Biomedical subjects

S Lang

Publications and source records attributed to S Lang.

At least 19 recordsLinked to original sources

PubMed2000

Prostatic luminal cell differentiation and prostatic steroid-binding protein (PBP) gene expression are differentially affected by neonatal castration.

BACKGROUND: Although normal prostatic development is androgen-dependent, the prostate continues to grow in the neonate despite castration. However, the manner in which neonatal growth of the prostate occurs, in the absence of the testis, remains largely unknown. The purpose of this study was to examine the differentiation of prostatic epithelial cells after neonatal castration. METHODS: Immunohistochemistry was utilized to detect the expression of differentiation products: basal-cell cytokeratin (CK 5), luminal-cell cytokeratin (CK 18), and prostatic steroid-binding protein (PBP), a ventral prostate-specific marker indicative of secretory function in luminal cells. The reverse transcription-polymerase chain reaction was used to detect transcription products of the three polypeptide subunits of PBP, designated C1, C2, and C3. Rats were castrated on day 5 after birth, and ventral prostates were collected on day 14. Dihydrotestosterone was injected (100 microg/animal every 2 days) in castrated animals to determine if PBP expression could be initiated by androgen. RESULTS: Although no major effects of castration were detected on the differentiation of stromal or basal cells (which differentiate prior to day 5), castration had a pronounced effect on luminal-cell differentiation. Castration inhibited PBP protein expression, but did not affect the expression of luminal-cell cytokeratin (CK 18) protein. Furthermore, castration reduced C1, C2, and C3 transcription. Androgen replacement to castrated animals allowed for the initiation of PBP expression, although its onset was delayed. CONCLUSIONS: These observations indicate that the testis is not necessary for prostatic luminal-cell differentiation, but is necessary for full expression of luminal-cell secretory phenotype. Furthermore, our study suggests that factors of testicular origin, in addition to androgen, are needed for proper timing of PBP expression. This investigation establishes that the cytological and the physiological differentiation of the rat prostate are differentially regulated.

Androgen-Binding Protein↗

PubMed2000

Absence of proximal duct apoptosis in the ventral prostate of transgenic mice carrying the C3(1)-TGF-beta type II dominant negative receptor.

BACKGROUND: Prostatic epithelial cells are sensitive to the inhibitory effects of TGF-beta. However, TGF-beta signaling in the prostate is dependent on androgenic status. Under the in vivo conditions, it is difficult to dissociate the effect of TGF-beta from that of androgen on the prostate. METHODS: The objective of the present study was to create and verify a transgenic mouse system in which epithelial cells of the ventral prostate are insensitive to the actions of TGF-beta. By using a modified prostate-specific promoter, C3(1), the TGF-beta dominant negative receptor is only expressed in the epithelial cells of the ventral prostate, and these cells are resistant to TGF-beta. Morphology of transgenic animal prostates was compared to wild-type animal prostates by immunohistochemistry and microscopy. RESULTS: The prostate of transgenic mice exhibited an abnormal morphology with multiple layers of epithelial cells lining the proximal ducts, in contrast to the simple cuboidal monolayer of cells seen in the normal prostate. This observation was accompanied by a loss of apoptosis in this region, as seen by TUNEL assay. There was no significant difference in serum levels of testosterone between the wild-type and transgenic animals. CONCLUSIONS: These results demonstrated that a loss of sensitivity to TGF-beta results in the accumulation of multiple layers of epithelial cells in the proximal region of the ventral prostate. This abnormal growth illustrates that TGF-beta plays an important role in regulating prostate growth. The current transgenic system can be used as an experimental model to study the functional role of TGF-beta in prostatic growth and function.

Activin Receptors, Type I↗

PubMed2000

B7.1 on human carcinomas: costimulation of T cells and enhanced tumor-induced T-cell death.

Human squamous cell carcinomas of the head and neck (SCCHN) do not express the costimulatory molecules B7.1 or B7.2 in situ or in culture. Transduction of B7.1(-) SCCHN cells with the retroviral B7. 1 and neo(r) genes resulted in the expression of high levels of the transgene in these tumor cells. When B7.1(+) SCCHN cells were used as stimulators of autologous or allogeneic PBL in mixed lymphocyte-tumor cultures (MLTC), T-cell proliferation and generation of antitumor effector T cells as well as levels of their lytic activity were significantly increased. At the same time, a proportion of activated T cells seen to undergo apoptosis was found to be significantly higher upon coincubation with B7.1(+) SCCHN than with B7.1(-) SCCHN. Both B7.1(+) and B7.1(-) SCCHN cells were found to express FasL on the cell surface and in the cytoplasm, as well as mRNA for FasL and mRNA for TRAIL. However, expression of the B7.1 transgene did not lead to increased expression of FasL protein on tumor cells. Yet, up to 50% of activated CD28(+) allogeneic T cells, which were CD95(+), showed evidence of DNA fragmentation in JAM and TUNEL assays upon incubation with an excess of B7.1(+) SCCHN for 24 h. Tumor-induced T-cell death was equally and only in part blocked by anti-Fas antibodies in both B7.1(+) and B7.1(-) MLTC. While surface expression of B7.1 molecules on SCCHN cells enhanced T-cell costimulation via B7.1-CD28 interactions, it did not rescue activated T cells from tumor-induced apoptosis. The outcome of MLTC under these conditions was dependent on the ratio of tumor to T cells. Thus, in the presence of an excess of B7.1(+) tumor cells, activated T cells showed increased sensitivity to apoptosis which did not appear to be Fas/FasL mediated. These data are important for the development of B7.1 gene therapy and efforts directed at the generation of effector cells in MLTC.

Apoptosis↗

PubMed2000

Prostatic ductal system in rats: changes in regional distribution of extracellular matrix proteins during castration-induced regression.

BACKGROUND: The extracellular matrix (ECM) is an intricate network composed of an array of molecules that play an integral role in the regulation of cell function, differentiation, and tissue-specific gene expression in various epithelia. In the present study, we examined the distribution of collagen type IV and laminin along the rat ventral prostatic duct before and after castration. METHODS: Mature Sprague-Dawley rats were castrated and their prostates processed for immunocytochemistry of ECM proteins, laminin, and collagen type IV. Tissue sections were also processed for apoptosis staining, using the 3' end-labeling technique. To examine the effect of ECM proteins on epithelial growth, rat ventral epithelial cells were cultured on ECM-coated surfaces. RESULTS: In the intact rat, laminin was localized in the basement membrane along all regions of the ventral prostate ductal system. Collagen type IV was found to be distributed evenly in the basement membrane of the distal and intermediate regions but was absent or poorly organized in the proximal region, where apoptosis in the epithelium occurs at a high rate. In the regressing prostate after castration, there was a shift in apoptosis from the proximal region to the distal intermediate regions of the prostatic duct. Associated with the shift was a remodeling of basement membrane proteins due to the specific loss of collagen type IV in the distal and intermediate regions. Collagen type IV reappeared underneath the epithelium 7 days after castration, when apoptosis in the epithelium stopped. In vitro, collagen type IV enhanced the growth of ventral prostatic epithelial cells, as assessed by cell number. CONCLUSIONS: Collagen basement membrane type IV mediates growth of rat ventral prostate epithelium, and its loss during tissue remodeling after castration is associated with cell death.

Animals↗

PubMed2000

Validation of excised bovine nasal mucosa as in vitro model to study drug transport and metabolic pathways in nasal epithelium.

The present work aims at the validation of excised bovine nasal mucosa as an in vitro model to address transport and metabolism pathways relative to the nasal mucosal uptake of therapeutic peptides. Preservation of the viability of the excised tissue in the course of in vitro studies of up to 3 h was demonstrated by (i) positive viability staining, (ii) constant transepithelial electrical resistance (42 +/- 12 Omega cm(2)), (iii) constant rates of metabolic turnover, and (iv) linear permeation profiles of therapeutic peptides and (3)H-mannitol. Using 1-leucine-4-methoxy-2-naphthylamide as a model substrate, we observed no difference between bovine and human nasal aminopeptidase activity. By a series of therapeutic peptides, no direct correlation was found between their effective permeability coefficients (from 0. 1 x 10(-5) to 5 x 10(-5) cm s(-1)) and their respective molecular masses (from 417 to 3,432 Da), indicating that other factors dominate nasal permeability. For instance, the permeabilities of metabolically labile peptides were concentration dependent and saturable, as demonstrated for two short thymopoietin fragments, Arg-Lys-Asp (TP3) and Arg-Lys-Asp-Val (TP4). By permeation studies using gonadorelin and two gonadorelin derivatives, buserelin and Hoe 013, without and in the presence of the chemical enhancer bacitracin, we also verified the ability of the model to assess chemical enhancer effects and their reversibility. In conclusion, our work demonstrates the potential of the investigated in vitro model, excised bovine nasal mucosa, to explore mechanistic aspects of nasal transport and metabolism of therapeutic peptides.

Absorption↗

PubMed2000

Possible cocarcinogenic effects of ELF electromagnetic fields may require repeated long-term interaction with known carcinogenic factors.

Literature on cancer-related biological effects of extremely low frequency (ELF) magnetic fields (MF) is discussed in the light of the current understanding of carcinogenesis as a multistep process of accumulating mutations. Different animal models and study designs have been used to address possible cocarcinogenic effects of MFs. Based on a comparison of the results, we propose a hypothesis that MF exposure may potentiate the effects of known carcinogens only when both exposures are chronic. We also discuss possible mechanisms of MF effects on carcinogenesis and the adequacy of the classical two-step initiation/promotion animal experiments for simulating human exposure to the complex mixture of environmental carcinogens. We conclude that experiments designed according to the two-step concept may not be sufficient for studying the possible role of MF in carcinogenesis. Possible further animal studies are more likely to be productive if they include models that combine chronic exposure to MFs with long-term exposures to known carcinogens.

Animals↗

PubMed2000

Early versus delayed initiation of breastfeeding.

EDITORIAL NOTE: This review has been withdrawn because it is out of date. The topic will be covered by a new review, 'The effect of the timing of feedings on the establishment of breastfeeding', the protocol for which is currently being prepared. BACKGROUND: It has been suggested that the timing of a baby's first breastfeed may influence breastfeeding duration and emotional attachment. OBJECTIVES: The objective of this review was to assess the effects of breastfeeding soon after birth (within 30 minutes) compared to being breastfed later (between 4 to 8 hours after delivery) on the duration of breastfeeding and the mother/infant relationship. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing early skin contact and breastfeeding with late skin contact and breastfeeding in women intending to breastfeed their healthy term infant. DATA COLLECTION AND ANALYSIS: Data were extracted by two reviewers. MAIN RESULTS: Three studies involving 209 women were included. Compared with late contact and breastfeeding, early contact and breastfeeding was associated with greater communication between mother and infants in a two minute observation period (odds ratio 0.14, 95% confidence interval 0.03 to 0.61). There was no difference detected for numbers of women breastfeeding after birth (odds ratio for 12 weeks after birth 0.73, 95% confidence interval 0.34 to 1.54). REVIEWER'S CONCLUSIONS: No differences were found between early and delayed contact in regard to breastfeeding duration. Early contact was associated with greater communication between mothers and infants.

Breast Feeding↗

PubMed2000

Feeding schedules in hospitals for newborn infants.

BACKGROUND: Regular breastfeeding times have been thought to help establish routines and promote infant digestion, while frequent breastfeeding has been recommended to enhance breastfeeding and infant growth. OBJECTIVES: The objective of this review was to assess the effects of frequent breastfeeding compared with less frequent breastfeeding in the early days after birth. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing on demand or frequent breastfeeding (two or three hourly) schedules in hospital compared with four hourly restricted feeds. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted independently by two reviewers. MAIN RESULTS: Three trials involving 400 women were included. There were significant methodological limitations in some of the studies. Compared to two hourly, three hourly or on demand breastfeeding, restricted (less frequent four hourly breastfeeding) was associated with greater discontinuation of breastfeeding by four to six weeks postpartum (relative risk 1.53, 95% confidence interval 1.08 to 2.15). Restricted breastfeeding was associated with increased incidence of sore nipples (relative risk 2.12, 95% confidence interval 1.22 to 3.68), engorgement (relative risk 2.10, 95% confidence interval 1.25 to 3.21) and the need to give additional (formula) feeds (relative risk 3.14, 95% 1.24 to 8.00). REVIEWER'S CONCLUSIONS: There appear to be a number of disadvantages from restricting breastfeeding to a four hourly schedule in the first few days after birth. More frequent or on demand breastfeeding is associated with fewer complications and longer duration of breastfeeding.

Breast Feeding↗

PubMed2000

Interventions for influencing sleep patterns in exclusively breastfed infants.

BACKGROUND: The difference between night and day may be reinforced in young babies by offering a 'focal feed' between 10pm and midnight and gradually lengthening the intervals between night-time feeds by a variety of other activities (such as nappy changing, re-swaddling and walking with the infant). OBJECTIVES: The objective of this review was to assess the effects of using a structured training programme to teach exclusively breastfed infants to sleep through the night by eight weeks old. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register. SELECTION CRITERIA: Acceptably controlled trials of a structured programme accentuating the difference between night and day compared with no intervention in first time parents of singleton babies, with mothers intending to exclusively breastfeed their infants for at least eight weeks post-partum. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted independently by two reviewers. MAIN RESULTS: One trial involving 33 couples was included. More infants in the treatment group were sleeping throughout the night by eight weeks of age than in the control group (odds ratio 0.04, 95% confidence interval 0.01 to 0.21). REVIEWER'S CONCLUSIONS: There is some evidence to show that first time parents using a structured sleeping programme can teach their babies to sleep through the night by eight weeks of age.

Breast Feeding↗

PubMed2000

Oxytocin for promoting successful lactation.

BACKGROUND: A rise in the concentration of oxytocin causes contraction of cells around the alveoli and milk ducts, in preparation for suckling. Lactation failure may result from insufficient oxytocin. OBJECTIVES: The objective of this review was to assess the effects of using oral or nasal oxytocin on lactation. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register. SELECTION CRITERIA: Randomised and quasi-randomised trials of variable doses of oxytocin and different methods of administration versus placebo in breastfeeding women using oxytocin to augment lactation. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted by two reviewers. MAIN RESULTS: Four trials of 639 women were included. There was potential for significant bias in these trials. Restricted breastfeeding schedules may have contributed to inadequate production of milk by the participants. Sublingual and buccal preparations of oxytocin were associated with an increase in milk production. Oxytocin did not appear to increase the incidence of breast pain and 100 international units of oxytocin appeared to be slightly more beneficial than 10 international units. REVIEWER'S CONCLUSIONS: An appropriate dose of sublingual or buccal oxytocin may help augment lactation where necessary. However if women are encouraged and supported with unrestricted breastfeeding, the need for oxytocin would probably be diminished.

Female↗

PubMed2000

Chemical shift imaging with continuously flowing hyperpolarized xenon for the characterization of materials.

In this contribution we report new approaches to the MRI of materials using continuously produced laser-polarized (129)Xe gas. This leads to vastly improved sensitivity and makes new kinds of information available. The hyperpolarized xenon is produced in a continuous flow system that conveniently delivers the xenon at low partial pressure to probes for NMR and MRI experiments. We illustrate applications to the study of micropore and other kinds of void space and show for the first time that with flowing hyperpolarized xenon it is possible to obtain chemical-shift-resolved images in a relatively short time.

Calcium↗

PubMed2000

Production and structure elucidation of glycoglycerolipids from a marine sponge-associated microbacterium species.

The bacterium Microbacterium sp., isolated from the sponge Halichondria panicea, produced four unusual cell-associated glycoglycerolipids and one diphosphatidylglycerol when grown on marine broth and on artificial seawater media. The lipids were isolated by chromatography on silica columns and their structures elucidated using a combination of multidimensional NMR and MS techniques. The main compound was 1-O-acyl-3-[alpha-glucopyranosyl-(1-3)-(6-O-acyl-alpha-mannopyranosyl )]glycerol (GGL.2) with 14-methyl-hexadecanoic acid and 12-methyl-tetradecanoic acid positioned at C-6 of the mannose unit and at the glycerol moiety. Glycolipid production was correlated with growth and reached a maximum value of 200 mg/L when grown on artificial seawater medium with 20 g/L glucose. The main compound decreased the surface tension of water down to 33 mN/m and the interfacial tension of the water/n-hexadecane system down to 5 mN/m. In addition to this good surface-active behavior, the main glycoglycerolipid showed antitumor activities.

Actinomycetales↗

PubMed2000

Platelet-derived growth factor-AA and -alpha receptor expression suggests an autocrine and/or paracrine loop in osteosarcoma.

Platelet-derived growth factor (PDGF) is a major mitogen and chemotactic factor for mesenchymal cells such as fibroblasts, smooth muscle cells, and osteoblasts. PDGF exists as disulfide-linked homo- or heterodimers composed of two polypeptide chains encoded by distinct genes, designated PDGF-A and PDGF-B. Upon binding to its tyrosine kinase receptor PDGF-alpha, especially PDGF-AA stimulates the proliferation of osteoblastic cells and may exert autocrine and paracrine effects in regulating bone-forming processes. The purpose of this immunohistochemical study was to determine the expression of PDGF-AA and PDGF-alpha receptor in benign and malignant neoplastic bone lesions. Polyclonal antibodies to PDGF-AA and PDGF-alpha receptor were used on paraffin sections of 23 osteosarcomas and 17 osteoblastomas. Immunostaining was assessed quantitatively by evaluating the percentage of reactive tumor cells. In osteosarcomas, the mean expression of PDGF-AA and PDGF-alpha receptor was 33.97% (range, 2 to 80%; SD, 24.26%) and 27.13% (range, 3.2 to 72%; SD, 18.38%), respectively. Osteoblastomas showed significantly lower expression of PDGF-AA than osteosarcomas (mean, 15.71%; range, 5 to 34%; SD, 9.43%; P = .019). Although the mean expression of PDGF-alpha receptor in osteoblastomas was much lower than in osteosarcomas (mean, 17.55%; range, 3.6 to 26.8%; SD, 6.47%), the difference was not significant (P = .122). For osteosarcomas, Spearman correlation coefficient (two-tailed) revealed a significant correlation between the expression of PDGF-AA and PDGF-alpha receptor (r = .688), which was not the case for osteoblastomas (r = .267). These data suggest that in contrast to osteoblastoma, the growth of osteosarcoma may be supported by the coordinate expression of the potent mitogenic growth factor and its receptor that exert their functions by autocrine and paracrine mechanisms.

Autocrine Communication↗

PubMed2000

Tumor cell-derived prostaglandin E2 inhibits monocyte function by interfering with CCR5 and Mac-1.

The cyclooxygenases (COX)-1 and COX-2 are key enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids. Whereas COX-1 is expressed ubiquitously, COX-2 is an immediate-early gene often associated with malignant transformation, and a role for the COX enzymes in tumor initiation and promotion is discussed. Nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin and indomethacin that block COX-1 and -2 have been shown to have beneficial effects for tumor patients. Therefore, these compounds have gained interest also among oncologists. However, the molecular mechanism by which NSAIDs inhibit carcinogenesis is not clearly understood. The prostaglandin-dependent and -independent effect may both account for their antineoplastic action. We show here that tumor cells derived from different tumors regularly produce prostaglandin E(2) (PGE(2)) interfering with the function of monocytes. In particular, PGE(2) inhibits the potential of monocytes to migrate in the direction of a chemotactic stimulus and to adhere to endothelial cell. This inhibition is most probably due to a modulation of the chemokine receptor CCR5 and the beta2-integrin Mac-1. Both down-regulation of CCR5 and reduced expression of Mac-1 may diminish the potential of peripheral blood monocytes to leave blood vessels and invade target tissues. Since both dysfunctions can be restored with NSAIDs, our findings help to explain the molecular chemopreventive action of NSAIDs on tumor formation and progression.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2000

Radiation synovectomy using 165Dy ferric-hydroxide and oxidative DNA damage in patients with different types of arthritis.

UNLABELLED: Radiation synovectomy is an effective treatment for chronic synovitis refractory to pharmacological treatment in patients with rheumatoid or seronegative arthritis. Concerns persist about possible radiation-induced cytogenetic damage after radiation synovectomy leading to recommendations to use this technique only in the elderly. Micronucleus (MN) frequency in lymphocytes and urinary excretion of 8-hydroxy-2'-deoxyguanosine (8OHdG) as an indicator of cellular oxidative DNA base damage are biomarkers of radiation-induced cytogenetic damage. The course of both biomarkers was studied in patients with different types of chronic synovitis undergoing radiation synovectomy with very short-lived 165Dy-ferric-hydroxide (DFH). METHODS: Radiation synovectomy of the knee was performed in 13 men and 12 women (mean age, 44+/-15 y) using a mean activity of 9.48+/-1.65 GBq 165Dy-DFH in 27 consecutive treatments. MN frequency in lymphocytes and urinary excretion of 8OHdG, measured by high-performance liquid chromatography, were assessed before and 4 (MN only) and 20 h after radiation synovectomy. RESULTS: Urinary excretion of 8OHdG in patients (in micromol/mol creatinine; pretreatment mean, 3.1+/-3.4; median, 2.27) was not significantly different from that in healthy volunteers (mean, 2.0+/-1.2; median, 1.87) and not altered by radiation synovectomy (post-treatment mean, 2.5+/-1.5; median, 2.04, NS). An increase in 8OHdG levels after radiation synovectomy of more than 1 SD was found in only 1 patient, who experienced leakage to the lymph nodes but who already had elevated urinary 8OHdG levels before treatment. The frequency of MN/500 binucleated cells (BNCs) was slightly lower in patients (pretreatment mean, 4.3+/-2.6; median, 4.25) than in healthy volunteers (mean, 5.4+/-2.3; median, 5.3) and did not significantly change after therapy, either (4-h post-treatment mean, 3.9+/-2.1, median, 3.8; 20-h post-treatment mean, 4.1+/-2, median 3.8 MN/500 BNC). In 22 of 27 treatments, no leakage to nontarget organs could be monitored, whereas leakage to the local lymph nodes and the liver was detected after 5 treatments. CONCLUSION: Radiation synovectomy using 165Dy-DFH causes no significant radiation burden to most patients as indicated by the absence of adverse changes in levels of biomarkers of cytogenetic damage and a low incidence of leakage. These data suggest that the risk of malignancy may not be elevated.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1999

[Socio-demographic and life-style factors in a Swiss study of HIV non-progression].

OBJECTIVES: The study investigates associations between socio-demographic or lifestyle factors and the progression of HIV. METHODS: We recruited a Swiss cohort (n = 56) of long-term survivors and conducted a cross-sectional study of laboratory data as well as factors concerning socio-demography, life-style, and psychology. On the basis of laboratory results, the cohort was divided into 2 subgroups, non-progressors (n = 31) and slow progressors (n = 25), which were subsequently compared. RESULTS: The comparison of socio-demographic factors showed that non-progressors were younger and had a higher income than slow progressors. Our data do not show an association between lifestyle and disease progression. DISCUSSION: Younger age as a cofactor of non-progression confirms various other studies. The association between income and disease progression, also found in another cohort, cannot be explained by unequal access to therapies since, in accordance with the inclusion criteria, no one in our cohort had received antiretroviral therapies. Further research in this field seems important to determine possible links between socio-economic status and disease progression. The lack of association between disease progression and lifestyle factors such as drug use, physical activity or nutrition is in contrast to a common view of HIV in our study population, but is confirmed by a majority of the research in this field.

Adult↗

PubMed1999

Simultaneous activation of T cells and accessory cells by a new class of intact bispecific antibody results in efficient tumor cell killing.

Bispecific Abs (bsAb) are promising immunological tools for the elimination of tumor cells in minimal residual disease situations. In principle, they target an Ag on tumor cells and recruit one class of effector cell. Because immune reactions in vivo are more complex and are mediated by different classes of effector cell, we argue that conventional bsAb might not yield optimal immune responses at the tumor site. We therefore constructed a bsAb that combines the two potent effector subclasses mouse IgG2a and rat IgG2b. This bispecific molecule not only recruits T cells via its one binding arm, but simultaneously activates FcgammaR+ accessory cells via its Fc region. We demonstrate here that the activation of both T lymphocytes and accessory cells leads to production of immunomodulating cytokines like IL-1beta, IL-2, IL-6, IL-12, and DC-CK1. Thus this new class of bsAb elicits excellent antitumor activity in vitro even without the addition of exogenous IL-2, and therefore represents a totally self-supporting system.

Animals↗

PubMed1999

Potential role of CD4+ T cell-mediated apoptosis of activated astrocytes in Theiler's virus-induced demyelination.

Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) into susceptible mouse strains results in a chronic, immune-mediated demyelinating disease similar to human multiple sclerosis. Here, we examined the role of astrocytes as an APC population in TMEV-induced demyelination and assessed the potential consequences of T cell activation following Ag presentation. IFN-gamma-pretreated astrocytes were able to process and present all the predominant T cell epitopes of TMEV to virus-specific T cell hybridomas, clones, as well as bulk T cells. Despite low levels of proliferation of T cells due to prostaglandins produced by astrocytes, such Ag presentation by activated astrocytes induced the production of IFN-gamma, a representative proinflammatory cytokine, in TMEV-specific Th cell clones derived from the CNS of virus-infected mice. Furthermore, these Th cell clones mediate lysis of the astrocytes in vitro in a Fas-dependent mechanism. TUNEL staining of CNS tissue demonstrates the presence of apoptotic GFAP+ cells in the white matter of TMEV-infected mice. These results strongly suggest that astrocytes could play an important role in the pathogenesis of TMEV-induced demyelination by activating T cells, subsequently leading to T cell-mediated apoptosis of astrocytes and thereby compromising the blood-brain barrier.

Amino Acid Sequence↗