapy of cancer.

T lymphocytes are classified into 2 subsets based on their T-cell receptor (TCR) expression. The vast majority of T cells expresses an alphabeta TCR heterodimer. These alphabeta T cells recognize antigenic peptides presented by MHC class I (for CD8(+) T cells) or MHC class II molecules (for CD4(+) T cells). Concepts of cancer immunotherapy are mostly concerned with activation of these MHC-restricted alphabeta T cells. Until recently, a numerically small subset of T cells, which expresses an alternative TCR composed of a CD3-associated gammadelta heterodimer, has received far less attention as a potential agent in cancer therapy. These gammadelta T cells share with alphabeta T cells certain effector functions such as cytokine production and potent cytotoxic activity but recognize different sets of antigens, usually in a non-MHC-restricted fashion. Different subsets of human gammadelta T cells recognize stress-inducible MHC class I-related molecules frequently expressed on epithelial tumor cells or phosphorylated metabolites which can be generated by tumor cells. In line with this, many tumor cells are highly susceptible to gammadelta T-cell mediated lysis. In our article, we summarize the available evidence for a contribution of human gammadelta T cells in tumor defense and discuss potential strategies for the immunotherapy of tumors based on the endogenous activation and/or adoptive transfer of tumor-reactive gammadelta T lymphocytes.

Antigens, Neoplasm↗