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PubMed1993

Expression of intercellular adhesion molecule-1 on transitional cell cancer. Possible significance in immunity against tumor cells.

Immunohistochemical examination demonstrated expression of intercellular adhesion molecule-1 (ICAM-1) on 17 of 44 transitional cell cancers (TCCs) but not on normal transitional cells. ICAM-1 was frequently expressed in higher stage tumors, especially in those with abundant immune cells scattered within tumor. Analysis of infiltrating immune cells showed that they were composed mainly of T lymphocytes and a smaller number of macrophages bearing the lymphocyte function-associated antigen-1 (LFA-1). Expression of ICAM-1 on transitional cell cancer cell lines was augmented by in vitro treatment with interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 beta. Furthermore, Northern blot analysis revealed higher quantities of a 3.3-kb RNA in T24 cells exposed to interferon-gamma or tumor necrosis factor-alpha. These results suggest that the expression of ICAM-1 on transitional cell cancers might be modified by cytokines produced by infiltrating immune cells, which might facilitate immune responses against cancer cells.

Aged↗

PubMed2026

Immune subtyping of colorectal adenoma identifies a subtype with activated adaptive immunity ahead of progressing to cancer.

BACKGROUND: Colorectal adenomas (CRA) represent precursor lesions with varying risks of malignant transformation. However, molecular subtyping, particularly immune-related classification, remains underexplored in adenomas. This study aims to characterize the immune landscape of CRA through immune subtyping and evaluate its association with cancer progression, gene expression signatures, and functional pathways. METHODS: We conducted a retrospective analysis of transcriptomic data from multiple cohorts of CRA samples. Immune subtypes were identified using non-negative matrix factorization (NMF) based on immune-related genes. Diverse deconvolution algorithms were used to estimate immune cell infiltration. The immune status alteration in premalignant lesion was further consolidated by single-cell transcriptome data. Differential gene expression analysis was performed between subtypes, followed by functional enrichment analyses (Gene Ontology [GO] and Kyoto Encyclopedia of Genes and Genomes [KEGG]). RESULTS: Two distinct immune subtypes were identified: an immune-enriched subtype characterized by high lymphocyte infiltration and elevated expression of immune-related genes, and an immune-deficient subtype with suppressed immune activity. Differential expression analysis revealed significant upregulation of immune response genes (e.g., CD4, CD86, HLA-DRA) in the immune-enriched subtype. GO and KEGG analyses highlighted enrichments in leukocyte transendothelial migration, chemokine signaling, and antigen processing and presentation pathways. Single-cell result revealed an early occurrence of TIGIT activation and exhausted CD8 T cell features in adenoma when compared to normal tissue. CONCLUSION: This study delineates distinct immune subtypes within CRAs. The immune-enriched subtype demonstrates activated adaptive immunity and may reflect a higher potential for immune surveillance, while the immune-deficient subtype exhibits stromal features suggestive of progressive transformation. These findings provide insights into early immune microenvironment alterations and may inform strategies for risk stratification and immunoprevention in colorectal carcinogenesis.

Colorectal adenoma↗

PubMed2005

Mycophenolate mofetil ameliorates nephropathy in the obese Zucker rat.

BACKGROUND: The obese Zucker rat has metabolic condition resembling type II diabetes, including hyperlipidemia, obesity, insulin resistance, and hyperglycemia. With advancing age, the obese Zucker rat develops glomerulosclerosis, proteinuria, and renal failure. Since immune cells play a central role in the development of chronic renal injury, we evaluated the potential benefit of mycophenolate mofetil (MMF), alone and in combination with angiotensin receptor type 1 blockade (ARB) in the obese Zucker rat. METHODS: Thirteen-week-old male obese Zucker rats (fa/fa) were randomly assigned to four experimental groups (five rats each) that received the following treatments for 3 months: (1) losartan (100 mg/L in the drinking water), (2) MMF (20 mg/kg/day), (3) MMF and losartan, and (4) placebo. Lean Zucker rats (N = 5) were included as normal controls. Renal function, biochemical parameters, renal histology, and immunohistology were evaluated. RESULTS: The placebo-treated obese Zucker rats exhibited proteinuria and significant glomerular and tubulointerstitial injury in association with renal immune cell infiltration. Proteinuria, histologic damage, and renal immune cell infiltration were all reduced by MMF treatment alone or in combination with ARB. The improvement of proteinuria and structural damage was more pronounced in the group that received the combination of MMF and losartan. CONCLUSION: MMF treatment alone, and especially in combination with ARB, improves nephropathy in the obese Zucker rat.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2026

Pan-cancer Bioinformatics Analysis Combined with Colon Cancer Experimental Validation: A Study on TMED3 as a Diagnostic and Prognostic Biomarker.

Transmembrane Emp24 Protein Transport Domain 3 (TMED3), a member of the p24 protein family, has been implicated in tumor proliferation, invasion, and migration. This study aimed to evaluate the expression patterns, prognostic significance, immune associations, and potential biological functions of TMED3 across multiple cancer types using pan-cancer bioinformatics analysis combined with immunohistochemical (IHC) validation in colon cancer. Multiomics datasets from The Cancer Genome Atlas, Genotype-Tissue Expression, UALCAN, Human Protein Atlas, and cBioPortal databases were analyzed to investigate TMED3 expression and genetic alterations in pan-cancer. Immunohistochemistry was performed to evaluate TMED3 protein expression in colon cancer tissues. Kaplan-Meier survival analysis and Cox regression analysis were used to assess the prognostic value of TMED3. Spearman correlation analysis was conducted to evaluate the associations of TMED3 with tumor mutational burden, microsatellite instability (MSI), immune cell infiltration, and immune checkpoints. Gene Set Enrichment Analysis was performed to investigate potential biological pathways associated with TMED3 in colon cancer. TMED3 expression was elevated in most tumor types and was associated with unfavorable overall survival and disease-specific survival in adrenocortical carcinoma, colon adenocarcinoma, and uveal melanoma. The greatest frequency of TMED3 genetic alterations was identified in mesothelioma, with amplification representing the predominant alteration type. In addition, TMED3 expression showed significant correlations with tumor mutational burden and microsatellite instability in kidney renal clear cell carcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma. TMED3 expression was also associated with immune infiltration and immune checkpoint expression in several tumors. IHC analysis demonstrated increased TMED3 expression in colon cancer tissues compared with normal colon tissues and showed an association with T stage. Functional enrichment analysis identified pathways related to ribosome, antigen processing and presentation, oxidative phosphorylation, and pentose phosphate. These findings indicate that TMED3 may represent a promising biomarker for the diagnosis and prognostic evaluation of colon cancer as well as other tumor types.

Humans↗

PubMed2026

Research on identification of key genes and immune-metabolic mechanisms in atrial fibrillation through integrated multi-cohort transcriptomic analysis and machine learning.

This study aimed to integrate multiple datasets for the identification of atrial fibrillation (AF)-related differentially expressed genes (DEGs), analyze their underlying mechanisms through functional enrichment and machine learning, construct diagnostic models, and explore immune-metabolic interactions to provide novel biomarkers and theoretical foundations. Gene expression datasets were integrated and normalized, with batch effects removed using principal component analysis. Differential expression analysis, functional enrichment analysis (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways), and machine learning-based feature gene selection and model construction were performed. Shapley additive explanations analysis was utilized to interpret the constructed models, while gene set enrichment analysis, gene set variation analysis, and immune cell infiltration analysis were conducted to investigate the associations between feature genes and immune infiltration. After integrating and normalizing gene expression data and eliminating batch effects via principal component analysis, 6 DEGs were identified, including 4 upregulated and 2 down-regulated ones. Functional enrichment analysis showed these DEGs were significantly enriched in neuro-related biological processes and pathways, indicating their key roles in AF pathogenesis. Five key feature genes were selected using LASSO, random forest, and support vector machine-recursive feature elimination algorithms. They had significant expression differences between the AF and control groups (P < .001) and were located on distinct chromosomes. The constructed random forest and support vector machine models performed excellently (area under the curve ≥ 0.85). Shapley additive explanations analysis revealed TNNI1 contributed most to model prediction, with its expression significantly positively correlated with immune cell infiltration. Gene set enrichment analysis and gene set variation analysis analyses further showed feature genes participated in AF pathogenesis by regulating immune modulation, metabolic pathways, and autophagy. Immune cell infiltration analysis found altered proportions of T-cell subsets and M0 macrophages in the AF group, along with complex links between feature gene expression and immune cell function. This study systematically elucidated the unique gene expression patterns and key regulatory pathways associated with AF, clarifying the crucial roles of feature genes in immune regulation, metabolic imbalance, and cellular dysfunction. These findings provide a theoretical basis and potential therapeutic targets for understanding AF pathogenesis and developing targeted treatment strategies.

Atrial Fibrillation↗

PubMed1999

Hyperacute rejection in the guinea pig-to-rat model without formation of the membrane attack complex.

The guinea pig (GP)-to-rat transplantation model has been widely used to study hyperacute rejection (HAR) of xenografts. In this model heart graft survival beyond 8 days has never been reported. In contrast, survival times of kidney and heart grafts up to 62 days have been reported in the discordant pig-to-primate model. It is not clear why it is so much more difficult to obtain long-term graft survival in the GP-to-rat model as compared to the pig-to-primate model. We hypothesized that mechanisms other than activation of complement may be involved in the rejection of guinea pig grafts by rat recipients. Therefore, we have studied in detail the rejection of GP aortic grafts by rat recipients, either PVG/c+ (complement competent, group 1), or PVG/c- (complement C6 deficient, group 2). PVG/c- rats are not able to form the membrane attack complex (MAC) of complement. Forty-four GP-to-rat aortic transplantations were performed successfully. Recipient rats were sacrificed at various intervals after transplantation (4, 24 and 48 h, and 7 and 28 days, three to six animals per time point per group). Twenty-four hours after transplantation the number of cells in the media was significantly decreased from 11.1 +/- 0.9 cells/mm2 to 3.1 +/- 2.8 cells/mm2 in group 1, whereas the number of medial cells in group 2 remained the same. The number of medial cells was significantly decreased in both groups at 48 h post-transplantation (group 1: 1.8 +/- 2.2 cells/mm2; group 2: 5.5 +/- 3.0 cells/mm2). At that time no infiltrating cells were apparent in the grafts of either two groups. Seven days after transplantation, the number of medial cells remained low in group 1 (1.8 +/- 2.9 cells/mm2) but was increased in group 2 (10.7 +/- 2.6 cells/mm2) as a consequence of infiltrating immune cells. These infiltrating cells consisted mainly of macrophages, but also T cells and NK cells. At 28 days after transplantation the grafts in both groups were completely reorganized and no distinction could be made between media and adventitia. These results show that rejection of GP grafts by rat recipients can occur in the absence of both MAC of complement and immune competent cells. This MAC and immune cells independent type of rejection has not been described before and may explain the difficulty in obtaining long-term graft survival in the GP-to-rat xenotransplantation model.

Acute Disease↗

PubMed1998

Evaluation of HLA-DR expression and T-lymphocyte infiltration in osteosarcoma.

Although in recent years the outcome of patients with osteosarcoma has considerably been improved by combining neoadjuvant chemotherapy with radical surgery, there still remains the problem of nonresponse to chemotherapy. T-lymphocytes play a critical role in tumor immunology, and MHC molecules are of central importance in the regulation of the immune response. It is the aim of this study to investigate whether T-lymphocyte infiltration of osteosarcomas and HLA-DR expression on tumor cells and infiltrating immune cells are of predictive or diagnostic value. Expression of CD3, CD8 and HLA-II was evaluated immunohistochemically on paraffin-embedded sections of 35 patients with high-grade osteosarcoma at the time of biopsy before chemotherapy and correlated with histologic response to chemotherapy, tumor size, age, alkaline-phosphatase serum levels and duration of symptoms. Thirty-four patients with osteoblastoma (n = 7), osteoid osteoma (n = 7) or fibrous dysplasia (n = 20) served as controls. Osteosarcomas were infiltrated by CD3+ (33/35, 95%) and CD8+ T-lymphocytes (24/35, 68%), non malignant bone tumors by CD3+ in 91% (31/34) and CD8+ T-lymphocytes in 74% (25/34), respectively. T-lymphocytes were positive for HLA-DR expression in 29% (10/35) in osteosarcomas and in 11% (4/34) in non-malignant controls. Osteosarcoma cells were positive for HLA-DR in 11/35 (31%) and non-malignant tumor cells in only 9% (3/34). Therefore, HLA-DR is overexpressed in osteosarcoma (p < 0.05). HLA-DR expression on osteosarcoma cells showed a positive correlation with HLA-DR expression on lymphocytes (p < 0.001) as well as with duration of symptoms and age (p < 0.05). Response to preoperative chemotherapy, gender, tumor size and serum alkaline-phosphatase levels did not correlate with the expression of the molecules tested. Our results show that HLA-DR is overexpressed in osteosarcoma cells compared to non-malignant bone-tumors. This overexpression, however, fails to serve as a predictive marker for response to neoadjuvant chemotherapy. The same is also true for tumor-infiltrating lymphocytes expressing CD3, CD8 and HLA-DR. Increased HLA-DR expression in osteosarcoma is most likely due to the immune response against the tumor.

Adolescent↗

PubMed2006

CD4+CXCR4highCD69+ T cells accumulate in lung adenocarcinoma.

The chemokine receptor CXCR4 is involved in the growth and metastasis of tumor cells. However, the expression of its ligand, the chemokine CXCL12, in tumors and its role in regulating the accumulation of immune cells within the tumors is not clear. Using ELISA and immunohistochemistry we found that CXCL12 is expressed in the majority of nonsmall cell lung cancer tissue sections obtained from stage IA to IIB nonsmall cell lung cancer patients undergoing operation. Histopathologic examination of these sections indicated that high CXCL12 expression correlated with increased tumor inflammation. In addition, disease recurrence rates in a subgroup of adenocarcinoma patients showed a tendency to correlate with high CXCL12 expression in the tumor. Isolation of adenocarcinoma-infiltrating immune cells demonstrated an increase in the percentage of CD4+CD69+CXCR4+ T cells as compared with normal lung tissue. About 30% of these cells expressed the regulatory T cell markers CD25high and FoxP3. The percentage of CD8 T cells within the tumor did not change, however; the percentage of NK and NK T cells was significantly reduced. In correlation with CXCR4 expression, CD4 T cells showed increased migration in response to CXCL12 compared with CD8 T cells and NK cells. Overall, these observations suggest that CXCL12 expression may influence tumor progression by shaping the immune cell population infiltrating lung adenocarcinoma tumors.

Adenocarcinoma↗

PubMed1992

Sequential immunocytological evaluation of murine transitional cell carcinoma during intralesional bacillus Calmette-Guerin and interleukin-2 immunotherapy.

The antitumor effect of intralesionally administered recombinant interleukin-2 was highly effective (90% complete response) in murine bladder cancer. We postulated that interleukin-2 may be integral to the Bacillus Calmette-Guerin-induced antitumor response in human bladder cancer. Flow cytometric evaluation of the tumor infiltrates was compared before and after intralesional treatment of an established, untreated murine bladder tumor model with recombinant interleukin-2, Bacillus Calmette-Guerin or saline. Large increases in the number of tumor infiltrating immune cells occurred between the day of randomization and the second day (one day after the first treatment) in all three groups. However, since tumor volume was reduced by treatment, the ratios of the immune cells to tumor volume was increased. The ratios of T(helper), T(cytotoxic)/suppressor cells, macrophages, and natural killer cells to tumor volume were 1.5 to 3.4 times higher in the interleukin-2 and Bacillus Calmette-Guerin groups in comparison to the saline group. The ratio of T(helper)/T(cytotoxic)/suppressor cells however, remained approximately the same despite treatment. Over the next 22 days all subpopulations of tumor infiltrating immune cells decreased in number and frequency to less than measurable levels. The similar modulation of infiltrating immune cell subpopulations by Bacillus Calmette-Guerin and interleukin-2 may indicate that the production of interleukin-2 is part of the tumor modulating mechanism of Bacillus Calmette-Guerin.

Animals↗

PubMed2025

COL5A1 in the tumor microenvironment predicts the prognosis of head and neck cancer.

ObjectivesThis study aims to investigate the significance of tumor microenvironment (TME)-related genes and signal transduction pathways in head and neck cancer (HNC).MethodsGene expression and clinical data of HNC patients were obtained from the Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were screened through a multi-step filtration approach to obtain candidate predictors. The biological role of COL5A1 in HNC was verified through rigorous bioinformatic analysis, experimental validation using quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) analysis from HNC samples, and IHC data from the Human Protein Atlas (HPA) database.ResultsCOL5A1 was significantly upregulated in HNC tissues and cell lines. High COL5A1 expression was significantly associated with advanced tumor grade (P < .05) and shorter survival (TCGA: P < .001; GSE42743: P = .004). COL5A1 was an independent prognostic indicator (univariate analysis: HR = 1.324, P = .001; Multivariate analysis: HR = 1.326, P = .005). It was enriched in pathways related to tumor invasion and immune responses, and its expression was associated with decreased levels of CD8+ T cells and increased levels of macrophages and neutrophils. Spatial distribution analysis revealed higher expression at the tumor's leading edge (vs. tumor core: P < .001). COL5A1 expression is associated with tumor stage, with more pronounced expression in advanced-stage tumors.ConclusionCOL5A1 represented a novel potential prognostic indicator and therapeutic target in an HNC database sample, as its expression is closely linked to tumor progression, immune cell infiltration, and adverse clinical outcomes. These findings, primarily derived from squamous cell carcinoma-dominated cohorts, warrant further functional validation.

Humans↗

PubMed2004

Angiotensin II type 1 and type 2 receptors reciprocally modulate pro-inflammatory/ pro-fibrotic reactions in activated splenic lymphocytes.

Angiotensin II (Ang II) type 1 receptor (AT1R) has been confirmed to confer renoprotection in the progressive, immune-mediated nephritis in animal models as well as in humans. However, the relative contributions of direct AT1R blockade, indirect counteractivation of Ang II type 2 receptor (AT2R), or both, to renoprotection through AT1R antagonism remains to be clarified. Immunohistochemical studies in the nephritic kidney revealed that tubular epithelial cells and infiltrating immune cells were positive for AT1R and AT2R. In the present study, we investigated the action of Ang II on both receptors on immune cells. A subpopulation of lipopolysaccharide-activated splenic lymphocytes (mixed lymphocyte populations) was positive for AT1R and AT2R. Ang II alone could not induce gene expression of a pro-inflammatory chemokine JE or a pro-fibrotic cytokine transforming growth factor-beta1 in those cells. However, Ang II could significantly suppress the expression of both genes in those cells under AT1R blockade, and this action was mediated through AT2R. Conversely, the pro-inflammatory/pro-fibrotic gene expression could be enhanced by AT2R blockade, and this was mediated through AT1R. AT1R and AT2R expressed in activated immune cells can modulate pro-inflammatory and pro-fibrotic reactions reciprocally. In advanced immune-mediated nephritic kidneys, AT1R antagonism likely confers renoprotection via activation of AT2R.

Animals↗

PubMedDate not supplied

Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems.

The interaction between components of the nervous system and multiple target cells in the cutaneous immune system has been receiving increasing attention. It has been observed that certain skin diseases such as psoriasis and atopic dermatitis have a neurogenic component. Neuropeptides released by sensory nerves that innervate the skin and often contact epidermal and dermal cells can directly modulate functions of keratinocytes, Langerhans cells (LC), mast cells, dermal microvascular endothelial cells and infiltrating immune cells. Among these neuropeptides the tachykinins substance P (SP) and neurokinin A (NKA), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and somatostatin (SOM) have been reported to effectively modulate skin and immune cell functions such as cell proliferation, cytokine production or antigen presentation under physiological or pathophysiological conditions. Expression and regulation of their corresponding receptors that are expressed on a variety of skin cells as well as the presence of neuropeptide-specific peptidases such as neutral endopeptidase (NEP) or angiotensin-converting enzyme (ACE) determine the final biological response mediated by these peptides on the target cell or tissue. Likewise, skin cells like keratinocytes or fibroblasts are a source for neurotrophins such as nerve growth factor that are required not only for survival and regeneration of sensory neurons but also to control responsiveness of these neurons to external stimuli. Therefore, neuropeptides, neuropeptide receptors, neuropeptide-degrading enzymes and neurotrophins participate in a complex, interdependent network of mediators that modulate skin inflammation, wound healing and the skin immune system. This review will focus on recent studies demonstrating the role of tachykinins, CGRP, SOM and VIP and their receptors and neuropeptide-degrading enzymes in mediating neurogenic inflammation in the skin.

Animals↗

PubMed2026

Screening and identification of key genes related to the immune microenvironment of rectal cancer influenced by radiotherapy based on bioinformatics methods.

OBJECTIVE: Radiotherapy (RT) plays a crucial role in the comprehensive treatment of rectal cancer. However, the impact of radiotherapy on the tumor microenvironment (TME), especially its effect on immune cell infiltration and immune-related gene expression, has not been fully studied. This study aims to screen and analyze key genes related to the immune microenvironment of rectal cancer influenced by radiotherapy based on bioinformatics methods for the purpose of identifying potential biomarkers and providing new insights for the personalized therapy of rectal cancer. METHODS: Using data from the Public Gene Expression Database (GEO) and the Cancer Genomics Database (TCGA), the impact of radiotherapy on the immune microenvironment of rectal cancer was explored using bioinformatics tools. Through screening differentially expressed genes (DEGs), correlation analysis, TIMER database analysis, immune infiltration score, and correlation analysis between key genes and prognosis, the effects of radiotherapy on the immune microenvironment of rectal cancer were investigated. RESULTS: Totally 7 upregulated and 4 downregulated differentially expressed genes were identified, among which MASP1, LTK, SLC9A3R2 were negatively correlated with myeloid suppressor cell infiltration (MDSCs), while ZP2 was positively correlated. The expression of MASP1 and SLC9A3R2 was closely related to the level of immune cell infiltration and played significant roles in the immune microenvironment. High expression of MASP1 was significantly correlated with survival benefits from immune checkpoint inhibitor therapy, while SLC9A3R2 was closely related to the efficacy of PD-L1 inhibitors and CTLA4 inhibitors. CONCLUSIONS: MASP1 and SLC9A3R2, as two key genes that may be related to the immune microenvironment of rectal cancer radiotherapy, deserve further exploration of their roles in the mechanism. The combination of radiotherapy and immunotherapy holds promising prospects in the treatment of rectal cancer, and exploration of related mechanisms will provide new strategies and targets for the treatment of various tumors and rectal cancer.

Bioinformatics↗

PubMed2003

Targeting of macrophage activity by adenovirus-mediated intragraft overexpression of TNFRp55-Ig, IL-12p40, and vIL-10 ameliorates adenovirus-mediated chronic graft injury, whereas stimulation of macrophages by overexpression of IFN-gamma accelerates chronic graft injury in a rat renal allograft model.

Adenovirus (Ad)-mediated gene transfer of immunoregulatory molecules prevents acute allograft rejection. It is here analyzed for the first time whether this approach may prevent the development of chronic renal allograft injury in rats. Renal allografts (F344-->Lewis rat) were ex vivo transduced in group I with control Ad-construct, group II with three different therapeutic Ad-constructs expressing the immunoregulatory molecules vIL-10, TNFRp55-Ig, and IL-12p40, and group III with AdIFN-gamma. Group IV served as untreated controls. Control grafts (IV) showed increasing proteinuria during the 24-wk follow-up. Chronic graft injury was accelerated by Ad-control (I) and even more by AdIFN-gamma (III). All rats carrying the AdIFN-gamma-transduced grafts died within 12 to 13 wk by advanced chronic renal failure associated with strong immune cell infiltration and immune gene expression. By contrast, the Ad-therapy group II showed less inflammation and improved graft histology and function if compared with the groups I and III. Moreover, significantly less infiltrating ED-1(+) macrophages and an improved histologic score even if compared with untreated controls (IV) was observed. However, after disappearance of therapeutic gene expression, group II showed increasing proteinuria probably as result of late T cell activation to the Ad-encoded proteins. Ex vivo transduction of allografts with Ad-control or even more AdIFN-gamma expression promotes intragraft inflammation and chronic graft injury. Targeting macrophage activation by a cocktail of therapeutic genes improved the results. These data support the pathogenetic role of cytokines in chronic graft injury; however, they also show the limitations of the Ad-mediated gene transfer.

Adenoviridae↗

PubMed2005

Embryonic stem cell immunogenicity increases upon differentiation after transplantation into ischemic myocardium.

BACKGROUND: We investigated whether differentiation of embryonic stem cells (ESCs) in ischemic myocardium enhances their immunogenicity, thereby increasing their chance for rejection. METHODS AND RESULTS: In one series, 129/SvJ-derived mouse ESCs (ES-D3 line) were transplanted by direct myocardial injection (1 x 10(6) cells) into murine hearts of both allogeneic (BALB/c, n=20) and syngeneic (129/SvJ, n=12) recipients after left anterior artery ligation. Hearts were procured at 1, 2, 4, and 8 weeks after ESC transplantation and analyzed by immunohistochemistry to assess immune cell infiltration (CD3, CD4, CD8, B220, CD11c, Mac-1, and Gr-1) and ESC differentiation (hematoxylin and eosin). In a second series (allogeneic n=5, sham n=3), ESC transplantation was performed similarly; however after 2 weeks, left anterior descending artery-ligated and ESC-injected hearts were heterotopically transplanted into naive BALB/c recipients. After an additional 2 weeks, donor hearts were procured and analyzed by immunohistochemistry. In the first series, the size of all ESC grafts remained stable and there was no evidence of ESC differentiation 2 weeks after transplantation; however, after 4 weeks, both allogeneic and syngeneic ESC grafts showed the presence of teratoma. By 8 weeks, surviving ESCs could be detected in the syngeneic but not in the allogeneic group. Mild inflammatory cellular infiltrates were found in allogeneic recipients at 1 and 2 weeks after transplantation, progressing into vigorous infiltration at 4 and 8 weeks. The second series demonstrated similar vigorous infiltration of immune cells as early as 2 weeks after heterotopic transplantation. CONCLUSIONS: In vivo differentiated ESCs elicit an accelerated immune response as compared with undifferentiated ESCs. These data imply that clinical transplantation of allogeneic ESCs or ESC derivatives for treatment of cardiac failure might require immunosuppressive therapy.

Animals↗

PubMed1998

Intercellular adhesion molecule-1 (ICAM-1), leucocyte function-associated antigen-1 (LFA-1) and leucocyte infiltration in proliferative human glomerulonephritis.

The expression of the intercellular adhesion molecule-1 (ICAM-1), infiltrating cells positive for its ligand leucocyte adhesion molecule-1(LFA-1), and the markers of total leucocytes (CD45RB), T cells (CD45RO), and monocytes/macrophages (CD68) were examined by an indirect immunoperoxidase method on renal biopsy specimens from 20 patients with mesangial proliferative glomerulonephritis-IgA negative (MesProGN) and 20 with IgA nephropathy (IgAN). Histologically, normal portions of the kidney tissue (n = 15) obtained from patients with renal trauma or renal tumours were used as controls. The expression of ICAM-1 was evident and extended in mesangium, on endothelial cells of peritubular capillaries, interstitial cells, several infiltrating immune cells and on tubular epithelial cells, particularly on atrophic tubuli in renal biopsies of MesProGN and IgAN. In both types of glomerulopathies a significant increase in the number of glomerular and interstitial LFA-1-positive cells correlated positively with the expression of ICAM-1. The number of glomerular and interstitial LFA-1-positive cells correlated positively with the number of monocytes/macrophages in glomeruli and interstitium. The strong correlation between expression of ICAM-1 and LFA-1 and between LFA-1-positive cells and immune cells makes these adhesion molecules useful markers of activity and suggest that they are involved in recruitment of leucocytes in the studied types of proliferative glomerulopathies.

Adolescent↗

PubMed2000

Cell contact interactions in rheumatology, The Kennedy Institute for Rheumatology, London, UK, 1-2 June 2000.

The intricate interactions that regulate relationships between endogenous tissue cells and infiltrating immune cells in the rheumatic joint, particularly in rheumatoid arthritis (RA), were the subject of the meeting. A better understanding of these interactions might help to define intervention points that could be used to develop specific therapies. The presentations and discussions highlighted the fact that, once chronic inflammation is established, several proinflammatory loops involv9ing tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta can be defined. Direct cellular contact with stimulated T lymphocytes induces TNF-alpha and IL-1beta in monocytes which in turn induce functions in fibroblast-like synoviocytes. The latter include the production of stromal cell-derived factor-1alpha (SDF-1alpha) which enhances the expression of CD40L in T cells, which stimulates SDF-1alpha production in synoviocytes, which in turn protects T and B cells from apoptosis and enhances cell recruitment thus favoring inflammatory processes. IL-1beta and TNF-alpha also induce IL-15 in fibroblast like synoviocytes, which induces the production of IL-17 which in turn potentiates IL-1beta and TNF-alpha production in monocyte-macrophages. This underlies the importance of TNF-alpha and IL-1beta in RA pathogenesis, and helps explain the efficiency of agents blocking the activity of these cytokines in RA. Factors able to block the induction of cytokine production (such as apolipoprotein A-I [apo A-I] and interferon [IFN]-beta) might interfere more distally in the inflammatory process. Furthermore, stimulated T lymphocytes produce osteoclast differentiation factor (ODF), which triggers erosive functions of osteoclasts. Therefore, factors capable of affecting the level of T lymphocyte activation, such as IFN-beta, IL-15 antagonist, or SDF-1alpha antagonist, might be of interest in RA therapy.

Arthritis, Rheumatoid↗

PubMed2004

The epidermal growth factor-like growth factor amphiregulin is strongly induced by the adenosine 3',5'-monophosphate pathway in various cell types.

We examined the cAMP-mediated regulation of the epidermal growth factor-like growth factor amphiregulin (AR) in T cells and observed a strong cAMP-induced up-regulation of AR mRNA in a time- and concentration-dependent manner independent of T cell activation. This regulation may be mediated in part through activation of a cAMP-responsive element in the AR promoter, because the cAMP-responsive element conferred cAMP responsiveness to a luciferase reporter in Jurkat TAg cells. Similar effects of AR mRNA induction were seen in T cells treated with cAMP-elevating agents such as prostaglandin E(2) and forskolin as well as with the phosphodiesterase inhibitors rolipram and isobutylmethylxanthine. Furthermore, the induction of AR mRNA by cAMP was strongly suppressed by a protein kinase A type I-selective inhibitor, whereas treatment with an exchange protein directly activated by cAMP-specific agonist did not increase AR levels. In addition, an increase in AR gene transcripts by cAMP was seen in MCF-7 mammary carcinoma cells and H295R adrenal cells. Moreover, the potent cAMP-mediated induction of AR mRNA resulted in increased secretion (5-fold) of AR from T cells. Furthermore, supernatants from cAMP-stimulated T cells containing secreted AR induced phosphorylated MAPK in OVCAR-3 carcinoma cells. In conclusion, our data suggest that AR is under strong regulation by the cAMP pathway in various cell types, and that prostaglandin E(2)- and cAMP-induced AR secretion from T cells may be highly relevant in a microenvironment consisting of tumor cells and infiltrated immune cells, because AR by activating the MAPK pathway through a paracrine route may contribute to proliferation of tumor cells and thus add to neoplastic processes.

Adenylyl Cyclases↗