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Results for “Immune cell subtypes”

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At least 19 recordsLinked to original sources

PubMed2006

Tissue compartment-specific role of estrogen receptor subtypes in immune cell cytokine production following trauma-hemorrhage.

Although 17beta-estradiol administration following trauma-hemorrhage attenuates plasma cytokines and alteration in immune cell cytokine production, it is not known whether the salutary effects are mediated via estrogen receptor (ER)-alpha or ER-beta. Accordingly, we examined which ER subtype predominantly mediates the salutary effects of 17beta-estradiol on systemic inflammatory response/immune cell cytokine production in various tissues following trauma-hemorrhage. Male rats underwent trauma-hemorrhage (mean blood pressure: 40 mmHg for 90 min) and fluid resuscitation. The ER-alpha agonist propyl pyrazole triol (PPT; 5 microg/kg), the ER-beta agonist diarylpropionitrile (DPN; 5 microg/kg), 17beta-estradiol (50 microg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation, and various measurements were made 24 h thereafter. 17beta-Estradiol or PPT administration following trauma-hemorrhage prevented the increase in plasma IL-6 and IL-10 levels that were observed in vehicle-treated animals. IL-6 and TNF-alpha production by Kupffer cells increased; however, splenic macrophages (SMPhi), alveolar macrophages (AMPhi), and peripheral blood mononuclear cells (PBMC) had decreased release of these cytokines after trauma-hemorrhage. IL-10 production, however, increased in all macrophage populations. Administration of 17beta-estradiol following trauma-hemorrhage prevented all of these alterations. PPT had the same effects as 17beta-estradiol on IL-6 and TNF-alpha production by Kupffer cells and SMPhi, and DPN had the same effects on AMPhi and PBMC. The same effects as 17beta-estradiol on IL-10 production were observed by PPT on Kupffer cells and DPN on PBMC. Both agonists were equally effective on SMPhi and AMPhi. Thus ER subtypes have tissue compartment-specific roles in mediating the effects of 17beta-estradiol on immune cell functions following trauma-hemorrhage.

Animals↗

PubMed2026

Identification of molecular subtypes in clear cell renal cell carcinoma based on chromatin regulators and tumor immune microenvironment profiling.

In the histological classification of renal cell carcinoma, clear cell renal cell carcinoma (ccRCC) accounts for the highest proportion and is the most common subtype. Despite advances in management, it continues to be associated with considerable incidence and mortality. Although surgery and systemic therapies are available, their efficacy is constrained by pronounced intratumoral heterogeneity and treatment resistance. Identifying robust biomarkers and clarifying the underlying biological mechanisms are therefore essential to improving diagnosis, risk stratification and therapeutic decision-making. In this work, we identified two ccRCC molecular subtypes displaying divergent chromatin regulator (CR) profiles and different clinical prognoses. Using the genes differentially expressed between these subgroups, we constructed a CR-related score (CRS) that effectively stratified patients according to survival. More analysis concluded that the low expression of CR was more linked with the immune-activated tumors, which encompassed the immune pathway enrichment, as well as the elevation of numerous immune cell subtypes. Moreover, elevated CRS was associated with improved immunotherapy responsiveness. Drug-sensitivity analyses nominated several candidate agents, and SMARCD3 knockdown in 786-O cells inhibited proliferation and migration and reduced sensitivity to masitinib. Collectively, these findings support the prognostic and therapeutic relevance of CR-related states in ccRCC and provide a framework for future experimental validation of chromatin-regulated tumor-immune interactions.

Humans↗

PubMed2006

Neuro-immune interaction in allergic asthma: role of neurotrophins.

The nature of persistent airway hyperreactivity and chronic inflammation in asthma remains unclear. It has been suggested that bi-directional neuro-immune interaction plays an important role in the pathogenesis of this disease, leading to enhanced airway narrowing after contact with unspecific stimuli, as well as infiltration, activation and degranulation of several immune cell subtypes. Important mediators in neuro-immune cross-talk are neurotrophins, which are produced by cells at the site of inflammation. In addition to modulating the function of several leucocyte subsets, they play an important role in the synthesis of neuropeptides by sensory nerve cells. Neuropeptides have been shown to cause smooth-muscle contraction and, in addition, modulate the production of pro-inflammatory molecules by leucocytes. The aim of the present review is to provide an overview of the molecular mechanisms by which neurotrophins and neuropeptides are involved in neuro-immune cross-talk in allergic asthma.

Animals↗

PubMed2026

Rethinking immune studies: population-level immune variations and the path forward.

Shifts in immune cell proportions underlie disease progression and immunotherapy response, positioning them as promising diagnostic biomarkers and therapeutic targets. However, these shifts also occur naturally across the lifespan and vary with demographic factors such as age and sex, which may complicate their interpretation and clinical utility. While demographic associations have been explored previously, there have been mixed results likely due to small sample sizes and cross-cohort population-specific differences. To address these limitations, we conducted a meta-analysis across 3 large, diverse cohort studies to evaluate associations between 20 immune cell subtypes, 3 informative cell ratios, and a range of sociodemographic variables such as age, sex, self-identified race and ethnicity (SIRE), and socioeconomic status. We find consistent and significant associations across all sociodemographic dimensions. Cytomegalovirus (CMV)-a key driver of immune senescence-emerged as a major contributor to variation in immune composition and CMV antibody levels were higher among women, individuals of lower socioeconomic status, and marginalized racial and ethnic groups. In addition, male sex showed similar patterns of association with immune profiles as aging, whereas race did not. These findings underscore the need to account for diverse sociodemographic factors in immunology study design and participant recruitment to avoid population-specific biases and ensure broadly generalizable results.

Humans↗

PubMed1999

Mononuclear cell subpopulations in preterm and full-term neonates: independent effects of gestational age, neonatal infection, maternal pre-eclampsia, maternal betamethason therapy, and mode of delivery.

Blood samples from 29 preterm (24-32 weeks of gestation) and 21 full-term (37-42 weeks of gestation) neonates were analysed for surface markers of lymphocyte subtypes and macrophages, and the effects of gestational age, neonatal infection, maternal pre-eclampsia, maternal betamethason therapy and mode of delivery were assessed with multiple regression analysis. Gestational age alone had few independent effects (increase in CD3+, CD8+CD45RA+, and CD11alpha+ cells, and decrease in CD14+, HLA-DR- cells) during the third trimester on the proportions of the immune cell subtypes studied. Neonatal infection and mother's pre-eclampsia had the broadest and very opposite kinds of effects on the profile of immune cells in the blood. Infection of the neonate increased the proportions of several 'immature' cells (CD11alpha-CD20+, CD40+CD19-, and CD14+HLA-DR-), whereas mother's pre-eclampsia decreased the proportions of naive cell types (CD4+CD8+, CD5+CD19+). In addition, neonatal infection increased the proportion of T cells (CD3+, CD3+CD25+, and CD4+/CD8+ ratio, and CD45RA+ cells), while maternal pre-eclampsia had a decreasing effect on the proportion of CD4+ cells, CD4+/CD8+ ratio, and proportions of CD11alpha+, CD14+ and CD14+HLA-DR+ cells. Maternal betamethason therapy increased the proportion of T cells (CD3+) and macrophages (CD14+, CD14+HLA-DR+), but decreased the proportion of natural killer (NK) cells. Caesarean section was associated with a decrease in the proportion of CD14+ cells. We conclude that the 'normal range' of proportions of different mononuclear cells is wide during the last trimester; further, the effect of gestational age on these proportions is more limited than the effects of other neonatal and even maternal factors.

Antigens, CD↗

PubMed2003

PKHDL1, a homolog of the autosomal recessive polycystic kidney disease gene, encodes a receptor with inducible T lymphocyte expression.

Autosomal-recessive polycystic kidney disease (ARPKD) is caused by mutation to a large gene, PKHD1, encoding a putative receptor protein, fibrocystin. We have identified, through analysis of human genomic sequence, a PKHD1 homolog, PKHDL1, in chromosome region 8q23. The PKHDL1 transcript of 13081 bp was amplified as 16 fragments and sequenced; the sequence of the murine ortholog, Pkhdl1 (chromosome region 15B3) was also determined. PKHDL1 contains 78 exons, covers a genomic region of approximately 168 kb and encodes a large protein, fibrocystin-L. Screening PKHDL1 in ARPKD patients with no PKHD1 mutations revealed several sequence variants but no clear mutations, making it unlikely that it is ARPKD-associated. Human fibrocystin-L is predicted to be a large receptor protein (4243 aa; 466 kDa) with a signal peptide, single transmembrane domain and short cytoplasmic tail. Fibrocystin-L is homologous to fibrocystin throughout most of the extracellular region with overall identity of 25.0% and similarity of 41.5%. Fibrocystin-L has extracellular domains similar to fibrocystin with 14 copies of the TIG domain and two regions of significant homology to the protein TMEM2. Genomic sequence analysis identified no other full-length fibrocystin homologs in humans, mice or other sequenced organisms. The Fugu fish has a fibrocystin-L ortholog but no fibrocystin, suggesting that the newly identified protein may be the ancestral form. PKHDL1 and Pkhdl1 are widely expressed at a low level in most tissues but only detected in blood-derived cell-lines. Low level expression was detected in many primary immune cell subtypes but up-regulated specifically in T lymphocytes, following activation signals, suggesting a role in cellular immunity.

Amino Acid Sequence↗

PubMed2026

Mapping the Immune cell-specific gene regulatory network in bipolar disorder: A framework from scTWMR to exploratory drug-target annotation.

BACKGROUND: Although the involvement of the immune system in the genetic susceptibility of bipolar disorder (BD) is widely acknowledged, the causal relationship between gene expression in specific immune cell subtypes and BD requires systematic elucidation. METHODS: We implemented an analytical framework integrating single-cell transcriptome-wide Mendelian randomization (scTWMR) with colocalization analysis. This approach utilized cis-expression quantitative trait loci (cis-eQTLs) derived from 14 distinct immune cell types as instrumental variables to interrogate BD genome-wide association study (GWAS) summary statistics (comprising 41,917 cases and 371,549 controls). Subsequent investigations encompassed functional enrichment analysis, protein-protein interaction (PPI) network construction, phenome-wide association study (PheWAS), and performed an exploratory drug-target annotation. RESULTS: Our analysis identified 33 gene-immune cell associations. Colocalization analysis provided robust evidence (PPH4 > 90%) for shared causal variants implicating the MAD1L1, APOM, and NFKBIL1 loci. Significantly enriched biological pathways included cell cycle regulation, circadian rhythm entrainment, and neuroinflammation. The PPI network revealed a core regulatory module centered on histone-encoding and immune-related genes. Exploratory drug-target annotation nominated compounds for further investigation for compounds targeting APOM, TMEM258, and NFKBIL1. CONCLUSION: This study systematically delineates a genetically supported regulatory network of immune cell-specific gene expression in BD, predominantly implicating CD8⁺ effector T cells, plasma cells, and B cells. The findings corroborate established pathological pathways while uncovering novel cell type-specific therapeutic targets, thereby providing a genetic framework for prioritizing candidate targets for future investigation.

Bipolar disorder↗

PubMed2001

Cannabinoids and the immune system.

The effect of cannabimimetic agents on the function of immune cells such as T and B lymphocytes, natural killer cells and macrophages has been extensively studied over the past several decades using human and animal paradigms involving whole animal models as well as tissue culture systems. From this work, it can be concluded that these drugs have subtle yet complex effects on immune cell function and that some of the drug activity is mediated by cannabinoid receptors expressed on the various immune cell subtypes. However, the overall role of the cannabinoid system of receptors and ligands in human health and disease is still unclear and requires extensive elucidation. Further studies will define the precise structure and function of the putative immunocannabinoid system, the potential therapeutic usefulness of these drugs in chronic diseases such as acquired immune deficiency syndrome and multiple sclerosis, the effects of these agents on tumour growth and induction of apoptosis, and the potential anti-inflammatory and proinflammatory properties of cannabimimetic compounds. It is likely that the cannabinoid system, along with other neuroimmune systems, has a subtle but significant role in the regulation of immunity and that this role can eventually be exploited in the management of human disease.

Animals↗

PubMed2026

Transcriptomic profiling across stages of non-muscle-invasive bladder cancer identifies fibroblast activation protein-alpha as a stromal biomarker associated with progression.

BACKGROUND: T1 non-muscle-invasive bladder cancer (NMIBC) represents a biologically aggressive subgroup with substantial heterogeneity in recurrence and progression risk. Current clinicopathological risk stratification tools lack sufficient precision to identify patients at the highest risk of progression to muscle-invasive bladder cancer (MIBC). OBJECTIVE: To characterize transcriptomic differences between T1 and < T1 (Ta/Tis) NMIBC and to explore the association of fibroblast activation protein-α (FAP) gene expression with disease progression. METHODS: Transcriptomic profiling was performed on formalin-fixed paraffin-embedded (FFPE) tumor tissue from 66 patients with primary, treatment-naïve NMIBC and 5 patients with T2 disease (included for exploratory comparisons). Analyses included differential gene expression, gene set enrichment analysis (GSEA), molecular subtyping, immune cell deconvolution, and evaluation of FAP expression in relation to recurrence and progression. External validation of FAP was conducted in three independent NMIBC cohorts. RESULTS: T1 tumors demonstrated a distinct transcriptomic profile compared with < T1 tumors, characterized by enrichment of cell cycle-related and metabolic pathways and a higher prevalence of aggressive molecular subtypes. Despite these molecular differences, no statistically significant differences in recurrence-free, progression-free, cancer-specific, and overall survival were observed, likely reflecting limited event numbers. Among recurrent tumors, early recurrences (≤ 24 months) were associated with epithelial-mesenchymal transition signatures. FAP expression increased with tumor stage (p = 0.0005) and was associated with progression (p = 0.002) and mortality (p = 0.01). Patients with tumors in the highest quartile of FAP expression had worse progression-free survival. This association was consistently observed in three external NMIBC cohorts. CONCLUSIONS: T1 NMIBC exhibits distinct transcriptomic features suggestive of increased biological aggressiveness. Elevated FAP expression is reproducibly associated with progression risk across multiple cohorts, supporting its potential role as a biomarker of aggressive disease. Given the limited number of progression events, these findings should be considered hypothesis-generating and warrant prospective validation before clinical implementation.

Humans↗

PubMed2006

Cross-subtype T-cell immune responses induced by a human immunodeficiency virus type 1 group m consensus env immunogen.

The genetic diversity among globally circulating human immunodeficiency virus type 1 (HIV-1) strains is a serious challenge for HIV-1 vaccine design. We have generated a synthetic group M consensus env gene (CON6) for induction of cross-subtype immune responses and report here a comparative study of T-cell responses to this and natural strain env immunogens in a murine model. Three different strains of mice were immunized with CON6 as well as subtype A, B, or C env immunogens, using a DNA prime-recombinant vaccinia virus boost strategy. T-cell epitopes were mapped by gamma interferon enzyme-linked immunospot analysis using five overlapping Env peptide sets from heterologous subtype A, B, and C viruses. The CON6-derived vaccine was immunogenic and induced a greater number of T-cell epitope responses than any single wild-type subtype A, B, and C env immunogen and similar T-cell responses to a polyvalent vaccine. The responses were comparable to within-clade responses but significantly more than between-clade responses. The magnitude of the T-cell responses induced by CON6 (measured by individual epitope peptides) was also greater than the magnitude of responses induced by individual wild-type env immunogens. Though the limited major histocompatibility complex repertoire in inbred mice does not necessarily predict responses in nonhuman primates and humans, these results suggest that synthetic centralized env immunogens represent a promising approach for HIV-1 vaccine design that merits further characterization.

AIDS Vaccines↗

PubMed2026

Cell Type-Resolved Causal Inference and Spatial Transcriptomic Integration Reveal Immune-Specific Genetic Drivers of Autoimmune and Malignant Thyroid Disease.

BACKGROUND: Thyroid diseases, including autoimmune thyroid disease (AITD) and thyroid cancer, are characterized by immune dysregulation, yet the cell type-specific genetic mechanisms underlying these conditions remain poorly understood. Most genome-wide association studies (GWAS) have relied on bulk tissue expression quantitative trait loci (eQTL), which cannot resolve the heterogeneity of immune cell populations. METHODS: We performed two-sample Mendelian randomization (MR) analyses using single-cell cis-eQTLs from 14 immune cell subtypes (OneK1K cohort) as instrumental variables against GWAS summary statistics for four thyroid outcomes: autoimmune hyperthyroidism, autoimmune hypothyroidism, thyroid cancer and autoimmune thyroiditis. Causal associations were validated through Bayesian colocalization, phenome-wide association analysis (PheWAS) and multi-layered transcriptomic validation encompassing spatial transcriptomics of AITD tissue (GSE248205), bulk RNA-seq of thyroid cancer (GSE3678) and single-cell RNA-seq of thyroid tumours (GSE250521). gsMap spatial LD score regression was applied to map disease heritability onto spatial tissue architecture. RESULTS: We identified six Bonferroni-significant causal gene-cell type pairs for autoimmune hyperthyroidism, including protective effects of ABHD16A in naïve/immature B cells (OR = 0.440), HIST1H3H in CD8 NC T cells (OR = 0.324), HMGN4 in NK recruiting cells (OR = 0.556) and ZKSCAN4 in CD8 S100B T cells (OR = 0.427), with five pairs showing strong colocalization (PP.H4 ≥ 86%). Three pairs reached significance for autoimmune hypothyroidism, including a risk association of HLA-F in CD4 NC T cells (OR = 1.139). For autoimmune thyroiditis, FAM134B/RETREG1 showed consistent suggestive protective associations across both CD4 and CD8 NC T cells (PP.H4 ≥ 90% for both), suggesting a possible involvement of ER phagy regulation in thyroiditis susceptibility. Thyroid cancer showed a suggestive association with HLA-G in classical monocytes (OR = 1.899, PP.H4 = 53%). Spatial transcriptomic validation demonstrated progressive immune infiltration from control tissue to Graves' disease to Hashimoto's thyroiditis (7.7%-15.7%, 46.1%-54.1%, respectively) and strong spatial correlation between target gene expression and corresponding cell type enrichment (e.g., plasma cell-HLA-DQB1: r = 0.491, p < 10-300). HLA-G was independently validated in thyroid cancer bulk (log2fc = 0.542, p = 9.51 × 10-3, AUC = 0.857) and single-cell datasets. PheWAS revealed no significant associations detected for the core candidates. gsMap identified significant enrichment of autoimmune hypothyroidism heritability in gastrointestinal tract, adrenal gland and adipose tissue (all Bonferroni p < 0.002). CONCLUSIONS: This study establishes a multi-scale analytical framework integrating cell type-resolved genetic inference with spatial tissue validation, revealing distinct immunogenetic architectures underlying autoimmune versus malignant thyroid disease. Protective genetic programs in autoimmune hyperthyroidism converge on chromatin remodelling (HIST1H3H, HMGN4, ZKSCAN4) and lipid metabolism (ABHD16A) across lymphocyte subsets, whereas thyroid cancer risk involves immune escape mediated by HLA-G in myeloid cells. The ER-phagy receptor RETREG1 represents a candidate pathway warranting further investigation in autoimmune thyroiditis. These findings provide genetically supported, cell type-specific therapeutic targets and demonstrate a generalizable strategy for dissecting the immune-mediated mechanisms of complex thyroid diseases.

Mendelian randomization↗

PubMed2006

Differential expression of the neurotrophin receptors p75NTR, TrkA, TrkB and TrkC in human peripheral blood mononuclear cells.

Neurotrophins are involved in the pathogenesis of allergic asthma. In addition to their influence on afferent sensory nerves within the lung, it has been shown in the last years that these factors modulate allergic airway inflammation. The knowledge about their immunomodulatory roles on diverse subsets of immune cells is still fragmentary and incomplete. Since neurotrophin receptor surface expression is essential for neurotrophin action, the aim of our study was to systematically investigate the expression pattern of the low affinity pan neurotrophin receptor p75NTR as well as the high-affinity receptors TrkA, TrkB and TrkC in human peripheral blood mononuclear cells. Our results show that each of the receptors has an individual expression pattern in diverse immune cell subtypes. However, there were no differences in neurotrophin receptor expression in healthy controls and patients with allergies.

Adult↗

PubMed2026

Nested co-expression network analysis identifies compact gene clusters in a black box.

MOTIVATION: Digital analysis of biological systems requires methods capable of identifying both broad and nested gene modules reflecting complex biological processes. Existing transcriptomic methods often miss compact gene sets corresponding to subprocesses in specialized cell types, limiting insights into functional heterogeneity. RESULTS: We present Nested-WGCNA, a two-stage unsupervised network analysis algorithm designed to identify coarse-grained and fine-grained gene modules. Applied to bulk RNA-Seq data, Nested-WGCNA reveals stable modules reproducible across datasets. When validated against scRNA-Seq data, these modules correspond to both major and minor immune cell subtypes. Application to immunotherapy response datasets uncovers predictive and prognostic biomarkers, highlighting its utility in treatment stratification and biomarker discovery. AVAILABILITY: The NestedWGCNA source code and analysis pipeline are available on GitHub (https://github.com/ilyada/NestedWGCNA) and archived on Zenodo (https://doi.org/10.5281/zenodo.18959244).

Algorithms↗

PubMed2004

Basic science for the clinician 28: T-helper cell subtypes.

The immune response is finely tuned to the various invaders that may cause damage and disease. There is an innate immune system and an acquired immune response, but there is much overlap and recruitment across these lines of demarcation. Broadly speaking, there are cellular immune responses (cellular effectors that identify intracellular pathogens and damage and kill the affected cell) and humoral (B cells become plasma cells which make antibodies to bind extracellular pathogens and their products) that draw upon both systems. At the pivotal point, where decisions are made whether to mount a primarily cellular or a humoral response are T-helper cells (CD4). As you may have read, CD4 cells come in at least 2 subtypes: TH1 cells predispose to the development of a primarily cellular responses and TH2 predispose to humoral responses. Not very complicated, but worthy of some discussion to look at the cytokines produced, the changes these cytokines evince, and how the balances (dare I say yin and yang) keep us healthy but also may get us into trouble!

Journal Article↗

PubMed1980

Further evidence for the partition of HLA-B14.

The minimal sequential absorption of 12 HLA-B14 antisera with B14 positive cells provided 10 antisera that showed a high correlation (r values > 0.8) with the original B14.1 and B14.2 sera of Dewar et al. (1977). The subdivisions defined by the absorbed sera corresponded to the B14 subtype of their immunizing cell. The subtyping of 112 B14 positive individuals showed the frequency of B14.1 to be 33.04%. B14 heterozygous individuals always typed for one but never for both subdivisions. Analysis of a population of 2,044 showed B14.1 to be in linkage disequilibrium with Aw32 and B14.2 with Aw33, Aw30 and A3. It is concluded that B14.1 and B14.2 are distinct antigens which, in the population tested, comprise the entire specificity of HLA-B14.

Antibody Specificity↗

PubMed2000

Somatostatin receptor subtypes in human immune cells.

Explore the source record for details and available documents.

Binding Sites↗

PubMed2004

Somatostatin receptor distribution and function in immune system.

Somatostatin and cortistatin, a recently discovered endogenous neuropeptide relative of somatostatin, have multiple modulatory effects on the immune system. The specific somatostatin receptor distribution might in part explain the heterogeneity of effects of somatostatin or its analogs on immunocytes. In fact, somatostatin receptor subtypes are differentially expressed on specific cell subsets within the organs of the immune system and the expression is dynamically regulated and seems to depend on the traffic of these cells through and within lymphoid structure and homing in tissues. Somatostatin effects on immune cells are mainly based on autocrine and paracrine modes of action. In fact, activated cells producing somatostatin (or cortistatin) may interact with other cells expressing the receptors. Here, we review the postulated modes of action of somatostatin and somatostatin-like peptides, including the currently available synthetic somatostatin analogs, in cells of the immune system. We also discuss the wide distribution of somatostatin and its specific five receptor subtypes in immune cell lines, as well as throughout animal and human lymphoid organs, in both normal and pathological conditions.

Animals↗

PubMedDate not supplied

A reappraisal of the role of the various opioid receptor subtypes in cell-mediated immunity.

Opioid peptides have been shown by several studies to modulate various parameters of the immune response, but scant experimental findings exist on the role played by specific opioid receptor subtypes in the control of immune mechanisms. This study focuses on the in vitro influences of [Trp4,Asn7]dermorphin, a mu-selective agonist, [D-Ala2]deltorphin I, a delta-selective agonist and U50,488, a kappa-selective agonist, on the proliferative response of splenocytes to concanavalin A (Con A). [Trp4,Asn7]dermorphin at low concentrations (10(-11P) and 10(-12) M) enhanced the proliferative response to Con A, whereas higher concentrations (10(-6) to 10(-7) M) inhibited it. Both effects were antagonized by naloxone. [D-Ala2]deltorphin I at very low concentrations (10(-12) to 10(-13) M) also produced a significant increase in the proliferative response of splenocytes to Con A. This effect was significantly antagonized by natrindole, a specific delta-receptor antagonist. Finally U50,488 at concentrations ranging from 10(-8) to 10(-9) M inhibited the proliferative response to Con A. The effects of U50,488 were mediated by the stimulation of the kappa-opioid receptors, since a preincubation of splenocytes with the selective antagonist norbinaltorphimine significantly reduced or abolished the U50,488-induced suppression of the mitotic response. In conclusion, our results clearly indicate that the different opioid receptor subtypes play a different role in the control of immune mechanisms and suggest that immunoenhancing effects of opioid peptides are very likely due to the stimulation of mu- and delta-receptors, whereas the immunosuppressive effects are mediated through the stimulation of kappa-opioid receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗