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Results for “Targeted expression”

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PubMed2004

Ets-dependent regulation of target gene expression during megakaryopoiesis.

Megakaryopoiesis is the process by which hematopoietic stem cells in the bone marrow differentiate into mature megakaryocytes. The expression of megakaryocytic genes during megakaryopoiesis is controlled by specific transcription factors. Fli-1 and GATA-1 transcription factors are required for development of megakaryocytes and promoter analysis has defined in vitro functional binding sites for these factors in several megakaryocytic genes, including GPIIb, GPIX, and C-MPL. Herein, we utilize chromatin immunoprecipitation to examine the presence of Ets-1, Fli-1, and GATA-1 on these promoters in vivo. Fli-1 and Ets-1 occupy the promoters of GPIIb, GPIX, and C-MPL genes in both Meg-01 and CMK11-5 cells. Whereas GPIIb is expressed in both Meg-01 and CMK11-5 cells, GPIX and C-MPL are only expressed in the more differentiated CMK11-5 cells. Thus, in vivo occupancy by an Ets factor is not sufficient to promote transcription of some megakaryocytic genes. GATA-1 and Fli-1 are both expressed in CMK11-5 cells and co-occupy the GPIX and C-MPL promoters. Transcription of all three megakaryocytic genes is correlated with the presence of acetylated histone H3 and phosphorylated RNA polymerase II on their promoters. We also show that exogenous expression of GATA-1 in Meg-01 cells leads to the expression of endogenous c-mpl and gpIX mRNA. Whereas GPIIb, GPIX, and C-MPL are direct target genes for Fli-1, both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. In contrast, GPIIb expression appears to be independent of GATA-1 in Meg-01 cells.

Base Sequence↗

PubMed1995

GM-CSF enhances IL-2-activated natural killer cell lysis of clonogenic AML cells by upregulating target cell expression of ICAM-1.

Acute myeloid leukemia (AML) cells express the surface adhesion proteins intercellular adhesion molecule-1 (ICAM-1, CD54) and lymphocyte function associated molecule-3 (LFA-3, CD58). Exposure to the myeloid growth-promoting cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) upregulates expression of ICAM-1 and LFA-3 on AML cells but does not increase their sensitivity to lysis by interleukin-2-activated natural killer cells (LAK) in 51Cr assays. However when AML cells are exposed to GM-CSF prior to incubation with LAK, their subsequent clonogenic activity is significantly reduced. If a blocking antibody to ICAM-1 is added during the incubation period of AML with LAK, the inhibitory effect is completely ablated. A less pronounced effect is observed with an antibody to LFA-3. ICAM-1 is expressed on a greater proportion of CD34+ than CD34- AML cells and exposure to GM-CSF induces a significantly greater upregulation of ICAM-1 on leukemic CD34+ cells than their CD34- counterparts. These data suggest that the inhibitory effect of IL-2-activated natural killer cells on clonogenic AML cells is mediated principally via the lymphocyte function associated molecule-1 (LFA-1)/ICAM-1 interaction. Interleukin-2 upregulates LFA-1 expression on natural killer cells. Simultaneous administration of effector cell activators such as IL-2 and target cell modulators such as GM-CSF may have a therapeutic benefit in patients with minimal residual myeloid leukemia.

Adult↗

PubMed2006

Lentivirus envelope protein exerts differential neuropathogenic effects depending on the site of expression and target cell.

We investigated the neuropathogenic effects of feline immunodeficiency virus (FIV) envelope proteins in the context of both extracellular exposure and intracellular expression in feline neural cells. The envelope from the neurovirulent CSF-derived FIV V1 strain (V1-CSF) conferred infectivity to pseudotyped viruses in peripheral blood mononuclear cells (P < 0.01) in contrast to other cell types. Intracellular V1-CSF envelope expression in macrophages and microglia but not astrocytes resulted in the induction of host inflammatory genes contributing to neurotoxicity including IL-1beta, TNF-alpha, and indolamine 2',3'-dioxygenase (IDO) (P < 0.05) with concurrent neuronal death (P < 0.05). Upregulation of the endoplasmic reticulum stress genes was evident in brains from FIV-infected animals (P < 0.05) and in FIV-infected macrophages (P < 0.05) relative to controls. Intrastriatal implantation of an FIV envelope pseudotyped virus led to marked neuroinflammation and neuronal injury associated with neurobehavioral deficits (P < 0.01). Thus, lentivirus envelope proteins exert differential neuropathogenic effects through mechanisms that depend on the infected or exposed cell type.

Animals↗

PubMed2004

Thermally oxidized dietary fat upregulates the expression of target genes of PPAR alpha in rat liver.

Oxidized fats affect animal metabolism in several ways. To gain a comprehensive understanding of the molecular mechanisms underlying the effects of dietary oxidized fats in rats at varying dietary vitamin E concentrations, the gene expression profile of the liver was monitored with an array containing 1176 binding sites for cDNAs. Rats were fed diets with a fresh fat and vitamin E concentrations of 25 or 250 mg alpha-tocopherol/kg (FF25, FF250 rats) or a fat heated at 50 degrees C for 38 d, with vitamin E concentrations of 25 or 250 mg alpha-tocopherol/kg (OF25, OF250 rats) for 63 d. Differences in gene expression were considered to be significant at a ratio of at least 1.4. In the OF25 rats, the expression of 47 genes was altered; in the OF250 rats, the expression of 37 genes was altered, and in the FF250 rats, the expression of 21 genes was altered compared with FF25 rats. In both OF25 and OF250 rats, a series of target genes of the peroxisome proliferator-activated receptor alpha (PPAR alpha) was upregulated. Determination of gene expression of acyl CoA oxidase and activity of catalase confirmed that oxidized fats caused peroxisome proliferation in the liver. In OF25 and OF250 rats, there was also upregulation of 12 and 5 genes involved in xenobiotic metabolism and stress response, of 7 and 7 genes involved in protein metabolism, of 5 and 2 genes encoding intracellular effectors or modulators and of 5 and 6 genes, respectively, encoding activators or repressors of transcription or translation. In conclusion, this study provides indirect evidence that dietary oxidized fats cause an activation of the PPAR alpha, irrespective of the dietary vitamin E concentration. Identification of several other differentially regulated genes may be helpful to understand the effects of oxidized fats on animal metabolism.

Acyl-CoA Oxidase↗

PubMed2001

Robust prostate-specific expression for targeted gene therapy based on the human kallikrein 2 promoter.

Tissue-specific transcriptional regulatory elements can increase the safety of gene therapy vectors. Unlike prostate-specific antigen (PSA/hK3), whose expression displays an inverse correlation with prostate cancer grade and stage, human glandular kallikrein 2 (hK2) is upregulated in higher grade and stage disease. Therefore, our goal was to develop a strong and prostate-specific hK2-based promoter for targeted gene therapy. We identified the minimum "full-strength" hK2 enhancer and built transcriptional regulatory elements composed of multiple tandem copies of this 1.2-kb enhancer, fused to the hK2 minimal promoter. Relative to the weak induction of the minimal hK2 promoter by androgen analog (R1881) in androgen receptor (AR)-positive LNCaP cells, transcriptional activity was increased by 25-, 44-, 81-, and 114-fold when one to four enhancers were spliced to the hK2 promoter, respectively. In contrast, the enhancer/promoter elements were inactive in the AR(-) prostate cancer line PC-3 and in a panel of nonprostate lines, including 293, U87, MCF-7, HuH-7, and HeLa cells. Furthermore, we generated a recombinant adenovirus, ADV.hK2-E3/P-EGFP, expressing enhanced green fluorescent protein (EGFP) under the control of the hK2 triplicate enhancer/promoter, and compared its properties with ADV.CMV-EGFP expressing EGFP under the control of the cytomegalovirus (CMV) enhancer/promoter. Unlike the CMV promoter, the hK2-E3/P promoter was at least 100-fold inducible by R1881 in the adenoviral backbone. Compared with in situ injection of subcutaneous LNCaP tumors with ADV.CMV-EGFP, which led to detectable EGFP expression in tumor, liver, and brain tissue, ADV.hK2-E3/P-EGFP injection led to robust but tumor-restricted EGFP expression. These results suggest that the hk2 multienhancer/promoter should be a powerful novel reagent for safer targeted gene therapy of prostate cancer.

Adenoviridae↗

PubMed2004

Her2/neu is not a commonly expressed therapeutic target in melanoma -- a large cohort tissue microarray study.

Melanoma is among the most chemotherapy-resistant malignancies. Numerous new agents have been developed that target specific molecules on cancer cells, including the monoclonal antibody trastuzumab, which targets Her2/neu and has been very beneficial in the treatment of breast cancer. There are conflicting reports in the literature about Her2/neu expression in melanoma specimens, but all of the cohorts studied have been small. We therefore examined Her2/neu expression in a very large cohort of melanoma specimens in order to determine the value of exploring trastuzumab therapy for melanoma patients. Immunohistochemical staining was performed on two tissue microarrays, together containing 600 intact specimens. Expression was evaluated semi-quantitatively and correlated with tumour stage and other clinicopathological data. Of the 600 specimens in the cohort, 31 patients (5.2%) had positive Her2/neu expression. Among the primary cutaneous specimens (n=269), 7% had positive Her2/neu staining, while 3.6% of the recurrent or metastatic specimens (n=331) had positive Her2/neu staining (P=0.06). Among the primary lesions there was no significant correlation between Her2/neu expression, Clark level and ulceration; however, Her2/neu expression was associated with lesions with a Breslow depth of < 2 mm (P=0.05). Using this very large cohort of melanoma specimens, we found only a few cases with aberrant Her2/neu expression, many of them being primary cutaneous lesions rather than recurrent or metastatic lesions. Our findings suggest that drugs that specifically target Her2/neu are not likely to be useful for the treatment of metastatic melanoma or as adjuvant therapy for melanoma patients at high risk for recurrence.

Cohort Studies↗

PubMed2006

Development of a flexible and potent hypoxia-inducible promoter for tumor-targeted gene expression in attenuated Salmonella.

To increase the potential of attenuated Salmonella as gene delivery vectors for cancer treatment, we developed a hypoxia-inducible promoter system to limit gene expression specifically to the tumor. This approach is envisaged to not only increase tumor specificity, but also to target those cells that are most resistant to conventional therapies. We demonstrate that the exponential growth of the attenuated bacteria is identical under normoxia and hypoxia. A hypoxia-inducible promoter (HIP-1) was created from a portion of the endogenous Salmonella pepT promoter and was shown to drive reporter gene expression under both acute and chronic hypoxia, but not under normoxia. Genetic engineering of the TATA- and FNR-box within HIP-1 allowed fine-tuning of gene induction, resulting in hypoxic induction factors of up to 200-fold. Finally, we demonstrate that HIP-1 can drive hypoxia-mediated gene expression in bacteria which have colonized human tumor xenografts in mouse models. Expression of both GFP and RFP under control of HIP-1 demonstrated an approximately 15-fold increase relative to a constitutive promoter when tumors were made hypoxic. Moreover, the use of a constitutive promoter resulted in reporter gene expression in both tumors and normal tissues, whereas reporter gene expressing using HIP-1 was confined to the tumor.

ATP-Binding Cassette Transporters↗

PubMed2000

Curbing the nuclear activities of beta-catenin. Control over Wnt target gene expression.

Wnt molecules control numerous developmental processes by altering specific gene expression patterns, and deregulation of Wnt signaling can lead to cancer. Many Wnt factors employ beta-catenin as a nuclear effector. Upon Wnt stimulation, beta-catenin heterodimerizes with T-cell factor (TCF) DNA-binding proteins to form a transcriptional activator complex. As the activating subunit of this complex, beta-catenin performs dual tasks: it alleviates repression of target gene promoters and subsequently it activates them. Beta-catenin orchestrates these effects by recruiting chromatin modifying cofactors and contacting components of the basal transcription machinery. Although beta-catenin and TCFs are universal activators in Wnt signaling, their target genes display distinct temporal and spatial expression patterns. Apparently, post-translational modifications modulate the interactions between TCFs and beta-catenin or DNA, and certain transcription factors can sequester beta-catenin from TCFs while others synergize with beta-catenin-TCF complexes in a promoter-specific manner. These mechanisms provide points of intersection with other signaling pathways, and contribute to the complexity and specificity of Wnt target gene regulation.

Animals↗

PubMed1998

Analysis of WT1 target gene expression in stably transfected cell lines.

The Wilms' tumour suppressor gene WT1 encodes a zinc finger protein that is mutated in a subset of Wilms' tumours. Mutation screening and animal studies revealed essential roles during development and later function of the kidneys and the entire genitourinary system. Sequence similarity suggested a possible role for WT1 as a transcription factor. Indeed, sequence specific DNA binding and transcriptional activation or repression potential could be demonstrated in transient transfection assays with various reporter constructs. To identify endogenous WT1 target genes we established HEK293 cell lines expressing the different WT1 isoforms in a tetracycline dependent manner. Differential display PCR (ddPCR) was performed on RNA from stable WT1 transfected HEK293 cell lines and two other WT1 transfected lines (G401 and Saos-2). In an extended survey of several thousand ddPCR bands only few differences in intensity were seen and none of these could unambiguously be verified as being WT1 regulated by subsequent Northern blot analysis. In addition, almost none of the WT1 target genes identified to date in transient co-transfection assays could be confirmed by either ddPCR or Northern hybridization in the three stable transfected cell lines. Among the nine genes expressed, the only exceptions were CSF1 and to a lesser extent IGF1R being induced in Saos-2/G401 and HEK293 cells, respectively. At least two of the cell lines tested had previously shown clear biological effects though -- either WT1 dependent apoptosis (Saos-2) or greatly reduced tumorigenicity (G401). This suggests that WT1 may regulate only a very small set of genes that escape the detection methods used or it may not act as a transcription factor that influences steady state levels of mRNA.

Blotting, Northern↗

PubMed2006

Imaging chemically modified adenovirus for targeting tumors expressing integrin alphavbeta3 in living mice with mutant herpes simplex virus type 1 thymidine kinase PET reporter gene.

UNLABELLED: The aim of this study was to change adenovirus tropism by chemical modification of the fiber knobs with PEGylated RGD peptide for targeting integrin alpha(v)beta(3) that is uniquely or highly expressed in tumor cells and neovasculature of tumors of various origins. METHODS: The first generation Ad (Ad) vector, which expresses the herpes simplex virus type 1 mutant thymidine kinase (HSV1-sr39tk) gene under the control of cytomegalovirus (CMV) promoter was conjugated with poly(ethylene glycol) (PEG) or RGD-PEG. The transduction efficiency of Ads (Adtk, PEG-Adtk, and RGD-PEG-Adtk) into different types of cells (293T, MCF7, MDA-MB-435, and U87MG) was analyzed and quantified by thymidine kinase (TK) assay using 8-(3)H-penciclovir (8-(3)H-PCV) as substrate. The in vivo infectivity of the Ad vectors after intravenous administration into integrin alpha(v)beta(3)-positive U87MG and MDA-MB-435 tumor-bearing athymic nude mice was measured by both noninvasive microPET using 9-[4-(18)F-fluoro-3-(hydroxymethyl)butyl]guanine ((18)F-FHBG) as a reporter probe and ex vivo TK assay of the tumor and tissue homogenates. RESULTS: PEGylation completely abrogated coxsackievirus and adenovirus receptor (CAR)-knob interaction and the infectivity of PEG-Adtk is significantly lower than that of unmodified Adtk in CAR-positive cells. RGD-PEG-modified virus (RGD-PEG-Adtk) had significantly higher infectivity than PEG-Adtk and the extent of increase is related to both CAR and integrin alpha(v)beta(3) expression levels. (18)F-FHBG had minimal nonspecific uptake in the liver and tumors that are void of sr39tk. Mice preinjected intravenously with unmodified Adtk resulted in high hepatic uptake and moderate tumor accumulation of the tracer. In contrast, RGD-PEG-Adtk administration resulted in significantly lower liver uptake without compromising the tumor accumulation of (18)F-FHBG. Expression of TK in the liver and tumor homogenates corroborated with the magnitude of (18)F-FHBG uptake quantified by noninvasive microPET. Analysis of liver and tumor tissue integrin level confirmed that RGD-integrin interaction is responsible for the enhanced tumor infectivity of RGD-PEG-Adtk. CONCLUSION: The results of this study suggest that RGD-PEG conjugation is an effective way to modify Ad vector tropism for improved systemic gene delivery. Noninvasive PET and (18)F-FHBG are able to monitor in vivo transfectivity of both Adtk and RGD-PEG-Adtk vectors in the liver and tumors after intravenous injection.

Adenoviridae↗

PubMed2002

Paracrine mediators of endometrial matrix metalloproteinase expression: potential targets for progestin-based treatment of endometriosis.

The endometrial lining of the human uterus is a highly specialized, steroid-sensitive tissue. Throughout the reproductive years, the endometrium undergoes dramatic cycles of growth, differentiation, and breakdown under the influence of ovarian steroids. In response to changes in steroid exposure throughout the menstrual cycle, the endometrium produces an array of bioactive growth factors and other cytokines that are critical components of paracrine communication. For example, cell-cell communication via paracrine factors directs the expression of matrix metalloproteinases (MMPs), enzymes that mediate tissue remodeling during the menstrual cycle. The disease endometriosis is thought to occur as a consequence of retrograde menstruation, and MMPs appear to contribute to the establishment and progression of ectopic endometrial growth in the peritoneal cavity. Although the risk for developing endometriosis is linked to a woman's steroid exposure, locally produced paracrine factors can modify steroid action on multiple gene targets, including the MMPs. Estrogen-associated growth factors as well as inflammatory cytokines are potent stimulators of MMP expression and may contribute to the ability of endometrial fragments to invade the peritoneal surface and establish ectopic sites of growth. In contrast, paracrine factors associated with progesterone action during early pregnancy inhibit MMP expression and prevent ectopic endometrial growth in an experimental model. For example, locally produced retinoic acid and transforming growth factor-beta (TGF-beta) act in concert with progesterone to suppress MMPs, while enhancing expression of MMP inhibitors (TIMPs) during endometrial differentiation. Targeting pregnancy-associated factors that inhibit endometrial-specific MMP expression and action may enhance the effectiveness of progestin-related treatments for endometriosis.

Endometriosis↗

PubMed1990

Expression and targeting of intracellular antibodies in mammalian cells.

Genes encoding the heavy and light chains of a hapten-specific IgM antibody were modified by site-directed mutagenesis to destroy the hydrophobic leader sequences and allow expression in the cytoplasm of non-lymphoid cells. The in situ assembly of the mutant heavy and light chains was tested in transfected cell lines by immunofluorescence using anti-idiotypic antibodies. A positive diffuse cytoplasmic staining was observed. This demonstrated that the antibody polypeptide chains could assemble in the cell cytoplasm and led us to ask whether antibodies could be further targeted to the nucleus. Mutations were therefore made in which the leader sequence of the light chain was replaced by the nuclear localization signal of the SV40 large T antigen. Transfectants in which the heavy chain lacking the hydrophobic leader was expressed together with a light chain carrying the nuclear localization signal were selected and a nuclear distribution of the assembled antibody was found. Thus, it should prove possible to target a specific antibody to the cell nucleus with the aim of interfering with the function of a nuclear antigen.

Amino Acid Sequence↗

PubMed1999

Semi-quantitative reverse-transcriptase polymerase chain reaction: an approach for the measurement of target gene expression in human brain.

Polymerase chain reaction (PCR) is a very powerful tool for qualitative evaluation of nucleic acids due to its high efficiency and convenience. Together with the reverse transcription (RT) reaction, the PCR method has been widely applied to the quantitative measurement of DNA and RNA messages. Since RT-PCR is much more sensitive than all of the traditional methods for quantification of mRNA, including Northern blot, ribonuclease protection, RNA blot, and solution hybridization assays, it is the method of choice for quantitative analyses of low abundance mRNA messages. However, because of the exponential nature of the PCR amplification, RT-PCR quantitation may be problematic, giving false estimates of the abundance of the target messages. By using the constitutively expressed 'housekeeping' gene cyclophilin as a reference gene to normalize mRNA levels, and by taking data from the exponential phase of the PCR amplification, we have developed a rapid and reliable semi-quantitative measurement of the relative abundance of dopamine transporter (DAT) mRNA. The semi-quantitative PCR method has been applied to illustrate its use for the measurement of DAT mRNA in post mortem human brain.

Adult↗

PubMed1998

HIV-1 DNA based vaccine induces a CD8 mediated cross-clade CTL response.

Novel approaches for the generation of more effective vaccines for HIV-1 are of significant importance. In this report we analyse the immunogenicity and efficacy of a DNA vaccination approach in a chimpanzee model system. Three chimpanzees were vaccinated with DNA constructs which express the env, rev, gag and pol proteins. These animals developed specific cellular responses to these proteins, although the nature of the responses varied among the animals. We demonstrated that DNA vaccination led to a CD8 mediated killing of targets expressing the homologous clade B envelope as well as targets expressing heterologous clade E envelope. In addition seronegative individuals have been inoculated with a DNA construct which expresses the env, rev proteins. These studies serve as an important benchmark for the use of DNA vaccine technology for the production of protective immune responses.

AIDS Vaccines↗

PubMed2004

Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands.

We have recently identified glucose-regulated protein-78 (GRP78) as a relevant molecular target expressed in metastatic tumors by fingerprinting the circulating repertoire of antibodies from cancer patients. Here we design and evaluate a ligand-receptor system based on the tumor cell membrane expression of GRP78. We show that GRP78 binding peptide motifs target tumor cells specifically in vivo and in human cancer specimens ex vivo. Moreover, synthetic chimeric peptides composed of GRP78 binding motifs fused to a programmed cell death-inducing sequence can suppress tumor growth in xenograft and isogenic mouse models of prostate and breast cancer. Together, these preclinical data validate GRP78 on the tumor cell surface as a functional molecular target that may prove useful for translation into clinical applications.

Animals↗

PubMed1998

MHC class I expression protects target cells from lysis by Ly49-deficient fetal NK cells.

Using appropriate conditions natural killer (NK) cells can be cultured from the liver and thymus of day 14 fetal mice. These fetal NK cells are phenotypically and functionally indistinguishable from adult NK cells with the exception that they lack measurable expression of all of the Ly49 molecules that can currently be detected with antibodies. Despite this, they preferentially kill tumor cells and blast cells deficient in the expression of major histocompatibility complex class I molecules, although the degree of discrimination is usually weaker than that shown by adult NK cells and varies depending on the particular combination of effector and target cells used. Polymerase chain reaction analysis revealed that although fetal NK cells are severely deficient in the expression of mRNA for Ly49A, B, C, D, G, H, and I they express high levels of Ly49E mRNA, raising the possibility that Ly49E may have an important and special function in the early development of the NK lineage.

Animals↗

PubMed2004

Analysis of microglial gene expression: identifying targets for CNS neurodegenerative and autoimmune disease.

Microglia are the tissue macrophage of the central nervous system (CNS) and their activation is among the earliest signs of CNS dysfunction and disease. Because microglia express many macrophage markers, they are presumed to act primarily as effectors of CNS inflammation and destruction. While such responses are beneficial to the extent that they destroy CNS pathogens, these responses do have the potential to have neurotoxic outcomes. Consequently, therapies for many CNS neurodegenerative and inflammatory diseases have been directed at suppressing microglial function. There is evidence to suggest that microglia play an important role during CNS development and maintenance of CNS function that may go beyond simple defense against pathogens. Molecular analysis of microglial phenotypes and function has revealed three striking findings: (i) that microglia are a unique CNS-specific type of tissue macrophage; (ii) that they are highly heterogeneous within the healthy CNS; and (iii) that microglial responses are exquisitely tailored to specific regions of the CNS and specific pathological insults. We suggest that ubiquitous suppression (rather than targeted manipulation) of microglial function may fail to fully ameliorate CNS pathology and may even ultimately promote maladaptive outcomes.

Animals↗

PubMed1988

AK cells were developed from NK cells during in vitro culture of allogeneic or F1 anti-parental stimulation: functional conversion in recognizing H-2 expression of target cells accompanied by phenotypical conversion.

In vitro sensitization of (CBA x A)F1 spleen cells for 3 days with allogeneic C57BL cells raised the killer activity to the NK-sensitive YAC-1 target. When (A x C57BL)F1 spleen cells were cultured with parental C57BL cells, the lytic activity to YAC-1, P815 and EL-4 targets occurred on Day 6 after the culture. Phenotypical analyses showed that these culture-activated killer (AK) cells were derived from asialo-GM1+Thy-1-NK cells; however, they expressed Thy-1 antigen but not asialo-GM1 antigen at the effector cell level. Generation of the AK cells was not evident in cultures of spleen cells from mice with a neonatally induced tolerance to stimulator antigen and in those from T-cell-depleted mice. The supernatant of allostimulated culture, which contained a low concentration of IL-2, rendered the above cells capable of evoking AK activity. The H-2-reduced target cells were sensitive to NK cells, but less sensitive to AK cells; on the contrary, the H-2 highly expressed cells (interferon-treated cells) were less susceptible to NK cells but highly susceptible to AK cells. Thus, the relation between NK susceptibility and susceptibility to AK cells is inverse. Our study shows that stimulation with lymphokines causes a functional conversion accompanied by a phenotypical conversion of NK cells. With reference to immunosurveillance, these observations lead to the idea that NK and AK cells represent two functionally distinct but complementary systems involved in cell-mediated immunosurveillance.

Animals↗