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Results for “Targeted expression”

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At least 127 records · Page 7Linked to original sources

PubMed1990

The effect of mutations in the MHC class I peptide binding groove on the cytotoxic T lymphocyte recognition of the Kb-restricted ovalbumin determinant.

The H-2Kb-restricted cytotoxic T lymphocyte (CTL) response directed against ovalbumin (OVA) is specific for a region contained within the sequence OVA253-276. In this study we have characterized this response by examining the class I-restricted presentation of OVA peptides by the naturally occurring Kb mutant (Kbm) glycoproteins Kbm1, Kbm3, Kbm5, Kbm8, Kbm10, Kbm11 and Kbm23. To facilitate this study we derived a series of somatic cell hybrid targets expressing the various Kbm class I molecules. Experiments using bulk OVA-specific CTL from C57BL/6 mice demonstrated that all the Kbm molecules except for Kbm1 and Kbm8 could present OVA peptides for effective T cell recognition. Clonal analysis revealed a more complex and relatively diverse pattern of CTL recognition of the Kbm/peptide combinations. This diversity is unlikely to result from the existence of multiple, independent Kb-restricted T cell determinants within OVA, since all CTL tested were specific for a single region between residues 259 and 273. Examination of the fine specificity of Kbm presentation identified individual changes at residues 77, 80 and 116 which affected T cell recognition. The results imply that these changes do not inhibit peptide binding since some clones could recognize peptide presented by a particular Kbm molecule, while other clones could not. All three residues reside within the peptide-binding cleft of the class I protein and are not expected to directly contact the T cell receptor. Although we did not formally demonstrate that OVA binding by Kbm vs. Kb is quantitatively identical, our results are best explained by postulating that the changes at residues 77, 80 and 116 indirectly affect T cell recognition by altering peptide conformation. Taken together our results suggest that changes within the class I binding site can profoundly modify peptide presentation without significantly inhibiting peptide-class I association.

Animals↗

PubMed1991

Evidence for quantitative and qualitative differences in functional activation of Mls-reactive T cell clones and hybridomas by antigen or TcR/CD3 antibodies.

In this study, we demonstrated that some V beta 6+, CD4+, Mls-1a-specific T cell clones had cytolytic activity when stimulated with anti-T cell receptor(TcR)/CD3 monoclonal antibodies (mAb), but not with targets expressing Mls-1a, although they produced lymphokines (interleukin 2 and interferon-gamma) in response to both types of stimuli. To examine the possibility that lack of cytolysis resulted from expression of the Mls-1a antigen on merely a fraction of splenic B blasts, we (a) used the B cell lymphoma LBB.3.4.16 and (b) measured esterase secretion which is generally concurrent with cytotoxic T lymphocyte (CTL) activity. The B cell lymphoma maximally stimulated the T cell clone for interferon-gamma production when responding and stimulating cells were incubated at a 1:1 ratio, but it was never killed by the Mls-1a-specific T cell clone unless TcR/CD3-specific mAb were added. Furthermore, a fivefold excess of the Mls-1a B cell lymphoma did not induce any secretion of esterase, which was observed only in the presence of the TcR/CD3-specific mAb. Comparison of the reactivity of two Mls-1a-specific T cell hybridomas expressing the same TcR at similar surface density, revealed both quantitative and qualitative differences between CD3-specific mAb and Mls stimulation of the hybridomas. A small quantitative difference in the sensitivity of hybridoma FJ22.5 to stimulation with V beta 6 or CD3-specific mAb resulted in a marked decrease in efficiency of stimulation by Mls-1a for interleukin 2 production and to inability to detect growth inhibition by Mls-expressing cells. A qualitative difference was observed when analyses of inositol phosphate production were performed under optimal conditions of stimulation of the highly responsive T cell hybridoma (FJ8.1): only stimulation with CD3-specific mAb, but not Mls-expressing cells, could induce detectable inositol phosphate production. Lack of cytolysis of Mls-1a class II-expressing B cells may have evolutionary significance in view of the recent mapping of Mls to mouse mammary tumor virus genes.

Animals↗

PubMed1990

Hyperplasia of mouse duodenal crypts and its control by NK cells during the initial phase of DMH carcinogenesis.

The possible regulatory role of NK cells on early events in chemical carcinogenesis remains undefined. The present study examined whether NK cells control 1,2-dimethylhydrazine (DMH)-induced hyperplasia of the duodenal crypt in CD1 mice. Mice receiving chronic DMH treatment showed a dose-dependent hyperplasia confined to the proliferative zone, with a parallel increase in mitotic and 3H-TdR-labelled cells and significant suppression of splenic NK activity. Complete ablation of splenic NK activity with anti-asialo GM-I antibody (alpha AGM-I) treatment slightly enhanced hyperplasia. Halving of the DMH dose for 2 weeks led to regression of hyperplasia, which was totally prevented by alpha AGM-I treatment. The alpha AGM-I treatment alone did not influence crypt size in normal mice. Finally, a stimulation of NK activity with Poly I:C treatment in DMH-treated mice caused regression of the DMH-induced hyperplasia. Our results suggest that hyperplastic cells with possible genetic alterations induced by the carcinogen express target structures for NK cells, but that simultaneous carcinogen-induced suppression of NK activity hampers their containment, allowing progression of hyperplasia to neoplasia, possibly owing to additional genetic changes.

1,2-Dimethylhydrazine↗

PubMed1992

Two subtypes of HLA-B51 differing by substitution at position 171 of the alpha 2 helix.

Newly defined antigens of the B5, B35 cross-reacting group have been found in Japanese and North American Indians. Nucleotide sequencing of the alleles encoding the Japanese B5.35 antigen and the variant B5 antigen from the Piman Indians show them to be identical. This new allele, B*5102, differs from B*5101 by a single nucleotide substitution that changes residue 171 from histidine to tyrosine. Residue 171, which is part of the alpha 2 helix, is believed to contribute directly to peptide interaction in the A pocket of the binding groove and is either histidine or tyrosine in all HLA-A, B, C heavy chains. Tyrosine 171 is shared by B*5102, B*3501, B*3502, and B*5301 and must be responsible for the serological cross-reactivities of these molecules not shared with B*5101. Stimulation of lymphocytes from a B*5101 positive donor with B*5102 positive cells failed to generate cytotoxic T cells with specificity for the difference between these molecules. However, one out of five clones of cytotoxic T cells raised against B*5101 failed to lyse targets expressing B*5102. Substitution of histidine for tyrosine at residue 171 affected recognition of HLA-B35-restricted human minor histocompatibility antigen-specific T cell clones.

Amino Acid Sequence↗

PubMed1988

SV40 T-antigen is a histocompatibility antigen of SV40-transgenic mice.

Although the extensive family of non-H-2 histocompatibility (H) antigens provides a formidable barrier to transplantation, the origin of their encoding genes are unknown. Recent studies have demonstrated both the linkage between H genes and retroviral sequences and the ability of integrated Moloney-murine leukemia virus to encode what is operationally defined as a non-H-2 H antigen. The experiments described in this communication reveal that skin grafts from an SV40 T-antigen transgenic C57BL/6 mouse strain are rejected by coisogenic C57BL/6 recipients with a median survival time of 49 days, which is comparable to those of many previously defined non-H-2 H antigens. The specificity of this response for SV40 T-antigen was demonstrated by the identification of SV40 T-antigen-specific cytolytic T lymphocytes and antibodies in multiply-grafted recipients. Although these cytolytic T lymphocytes could detect SV40 T-antigen on syngeneic SV40-transformed fibroblasts, they neither could be stimulated by splenic lymphocytes from T-antigen transgenics nor could they lyse lymphoblast targets from T-antigen transgenics. These observations suggest a limited tissue distribution of SV40 T-antigen in these transgenics. These results confirm the role of viral genes in the determination of non-H-2 histocompatibility antigens by the strict criteria that such antigens stimulate (1) tissue graft rejection and (2) generation of cytolytic T lymphocytes. Furthermore, they suggest that the SV40 enhancer and promoter region can target expression of SV-40 T-antigen to skin cells of transgenic animals.

Animals↗

PubMed1985

Tumor growth and evasion of immune destruction: UV-induced tumors as a model.

A number of complex interrelating mechanisms contributing to progressive growth of an immunogenic tumor and its evasion of immune destruction are exemplified in the model of the UV-induced tumor 1591 (fig. 3). The effects of (i) carcinogen-induced immune suppression, (ii) age-related changes in immune competence, (iii) generation and immunoselection of tumor cell variants which do not express target tumor antigen and (iv) tumor-induced immune suppression have been documented. The findings may help to assess the problems and the possibilities of immunotherapy of cancer. The problems reside in the many avenues of escape available to the tumor. The possibilities for immunotherapy derive from the fact that progressively growing tumors may still retain immunogenic antigens and therefore be susceptible to immune attack.

Aging↗

PubMed1991

Live attenuated Salmonella vaccines and their potential as oral combined vaccines carrying heterologous antigens.

Live attenuated salmonellae are protective, and are candidate vaccines against invasive salmonella infections in man and animals. Different attenuating mutations have been described, and more than one can be incorporated in a vaccine for added safety. Combined salmonella vaccines express target carbohydrate and protein antigens or epitopes from viruses, bacteria and eukaryotic parasites, either within or on the surface of the cell, as capsules, fimbriae, or in the flagellin. Humoral, secretory and cellular responses to the recombinant antigens has been demonstrated. Experimental protection against diseases including streptococcal infection, tetanus, influenza and malaria has been obtained.

Administration, Oral↗

PubMed1990

Autoantibodies to cytokines--friends or foes?

Cytokines form a network of communication signals between cells of the immune system, and between the immune system and other organs. They interact with structurally complex and often dynamically expressed target cell receptors. The recent demonstration of autoantibodies to cytokines, even in sera of normal individuals, suggests further complexities in the way that nature regulates cytokine functions. Based mainly on evidence obtained by investigating autoantibodies to interleukin 1 alpha (IL-1 alpha), Klaus Bendtzen and colleagues discuss the possibility that naturally occurring antibodies may function as specific physiological carriers and regulators of cytokines.

Animals↗

PubMed2025

Network-based drug repurposing for psychiatric disorders using single-cell genomics.

Neuropsychiatric disorders lack effective treatments due to a limited understanding of the underlying cellular and molecular mechanisms. To address this, we integrated population-scale single-cell genomics data and analyzed 23 cell-type-level gene regulatory networks across schizophrenia, bipolar disorder, and autism. Our analysis revealed potential druggable transcription factors co-regulating known risk genes that converge into cell-type-specific co-regulated modules. We applied graph neural networks on those modules to prioritize novel risk genes and leveraged them in a network-based drug repurposing framework to identify 220 drug molecules with the potential for targeting specific cell types. We found evidence for 37 of these drugs in reversing disorder-associated transcriptional phenotypes. Additionally, we discovered 335 drug-cell quantitative trait loci (eQTLs), revealing genetic variation's influence on drug target expression at the cell-type level. Our results provide a single-cell network medicine resource that provides potential mechanistic insights for advancing treatment options for neuropsychiatric disorders.

Drug Repositioning↗

PubMed2026

HIF-1 signaling contributes to lenvatinib resistance in patient-derived HCC organoids.

Resistance to lenvatinib remains an important limitation in hepatocellular carcinoma treatment. Six patient-derived organoid lines were established and classified as sensitive or resistant according to ex vivo drug responses, retaining histological and immunophenotypic features of matched parental tumors. Resistant organoids showed unchanged ATP activity, whereas sensitive ones exhibited pronounced morphological changes and reduced ATP activity at higher concentrations. Transcriptome sequencing identified 408 upregulated and 269 downregulated genes in resistant versus sensitive organoids, with HIF-1 signaling among altered pathways. In resistant organoids, lenvatinib increased HIF-1α, ANGPT2, and HK3 mRNA, whereas comparable changes were not detected in sensitive organoids. KC7F2 reduced these transcripts and further decreased ATP activity when combined with lenvatinib. In organoid-derived xenografts, this combination suppressed tumor growth and HIF-1 target expression more than lenvatinib alone, indicating HIF-1 signaling contributes to the resistant phenotype and its inhibition may enhance response.

Drug resistance↗

PubMedDate not supplied

Selection of the T-cell repertoire during ontogeny.

This report examines conflicting hypotheses concerning T-cell repertoire selection in terms of H-2 restriction during ontogeny. The experiments described in this report were incompatible with the hypothesis that bias in the repertoire is solely a consequence of "more or less intentional priming" by foreign antigen. Rather, results indicate that the repertoire is selected by self major histocompatibility complex (MHC) antigens in the absence of foreign antigens. Allorestricted T cells, the existence of which was previously thought to be incompatible with the concept of complete repertoire selection by self MHC antigens, were shown to significantly cross-react on targets expressing self MHC antigens. Thus, it is possible that allorestricted T cells are simply cross-reactive T-cell clones restricted by self MHC antigens; indeed, all experimental data were compatible with the idea of complete selection of the T-cell repertoire in terms of H-2 restriction by self MHC antigens.

Animals↗

PubMed1988

Targeting of an inducible toxic phenotype in animal cells.

We have developed a toxic, or suicide, vector whose action is based on the targeted expression of the herpes simplex virus 1 thymidine kinase gene product in cultured cells or transgenic animals. This protein is able to convert nucleoside analogs such as acyclovir and 1-(2-deoxy-2-fluoro-beta-D-arabino-furanosyl)-5-iodouracil (FIAU) to toxic intermediates. The activation of these compounds disrupts cellular DNA replication, leading to rapid cell death. Neither acyclovir, FIAU, nor the herpes thymidine kinase alone is harmful to cells. This approach is simple and should have widespread applicability in studying lineage formation in cultured cells and transgenic animals.

Acyclovir↗

PubMed1992

Directed establishment of rat brain cell lines with the phenotypic characteristics of type 1 astrocytes.

Interest in obtaining cell lines for use in studies on the development and biochemistry of the central nervous system has motivated efforts to establish cells from primary brain cultures by the use of oncogene-transfer techniques. In previous reports, cell lines derived from astrocytes in this way have had immature or abnormal phenotypes. We have explored the possibility of specifically "targeting" expression of exogenous oncogenes to differentiated astrocytes by using the promoter of the gene encoding glial fibrillary acidic protein, which is expressed almost exclusively in such cells. We report here that cell lines displaying the phenotypic characteristics of type 1 astrocytes can be established reproducibly in this manner. Given the heterogeneity of primary cultures, the availability of clonal cell lines displaying characteristics of type 1 astrocytes should greatly facilitate our understanding of the biology of these cells.

Animals↗

PubMed1992

Generation and synchronization of gonadotropin-releasing hormone (GnRH) pulses: intrinsic properties of the GT1-1 GnRH neuronal cell line.

The immortalized neuronal cell line GT1-1 was used to investigate the endogenous pattern of GnRH release. The GT1-1 cell line was derived from a GnRH-secreting tumor in a transgenic mouse induced by genetically targeted expression of the potent simian virus 40 oncogene encoding tumor antigen. Cells attached to coverslips were superfused in Sykes-Moore chambers with Locke's medium, Ca(2+)-free Locke's medium, or Opti-MEM (another defined medium) for 2 hr, and samples were collected at 4-min intervals. Release of GnRH in 17 of 18 superfusion chambers was seen to be pulsatile when data were analyzed by cluster analysis. No significant differences were observed whether only one or both of the coverslips forming the chamber were coated with cells. Pulses exhibited a mean interpulse interval of 25.8 +/- 1.5 min, a mean duration of 18.8 +/- 1.4 min, and a mean amplitude of 150.5 +/- 6.0% above preceding nadir. The removal of Ca2+ from the Locke's medium resulted in the progressive reduction of the amplitude and eventually in the absence of identifiable pulses. Pulses reappeared after the return of Ca2+ to the medium. It is concluded that the GT1-1 cell line secretes GnRH in a rhythmic pattern. These findings suggest that the pulsatile release of GnRH (GnRH pulse generator) may be an intrinsic characteristic of the GnRH neurons. Synchronization of pulsatile release from individual neurons could be mediated via numerous cell-to-cell contacts observed in the cultured cells on coverslips. Synchronization of GnRH release from cells on two physically separated coverslips forming a chamber would appear to be accomplished by a diffusible mediator.

Animals↗

PubMed1983

Lack of donor-specific tolerance in mice with established anti-Ia-treated islet allografts.

Pancreatic islet allografts pretreated in vitro with monoclonal Ia antibody and transplanted beneath the renal capsule result in normoglycemia beyond 100 days in streptozotocin-induced diabetic recipient mice that differ only at H-2 K, H-2 K + I, or H-2 K + I + D from the donors. Mice with established islet allografts are not tolerant of donor-specific skin or islet antigens, but rather reject donor skin grafts in an accelerated fashion. Established anti-Ia antibody pretreated islet allografts continue to express target antigens and remain susceptible to rejection after challenge with donor skin grafts.

Animals↗

PubMed1989

Immunosuppression by anti-CD4 treatment in vivo. Persistence of secondary antiviral immune responses.

Elimination of CD4+ helper T cells by treatment with monoclonal antibodies (mcAb) in vivo has been used as a new mode of immunosuppression in organ transplantation and autoimmune diseases. To explore the potential risks of this therapeutic approach we have studied antiviral responses in mice depleted of CD4+ T cells. Depletion of CD4+ T cells in vivo completely suppressed the generation of a primary virus-specific cytotoxic response. Injection of high doses of recombinant interleukin-2 (rIL-2) given after virus immunization restored the responsiveness of helper cell-depleted mice to virus-expressing target cells, suggesting a crucial role of IL-2 in antiviral defense mechanisms. In contrast to primary responses, memory cytolytic responses to viral antigens persisted despite depletion of greater than 90% of CD4+ helper T cells. The generation of such memory cytotoxic responses was dependent upon help provided by CD4+ lymphocytes surviving the antibody therapy. After antibody treatment, frequencies of virus-specific helper cells were minimal in primed mice, excluding insufficient helper cell elimination as the reason for the persistence of memory responses. Data presented here suggest that there exist distinct helper pathways in primary and secondary cytolytic antiviral responses that might represent several subsets of helper T cells as well as differences in helper signals required by distinct effector cells.

Animals↗

PubMed1991

Transgenic mice provide new insights into the role of TGF-alpha during epidermal development and differentiation.

Transforming growth factor-alpha (TGF-alpha) is thought to be the major autocrine factor controlling growth in epidermal cells. To explore further the role of TGF-alpha in epidermal growth and differentiation, we used a human keratin K14 promoter to target expression of rat TGF-alpha cDNA to the stratified squamous epithelia of transgenic mice. Unexpectedly, the only regions of epidermis especially responsive to TGF-alpha overexpression were those that were normally thick and where hair follicle density was typically low. This included most, if not all, body skin from 2-day- to 2-week-old mice, and ear, footpad, tail, and scrotum skin in adult mice. In these regions, excess TGF-alpha resulted in thicker epidermis and more stunted hair growth. Epidermal thickening was attributed both to cell hypertrophy and to a proportional increase in the number of basal, spinous, granular, and stratum corneum cells. During both postnatal development and epidermal differentiation, responsiveness to elevated TGF-alpha seemed to correlate with existing epidermal growth factor (EGF) receptor levels, and we saw no evidence for TGF-alpha-mediated control of EGF receptor (EGFR) expression. In adults, no squamous cell carcinomas were detected, but benign papillomas were common, developing primarily in regions of mechanical irritation or wounding. In addition, adult transgenic skin that was still both sensitive to TGF-alpha and subject to mild irritation displayed localized regions of leukocytic infiltration and granular layer loss, characteristics frequently seen in psoriasis in humans. These unusual regional and developmental effects of TGF-alpha suggest a natural role for the growth factor in (1) controlling epidermal thickness during development and differentiation, (2) involvement in papilloma formation, presumably in conjunction with TGF-beta, and (3) involvement in psoriasis, in conjunction with some as yet unidentified secondary stimulus stemming from mild mechanical irritation/bacterial infection.

Animals↗

PubMed1982

Killing of measles virus-infected cells by human cytotoxic T cells.

Lymphocytes from normal individuals were tested for the capacity to generate measles virus-specific cytotoxic T-cell responses after in vitro stimulation with measles virus. Approximately 12% (5 of 40) of the normal adults tested produced significant cytotoxic responses. The cytotoxic response was measles virus specific both at the level of stimulation and at the effector level. Studies of the specificity of cytotoxic effectors from five normal donors by direct lysis or cold target inhibition or both indicated that most, if not all, of the virus-specific activity was self-specific. A detailed analysis of one donor (W6) indicated that measles-specific cytotoxicity was largely HLA-A and -B restricted; unexplained cross-reactive lysis was observed with some targets, but this lysis appeared to be HLA related, since all of the targets expressed HLA-B12. An analysis of the cellular requirements for the production of measles-immune cytotoxic T lymphocytes demonstrated that T cells and macrophages (depleted of natural killer and K cells) were sufficient for the generation of killer cells. Most of the cytotoxic effector activity was mediated by OKT3+ OKT4- OKT8+ cells.

Adolescent↗