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PubMed1998

Efficacy evaluation of prime-boost protocol: canarypoxvirus-based feline immunodeficiency virus (FIV) vaccine and inactivated FIV-infected cell vaccine against heterologous FIV challenge in cats.

OBJECTIVE: To evaluate the immunogenicity and prophylactic efficacy of immunization schemes employing a recombinant canarypoxvirus ('ALVAC')-based feline immunodeficiency virus (FIV) vaccine alone or in combination with an inactivated FIV-infected cell vaccine against homologous and heterologous FIV challenges in cats. METHODS: Specific pathogen-free cats were given a total of three immunizations with subtype A vaccines and challenged 4 weeks after the final immunization with 50 median animal infectious doses (ID50) of FIV-Petaluma, a subtype A isolate. Following the initial challenge, protected cats received a second challenge with 75 ID50 of FIV-Bangston, a subtype B isolate. FIV-specific humoral and cell-mediated responses were measured to determine the immune correlates of protection. RESULTS: Two of three cats immunized with the ALVAC FIV recombinants alone were protected from homologous FIV challenge in the presence of FIV-specific cytotoxic T-lymphocyte (CTL) responses but in the absence of FIV-specific humoral responses. All three cats immunized with the ALVAC-FIV recombinant and boosted with FIV-infected cell vaccine were also protected from homologous FIV challenge in the presence of both FIV-specific CTL and humoral responses. Partial to full protection was observed in ALVAC-FIV/FIV-infected cell vaccine-immunized cats against a heterologous FIV challenge given 8 months after the initial challenge. Two out of three cats had transient infection and the remaining cat had no sign of FIV infection at a dose at which all three control cats were readily infected. CONCLUSIONS: Immunization schemes employing ALVAC-based FIV vaccines in combination with inactivated FIV-infected cell vaccine generate protective immune responses that can cross-react with FIV isolates that are genetically distinct from the vaccine strains.

Animals↗

PubMed2026

Myeloid-Mediated Immunoregulation and Resistance to Immune Checkpoint Inhibitor Therapy Across Squamous Cell Carcinomas: Mechanisms and Reprogramming Strategies.

Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have improved outcomes across squamous cell carcinomas (SCCs) of the head and neck, lung, esophagus, and skin, yet durable responses remain confined to a subset of patients in every subtype. Objective response rates vary substantially across SCCs despite overlapping genomic alterations, comparable tumor mutational burden, and high PD-L1 expression, indicating that tumor-intrinsic biomarkers alone do not explain this variability. Growing evidence points to the tumor immune microenvironment, and in particular the myeloid compartment, as a critical determinant of immunotherapy responsiveness. In this review, we synthesize current evidence on myeloid-mediated immune regulation across SCC subtypes, focusing on tumor-associated macrophages, myeloid-derived suppressor cells/tumor-associated neutrophils, and dendritic cells, and the mechanisms by which these populations impair antigen presentation, restrict T cell infiltration, and sustain immunologically "cold" tumor states. We further examine therapeutic strategies aimed at reprogramming rather than simply depleting suppressive myeloid populations, including radiation therapy, STING agonism, and myeloid-targeted agents (CSF1R, PI3Kγ, and CXCR2 inhibition), each of which has shown encouraging preclinical and early clinical activity in combination with ICI. Collectively, this evidence supports a model in which the myeloid compartment functions as an actionable, convergent determinant of ICI resistance across SCC subtypes, rather than merely a passive biomarker. We propose that through the integration of spatial and single-cell profiling of myeloid states with clinical history it will be possible to predict response to immune checkpoint therapy and personalize myeloid-directed combination strategies, though the specific biomarkers needed to match individual patients to a given myeloid-targeted approach remain to be defined. We further discuss the toxicity considerations associated with both immune checkpoint blockade and radiation-based combination approaches, the early-phase status of most myeloid-targeted agents currently in clinical development, and the extent to which mechanistic insight, derived predominantly from HNSCC, generalizes to squamous cell carcinomas arising at other anatomic sites.

dendritic cells↗

PubMed1975

The protective role of thymus-derived lymphocytes in arbovirus-induced meningoencephalitis.

The inflammatory response in mouse brain and the elimination of virus from the brain following intracerebral inoculation of a group A arbovirus has been shown to be T-cell dependent. Virus persists in the brain of T-cell depleted mice, and inflammation is depressed. Virus persists in the brain of T-cell depleted mice, and inflammation is depressed. Inflammation is restored by transfer of immune cells but not by immune serum, and the transferred cells are effective in reducing virus titres in the absence of circulating antibody. Transferred antibody is not efficient in protecting infected mice. The cells that restore inflammation can come from mice immunized with a group A arbovirus of the same subtype but not from mice immunized with more distantly related viruses. Macrophages may be important effector cells working in collaboration with T cells.

Animals↗

PubMed2005

[A DNA vaccine encoding the extracellular domain of porcine endoglin induces antitumor immunity in a mouse colon carcinoma model].

BACKGROUND & OBJECTIVE: Endoglin is a marker of tumor angiogenesis. Increasing evidences proved that passive immunotherapy with anti-endoglin monoclonal antibody can effectively inhibit tumor growth, and xenogeneic homologous DNA vaccine can inhibit cross antitumor immunity. This study was to explore the inhibitory effect of a DNA vaccine encoding the extracellular domain of porcine endoglin (ppEDG) on tumor growth in a mouse colon carcinoma model. METHODS: ppEDG was used as a DNA vaccine to actively immunize the colon carcinoma-bearing mice. Tumor volume and survival rate of the mice were observed in 3-day intervals. Microvessel density (MVD) was detected by immunohistochemistry; antibodies against self-endoglin were detected by Western blot and ELISA; the B cells that secrete auto-antibodies against self-endoglin were detected by ELISPOT assay. RESULTS: Eighteen days after tumor cell inoculation, the tumor volume was significantly smaller in ppEDG-immunized group than in empty plasmid (e-p) group and normal saline (NS) group (P<0.05), and the survival time was significantly longer in ppEDG-immunized group than in the control groups (P<0.001). MVD was significantly lower in ppEDG-immunized group than in e-p group and NS group (19.2+/-4.5 vs. 76.9+/-14.4 and 81.4+/-16.9, P<0.001). The antibodies against self-endoglin were identified in ppEDG-immunized group; the major subtypes were IgG(1) and IgG(2b). The auto-antibody-producing B cells were much more in ppEDG-immunized group than in e-p group and NS group (82.5+/-14.1 vs. 3.6+/-1.3 and 4.7+/-2.0, P<0.001). CONCLUSION: ppEDG DNA vaccine could induce the production of auto-antibodies against self-endoglin, which further inhibit angiogenesis and growth of colon carcinoma.

Adoptive Transfer↗

PubMedDate not supplied

P2X7 receptors and apoptosis in tuberculosis infection.

Immune cells express P2 purinoceptors of the P2Y and P2X subtypes. Evidence accumulated has shown that many different cell types are killed by sustained exposure to high concentrations of extracellular ATP. Depending on the ATP dose, length of stimulation and receptor subtype, P2X receptor stimulation may cause necrosis or apoptosis. Triggering of apoptosis, in response to intracellular infection, has been identified for a wide range of pathogens and host organisms, and there is now emerging interest about mechanism mediating host cell death and its role in pulmonary tuberculosis. The physiological meaning of P2X receptor-dependent cell death is not completely understood, but and involvement in immune-mediated reactions is postulated.

Adenosine Triphosphate↗

PubMed2002

Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis.

Antigen-specific T helper type 1 (Th1) cells mediate protective immunity against a range of infectious diseases, including that caused by Bordetella pertussis. Distinct T cell subtypes that secrete interleukin (IL)-10 or tumor growth factor (TGF)-beta are considered to play a role in the maintenance of self-tolerance. However, the antigens recognized by these regulatory T cells in vivo have not been defined. Here we provide the first demonstration of pathogen-specific T regulatory type 1 (Tr1) cells at the clonal level and demonstrate that these cells are induced at a mucosal surface during an infection where local Th1 responses are suppressed. Tr1 clones specific for filamentous hemagglutinin (FHA) and pertactin were generated from the lungs of mice during acute infection with B. pertussis. The Tr1 clones expressed T1/ST2 and CC chemokine receptor 5, secreted high levels of IL-10, but not IL-4 or interferon (IFN)-gamma, and suppressed Th1 responses against B. pertussis or an unrelated pathogen. Furthermore, FHA inhibited IL-12 and stimulated IL-10 production by dendritic cells (DCs), and these DCs directed naive T cells into the regulatory subtype. The induction of Tr1 cells after interaction of a pathogen-derived molecule with cells of the innate immune system represents a novel strategy exploited by an infectious pathogen to subvert protective immune responses in vivo.

Adhesins, Bacterial↗

PubMed1998

Cannabinoid receptors and the cytokine network.

Splenocyte cultures from BALB/c mice were treated with THC and mitogen and shown to produce less Th1 cytokine, IFN gamma, and more Th2 cytokines, IL-4 and IL-10. This suggested that drug treatment caused a shift in the development of Th1 and Th2 cells. In studies designed to look at molecular mechanisms, the CBI antagonist, SR141716A, did not attenuate the THC enhancement of IL-4 production, but pertussis toxin attenuated the drug effect and the CB2 agonist, JWH-051, increased IL-4 production similar to THC. These results suggest that cannabinoids may increase Th2 development and IL-4 production in cultured immune cells through the activity of the CB2 receptor subtype. Studies are currently in progress to further define the molecular and cellular mechanisms involved.

Adjuvants, Immunologic↗

PubMed2002

[Humoral and cellular immunity investigation in idiopathic uveitis].

OBJECTIVES: There is an amount of controversy regarding the patho-physiology of uveitis. Due to the fact that the eye (and especially the highly vascular tissues such as the uvea and the conjunctiva) is considered a special "target" for the immunopathologic reactions, the goal of our study is to contribute to the understanding of the causal role of the immune reactions in the development of idiopathic uveitis. MATERIAL AND METHODS: We have studied 48 patients with idiopathic uveitis and 20 control subjects (with no ocular symptomatology) for the following humoral and cellular immune markers: IgM and IgG, the C3 complement fraction, circulating immune complexes, autoantibodies (antinuclear autoantibodies, anti-double stranded DNA autoantibodies, anti-smooth muscle autoantibodies, anti-neutrophilic cytoplasm autoantibodies, anti-cardiolipin autoantibodies, anti-parietal cell autoantibodies), and lymphocyte subtypes. RESULTS: Changes in the serum levels of the immune humoral and cellular markers have been noted in 39 (81.25%) of the patients studied. C3 was decreased in 12 (30%) of all cases; the immune complex level was increased over 50 U/mL in 20 patients (51.28%). The presence of the above-mentioned autoantibodies was seen in 19 patients (48.71%), with different incidence. By flow cytometry the percentage of CD4+ (T helper lymphocytes) has been found to be decreased, and the percentage of CD8+ was found to be increased in 8 cases (20.51%). The opposite, the increase in the percentage of CD4+ lymphocytes, and the decrease in the percentage of CD8+ cells was seen in 25 (64.10%) of the studied patients. Taking into consideration the clinical symptoms and the level of the immune humoral and cellular parameters, the cases included in the study have been included in two groups: anterior uveitis (acute and chronic), and posterior uveitis. CONCLUSIONS: By comparing the results, we conclude that the autoimmunity and the immediate hypersensitivity mediated by immune complexes may be involved in the appearance and the development of the intraocular inflammation in certain cases of idiopathic uveitis.

Adult↗

PubMed1994

The immune system during exposure to extreme physiologic conditions.

It is not clear how the immune system is modulated in response to physical stress (e.g. trauma, surgery, burn and sepsis). In order to better understand the stress-induced immune changes, effects of isolated stressors are evaluated. Human experiments include hypoxia, head-up tilt, hyperthermina and exercise, which influence all lymphocyte subtypes and especially so the natural killer (NK) cells. In essence, the immune response is enhanced even by light physical stress, but suppressed after prolonged, intense stress.

Exercise↗

PubMed2026

Single-cell multiomics reveals exosome-mediated reprogramming and clonotypic remodeling of T cells in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive and immunogenic subtype lacking targeted therapies. While tumor-derived exosomes are known to modulate immune function, their direct impact on human T cell plasticity and antigen specificity remains poorly defined. Here, we conducted a comprehensive single-cell multiomic analysis of primary human T cells exposed to exosomes derived from 17 genomically diverse TNBC cell lines and 35 patient samples. Integrating single-cell RNA-seq, V(D)J sequencing, non-coding RNA profiling, bulk and single-cell cytokine analyses, we uncovered conserved and subtype-specific immunomodulatory programs induced by TNBC exosomes. Exosome-treated T cells displayed skewing toward regulatory and dysfunctional phenotypes, including Th17-like, Treg, and PD-1⁺/PD-L1⁺ Tfh cells. Functional profiling revealed suppression of early activation markers and cytokine responses, alongside selective preservation of cytotoxic features in γδ T and NKT subsets. Transcriptomic and miRNA network analyses demonstrated widespread downregulation of immune effector genes (e.g., HBEGF and TNFSF9) mediated by exosome-delivered regulatory miRNAs (has-miR-98-5p). Notably, exosome-stimulated T cells displayed distinct clonotypic expansions, characterized by the emergence of five tumor-specific γδ TCR clonotypes and 30 unique αβ TCR CDR3 sequences that were absent in mock-treated controls, underscoring the role of exosomes in shaping TCR repertoire dynamics.

Humans↗

PubMed1987

Characterization of subtype-specific and cross-reactive helper-T-cell clones recognizing influenza virus hemagglutinin.

The specificity and function of two T-cell clones derived from A/Memphis/1/71 (H3) influenza virus (Mem 71)-immune BALB/c spleen cells have been compared. One clone, X-31 clone 1, was subtype specific, proliferating in response to influenza strains of the H3 subtype only. The other, Jap clone 3, cross-reacted in proliferation assays with heterologous subtypes of influenza A, but not type B. Both clones recognized the HA1 chain of the hemagglutinin (HA) molecule and their proliferation in response to detergent-disrupted virus could be specifically inhibited by monoclonal antibodies to the HA. The T-cell clones were of the L3T4+ phenotype. Both recognized antigen in association with I-Ed, as indicated by studies with H-2 recombinant strains of mice and by blocking with monoclonal anti-I-E antibody. In vivo, both clones elicited a delayed-type hypersensitivity (DTH) reaction when inoculated into mouse footpads together with virus, X-31 clone 1 again displaying subtype specificity and Jap clone 3 being cross-reactive. The clones were also able to provide factor-mediated help in vitro to virus-primed B cells in an anti-HA antibody response. The cross-reactive T-cell clone provided help not only for B cells primed with influenza A subtype H3 and responding to H3 virus in culture, but also for H2 virus-primed B cells making anti-H2 antibody.

Animals↗

PubMed2006

Improving antitumor immune responses by circumventing immunoregulatory cells and mechanisms.

Although numerous immunotherapeutic strategies have been studied in patients with cancer, consistent induction of clinical responses remains a formidable challenge. Cancer vaccines are often successful at generating elevated numbers of tumor-specific T lymphocytes in peripheral blood, however, despite this, tumors usually continue to grow unabated. Recent evidence suggests that endogenous regulatory cells, known to play a major role in the induction of immune tolerance to self and prevention of autoimmunity, as well as suppressive myeloid cells invoked in the tumor-bearing state, may be largely responsible for preventing effective antitumor immune responses. This review will focus on the major regulatory cell subtypes, including CD4(+)CD25(+) T-regulatory cells, type 1 regulatory T cells, natural killer T cells, and immature myeloid cells. Studies in humans and in animal models have shown a role for all of these cells in tumor progression, although the mechanisms by which they act to suppress immunity remain largely undefined. Elucidation of the dominant molecular mechanisms mediating immune suppression in vivo will allow more precise targeting of the relevant regulatory cell populations, as well as the development of novel strategies and clinical reagents that will directly block molecules that induce the suppression of antitumor immunity.

Animals↗

PubMed2004

CD2-SLFA3/T11TS interaction facilitates immune activation and glioma regression by apoptosis.

OBJECTIVE: Exogenous application of T11TS/SLFA3 in glioma model had shown the regression of tumor load through immunopotentiation. The mechanistic module of this interaction on immunological synapse formation and resulting effect in glioma regression is searched for delineating immunotherapeutic efficacy of T11TS. METHODS: After purification of T11TS/SLFA3 from sheep erythrocytes the glycoprotein was characterized by SDS-PAGE analysis and glycoprotein staining. The modulatory effect of T11TS application on glioma animals were studied by CD2 and MHC class II expression on peripheral lymphocytes, PMN, macrophages and intracranial microglia by flowcytometric analysis. Finally apoptotic killing of brain cells were studied through annevin-V expression and measuring fragmented cytoplasmic DNA by ELISA. RESULTS: Compared to healthy normal counter-parts the CD2 receptor downregulation by ENU treatment in lymphocytes and PMN were upregulated with three consecutive doses of T11TS. Splenic antigen presenting macrophages and intracranial mocroglia had shown CD2 and MHC class II modulation simultaneously in their different subtypes. These receptor studies revealed significant boosting of the immune competent cells most effectively in second dose of T11TS whereas the third dose had some regulatory effect. Sharp increase of apoptosis in brain cells was found by phosphatidylserine externalization and presence of fragmented DNA in cytoplasm with application of T11TS in consecutive doses as a result of immune potentiation. CONCLUSION: Receptor studies revealed modulation of CD2 and MHC class II, two important constituents of immunological synapse successfully help to form the TCR-p-MHC complex and provide required co-stimulation for activation. Potentiated immune effector machinery was then directed to abrogate glioma by apoptosis signifying T11TS as an immunotherapeutic probe.

Animals↗

PubMed2001

Immunization with HIV-1 subtype B gp160-DNA induces specific as well as cross reactive immune responses in mice.

BACKGROUND & OBJECTIVES: HIV-1 gp160 is an important structural protein for the virus cell interaction and virus entry. Therefore, it is regarded as the most important target for HIV-1 vaccine development. In this study we investigated the use of HIV-1 gp160-DNA construct in eliciting specific and cross reactive cell mediated immune response in mice. METHODS: DNA segment encoding env, tat and rev genes of HIV-1 subtype B (strain BRU-2) was amplified and cloned into mammalian expression vector pCI to generate plasmid pCIBRU-TRE. Mice were injected intramuscularly four times at biweekly intervals with 100 micrograms/dose of pCIBRU-TRE in normal saline, and subsequently analysed for anti HIV-envelope (env) immune responses. RESULTS: A low antibody level was detected as determined by ELISA after 4 doses. Subsequent inoculations failed to increase the antibody titres significantly. Spleen cells from the immunized mice were used for the detection of cellular immune response by lymphocyte proliferation assays (LPA), in vitro production of cytokines and cytotoxic T lymphocyte (CTL) assays. T cell response which was seen from the second week onwards, persisted even at the end of 24 wk following the last dose. Similar levels of T cell proliferation were observed on stimulation with either homologous or heterologous peptides. Cytokine studies showed a Th1 type of response. A cross clade MHC class I restricted CTL response was observed against target cells stimulated with either homologous or heterologous HIV antigens. INTERPRETATION & CONCLUSION: This study demonstrated that DNA encoding full length HIV-1 env glycoprotein gp160 induces specific as well as cross reactive cell mediated immune responses in mice. However, the induction of antibody response was poor.

AIDS Vaccines↗

PubMed1987

T-cells and macrophages in rapidly progressive glomerulonephritis: clinicopathologic correlations.

We phenotyped with monoclonal antibodies (MAb) the cellular infiltrates in kidneys of patients with rapidly progressive glomerulonephritis (RPGN) responsive (R) or nonresponsive (NR) to pulse methylprednisolone therapy (PM)-eight anti-GBM, six no immune deposits, three immune complex, two vasculitis, and one proliferative GN. There were glomerular, periglomerular, crescentic, and interstitial T and T-cell subsets. Few interstitial and no glomerular B and NK cells were observed. TH cells were much more common than TS. Phenotypes were quantitatively evaluated in 221 nephritic and 32 control glomeruli. T and/or TH cells were positively correlated with M phi, r = 0.30 to 0.74, P less than 0.05 to 0.0005. Although differences in phenotypes were observed, these differences were insufficient to distinguish between subtypes. Analysis of R and NR revealed no relationship to percent crescents, entry serum creatinine, oliguria, or need for dialysis. NR was related to presence of anti-GBM disease, P = 0.001, as was ability to stop dialysis, 0 of 7 GBM versus 9 of 10 other, P less than 0.001. Mild infiltrates of lymphocytes and M phi correlated with R, P less than or equal to 0.02. R had fewer numbers of TH and M phi in glomeruli, P = 0.0001, in crescents, P less than 0.02, and total TH and M phi compared to NR, P less than 0.001. Crescentic and total TH/S ratios were lower in NR than R, P less than 0.05. These findings demonstrate that components of the cell-mediated immune (CMI) system are present by MAb analysis, that subtypes cannot be differentiated by CMI constitution, and R to PM is related to intensity and composition of CMI involvement. Independence of the CMI system relative to anti-GBM disease remains to be clarified.

Antibodies, Monoclonal↗

PubMed2006

Helminth infection suppresses T-cell immune response to HIV-DNA-based vaccine in mice.

A number of HIV-1 vaccines are in various phases of clinical trials and many more are in the developmental pipeline. Vaccines are especially needed for developing countries where morbidity and mortality due to HIV/AIDS is most severe, the prevalence of HIV infection is highest, and its incidence is often still rising dramatically. Individuals living in these regions are often infected with one or more helminth parasites which systemically bias the immune system towards Th2-type as well as drive immune anergy. The goal of this study was to develop a multi-T-cell epitope DNA-based vaccine for HIV-1 subtype C and to determine the impact of helminth infection on the immune response to this vaccine. We found that vaccination of naïve mice with the multi-epitope vaccine, designated TD158, induced a strong HIV-1C-specific T-cell immune response, and that the addition of the Igkappa leader sequence to the TD158 vaccine construct significantly increased the frequencies of IFN-gamma secreting CD8+ T cells. However, the TD158 vaccine specific response of mice infected with the human helminth Schistosoma mansoni was significantly suppressed. The impact of schistosome infection on suppressing the virus-specific immune response was the same whether mice were vaccinated with the TD158 vaccine or with the Igkappa enhanced TD158. The results of this study suggest that helminth infection may pose a serious problem for vaccination with the DNA-based HIV-1 vaccine in developing country populations, and that the prevalence of helminth infections in the vaccine cohorts should be taken into account for HIV-1 vaccine trial design.

AIDS Vaccines↗

PubMed2026

Integrated Genomic and Proteomic Analysis Reveals T-B Lymphocyte Signatures in the MYCN Driven "Immune Desert" of Specific Neuroblastoma Subtypes.

AIMS: This study aims to systematically dissect how MYCN amplification shapes the immunosuppressive tumor microenvironment (TME) in high-risk neuroblastoma, elucidating key mechanisms underlying immune evasion. METHODS: We performed an integrated multi-omics analysis of bulk RNA-seq (n = 721), single-cell RNA-seq (n = 9), proteomic data (n = 49) and spatial transcriptomics (Visium, with external validation in melanoma). Analyses included unsupervised clustering, cell-cell communication inference, transcriptional regulatory network reconstruction, and spatial proximity assessment to map the immune landscape. RESULTS: A distinct molecular subtype (Class C), defined by MYCN amplification and poor prognosis, exhibited a comprehensive "immune desert" phenotype characterized by low immune scores and minimal leukocyte infiltration. Single-cell analysis confirmed significant depletion of T and B lymphocytes within the Class C TME. Dysregulated transcriptional networks were identified, including upregulation of REL and EOMES in T cells-with EOMES potentially driving exhaustion via regulation of Transient Receptor Potential (TRP) genes, and REL inhibition enhancing cytotoxic function in vitro. A unique immunosuppressive B-cell subset (B7) engaged in enhanced crosstalk with exhausted T cells and harbored a MYC-centered network linked to cell cycle dysregulation and poor survival. Spatial transcriptomics revealed significant proximity between B7-active regions and Treg/exhaustion-enriched areas, externally validated in melanoma. Proteomic data validated elevated REL expression in MYCN-amplified tumors. CONCLUSION: This work delineates the immunosuppressive architecture of MYCN-driven neuroblastoma, revealing novel regulatory nodes within specific lymphocyte compartments. Integrating single-cell, spatial, and proteomic evidence, we propose REL inhibition as a therapeutic candidate, the EOMES/TRP axis as a bioinformatically supported hypothesis, and the B7/MYC hub as a hypothesis supported by transcriptomic and spatial evidence.

Humans↗

PubMed1996

Exclusive expression of the Gs-linked prostaglandin E2 receptor subtype 4 mRNA in mononuclear Jurkat and KM-3 cells and coexpression of subtype 4 and 2 mRNA in U-937 cells.

Prostaglandin E2 (PGE2) is regarded as a potent regulator of the immune system. It can regulate apoptosis in mononuclear cells and modulate the cytokine secretion pattern from T-helper cell subpopulations via an increase in cyclic AMP (cAMP). Of the 4 PGE2 receptor subtypes (EP1-EP4) that are defined pharmacologically by their affinity to subtype-specific ligands and their coupling to G proteins, EP2 and EP4 receptors couple to Gs. It is as yet unknown which of these two receptor subtypes mediates the immunomodulatory effects. By quantitative RT-PCR, the mRNA for EP4 receptors was demonstrated and quantified in the human mononuclear cell lines Jurkat, KM-3 and U-937. However, EP2 receptor mRNA was only present in U-937 cells and was 100-fold less abundant than EP4 receptor mRNA. PGE2 increased cAMP formation with an ED50 of 50-100 nM in all cell lines. cAMP formation was inhibited by the EP4R-specific antagonist AH23848. Since AH23848 inhibited PGE2-induced cAMP formation in U-937 cells to a similar extent as in Jurkat and KM-3, EP2 receptors seem to play, if any, only a secondary role for the PGE2-mediated cAMP formation in U-937 cells.

Biphenyl Compounds↗