Integration of Immunome With Disease-Gene Network Reveals Common Cellular Mechanisms Between IMIDs and Drug Repurposing Strategies

ObjectiveDevelopment and progression of immune-mediated inflammatory diseases (IMIDs) involve intricate dysregulation of the disease-associated genes (DAGs) and their expressing immune cells. Identifying the crucial disease-associated cells (DACs) in IMIDs has been challenging due to the underlying complex molecular mechanism.MethodsUsing transcriptome profiles of 40 different immune cells, unsupervised machine learning, and disease-gene networks, we constructed the Disease-gene IMmune cell Expression (DIME) network and identified top DACs and DAGs of 12 phenotypically different IMIDs. We compared the DIME networks of IMIDs to identify common pathways between them. We used the common pathways and publicly available drug-gene network to identify promising drug repurposing targets.ResultsWe found CD4+Treg, CD4+Th1, and NK cells as top DACs in inflammatory arthritis such as ankylosing spondylitis (AS), psoriatic arthritis, and rheumatoid arthritis (RA); neutrophils, granulocytes, and BDCA1+CD14+ cells in systemic lupus erythematosus and systemic scleroderma; ILC2, CD4+Th1, CD4+Treg, and NK cells in the inflammatory bowel diseases (IBDs). We identified lymphoid cells (CD4+Th1, CD4+Treg, and NK) and their associated pathways to be important in HLA-B27 type diseases (psoriasis, AS, and IBDs) and in primary-joint-inflammation-based inflammatory arthritis (AS and RA). Based on the common cellular mechanisms, we identified lifitegrast as a potential drug repurposing candidate for Crohn’s disease and other IMIDs.ConclusionsExisting methods are inadequate in capturing the intricate involvement of the crucial genes and cell types essential to IMIDs. Our approach identified the key DACs, DAGs, common mechanisms between IMIDs, and proposed potential drug repurposing targets using the DIME network. To extend our method to other diseases, we built the DIME tool (https://bitbucket.org/systemsimmunology/dime/) to help scientists uncover the etiology of complex and rare diseases to further drug development by better-determining drug targets, thereby mitigating the risk of failure in late clinical development.

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The Crosstalk Between Tumor Cells and the Immune Microenvironment in Breast Cancer: Implications for Immunotherapy

Frontiers in Oncology ◽

10.3389/fonc.2021.610303 ◽

2021 ◽

Vol 11 ◽

Author(s):

Vincenzo Salemme ◽

Giorgia Centonze ◽

Federica Cavallo ◽

Paola Defilippi ◽

Laura Conti

Keyword(s):

Breast Cancer ◽

Nk Cells ◽

Tumor Cells ◽

Immune Cells ◽

Histone Deacetylase Inhibitors ◽

Lymphoid Cells ◽

New Combination ◽

Cell Contact ◽

Tumor Escape ◽

Complex Interplay

Breast cancer progression is a complex process controlled by genetic and epigenetic factors that coordinate the crosstalk between tumor cells and the components of tumor microenvironment (TME). Among those, the immune cells play a dual role during cancer onset and progression, as they can protect from tumor progression by killing immunogenic neoplastic cells, but in the meanwhile can also shape tumor immunogenicity, contributing to tumor escape. The complex interplay between cancer and the immune TME influences the outcome of immunotherapy and of many other anti-cancer therapies. Herein, we present an updated view of the pro- and anti-tumor activities of the main immune cell populations present in breast TME, such as T and NK cells, myeloid cells, innate lymphoid cells, mast cells and eosinophils, and of the underlying cytokine-, cell–cell contact- and microvesicle-based mechanisms. Moreover, current and novel therapeutic options that can revert the immunosuppressive activity of breast TME will be discussed. To this end, clinical trials assessing the efficacy of CAR-T and CAR-NK cells, cancer vaccination, immunogenic cell death-inducing chemotherapy, DNA methyl transferase and histone deacetylase inhibitors, cytokines or their inhibitors and other immunotherapies in breast cancer patients will be reviewed. The knowledge of the complex interplay that elapses between tumor and immune cells, and of the experimental therapies targeting it, would help to develop new combination treatments able to overcome tumor immune evasion mechanisms and optimize clinical benefit of current immunotherapies.

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The Liver Can Host Donor Hematopoiesis and Maintains a Strong Population of Innate Immune Cells That Contributes to Host Protection After Transplantation of Purified Hematopoietic Stem Cells.

Blood ◽

10.1182/blood.v114.22.3545.3545 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3545-3545

Author(s):

Pelu Tran ◽

Antonia MS Mueller ◽

Judith Shizuru

Keyword(s):

Stem Cells ◽

Innate Immunity ◽

T Cells ◽

Hematopoietic Stem Cells ◽

Nk Cells ◽

Immune Cells ◽

Lymphoid Cells ◽

Hematopoietic Stem ◽

Host Protection

Abstract Abstract 3545 Poster Board III-482 Standing in the line of first defense, the liver is a critical immunocompetent organ. It is armed with lymphocytes, including T cells (TC), natural killer (NK) cells, NK T cells, and a variety of antigen-presenting cells (APC), such as dendritic cells and resident macrophages (Mph), called Kupffer cells. Because it is exposed to large amounts of toxins and antigens, both destructive and harmless, liver immunity must provide immunogenic and tolerogenic mechanisms. Moreover, as the organ of fetal blood production the liver can, if required, resume its hematopoietic function. Here, we studied the role of the liver as a hematopoietic and lymphatic organ after hematopoietic cell transplantation (HCT). Lethally irradiated BALB.K and BALB.B mice were given MHC-matched, FACS purified hematopoietic stem cells (HSC; cKit+Sca1+Thy1.1loLin-) from AKR/J and C57BL/6 donors, respectively, alone or supplemented with 10∧7 splenocytes (SP) for GVHD induction. Mononuclear cells (MNC) were Ficoll-separated from flushed livers 1 to 6 weeks (w) post transplant (pTX) and FACS analyzed. In recipients of TC-containing grafts, the liver was a major target organ of acute graft-vs-host disease (GVHD) with prominent donor lymphocyte expansion causing destruction of the hepatic portal morphology. Rare HSC-derived cells were observed in the livers. In contrast, mice given purified HSC showed no clinical or histological signs of GVHD, yet early pTX a high proportion of donor HSC-derived MNC was observed within the livers, comprising ∼75% of the MNC at 2w. Phenotype analysis revealed that these HSC-derived MNC were primarily NK cells (DX5+CD122+) or Mph (Mac1+F4/80+). In fact, amongst all nucleated cells, NK cells represented >10% and were mixed donor/host type. Interestingly, the Mph were all donor derived. This observation of over-representation by cells of innate immunity (including NK cells and Mph) in livers of recipients of HSC alone led us to hypothesize that these cells might exert protective functions against increased amounts of pathogens and toxins entering the circulation from irradiation-damaged intestines. Thus, to suppress donor Mph reconstitution pTX, silica was injected intraperitoneally on d-1, and every 3d thereafter. All recipients of HSC alone recovered rapidly after irradiation (d5-7), while at this time point recipients of HSC plus silica showed severe weight loss, hunched posture, ruffled fur, diarrhea, with <50% (7/15) survival. These survivors clinically stabilized around d12, suggesting that the intestines recovered from injury. To test if the presence of the HSC derived NK cells and APC could contribute to host protection from GVHD, a lethal dose of SP (10∧7) was injected simultaneously with HSC, or with a delay of 7d or 9d. All mice given SP on d0 died within 9d and 3/5 of those receiving SP on d7 died by d12. However, all mice given SP on d9 recovered fully and showed no signs of GVHD, despite the lymphopenic host environment that usually promotes homeostatic expansion of mature donor TC. In conclusion, the role of the liver as an immunologically active organ after ‘conventional’ HCT is often masked by donor TC expansion with subsequent GVHD. Here, we provide evidence that if grafts are devoid of mature lymphoid cells, innate immunity recovers rapidly, and in fact exceeds unmanipulated controls. Donor Mph may protect the host from pathogens and endotoxemia. Moreover, they may neutralize activated donor TC and thereby mediate tolerance between donor and host. Likewise, the elevated proportion of donor and host NK cells, which is lacking in GVHD affected mice, suggest another beneficial mechanism of protection, as NK cells have been reported to be capable of reducing GVHD. Immunohistochemical studies for a better quantitative assessment of resident immune cells in the liver pTX are underway. Disclosures: No relevant conflicts of interest to declare.

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Systems Pharmacology-Based Approach of Connecting Disease Genes in Genome-Wide Association Studies with Traditional Chinese Medicine

International Journal of Genomics ◽

10.1155/2018/7697356 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Jihye Kim ◽

Minjae Yoo ◽

Jimin Shin ◽

Hyunmin Kim ◽

Jaewoo Kang ◽

...

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Target Gene ◽

Target Genes ◽

Disease Gene ◽

Drug Repurposing ◽

Genome Wide Association Studies ◽

Systems Pharmacology ◽

Potential Drug ◽

Gene Pairs

Traditional Chinese medicine (TCM) originated in ancient China has been practiced over thousands of years for treating various symptoms and diseases. However, the molecular mechanisms of TCM in treating these diseases remain unknown. In this study, we employ a systems pharmacology-based approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. We studied 102 TCM components and their target genes by analyzing microarray gene expression experiments. We constructed disease-gene networks from 2558 GWAS studies. We applied a systems pharmacology approach to prioritize disease-target genes. Using this bioinformatics approach, we analyzed 14,713 GWAS disease-TCM-target gene pairs and identified 115 disease-gene pairs with q value < 0.2. We validated several of these GWAS disease-TCM-target gene pairs with literature evidence, demonstrating that this computational approach could reveal novel indications for TCM. We also develop TCM-Disease web application to facilitate the traditional Chinese medicine drug repurposing efforts. Systems pharmacology is a promising approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. The computational approaches described in this study could be easily expandable to other disease-gene network analysis.

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Integration of immunome with disease gene network reveals pleiotropy and novel drug repurposing targets

10.1101/2019.12.12.874321 ◽

2019 ◽

Author(s):

Abhinandan Devaprasad ◽

Timothy RDJ Radstake ◽

Aridaman Pandit

Keyword(s):

Immune Cells ◽

Gene Networks ◽

Disease Gene ◽

Immune Cell ◽

Drug Repurposing ◽

Complex Diseases ◽

Immune Functions ◽

Immune Mediated ◽

Gene Database ◽

Disease Associated Genes

AbstractImmune system is crucial for the development and progression of immune-mediated and non-immune mediated complex diseases. Studies have shown that multiple complex diseases are associated with several immunologically relevant genes. Despite such growing evidence, the effect of disease associated genes on immune functions has not been well explored. Here, we curated the largest immunome (transcriptome profiles of 40 different immune cells) and integrated it with disease gene networks and drug-gene database, to generate a Disease-gene IMmune cell Expression network (DIME). We used the DIME network to: (1) study 13,510 genes and identify disease associated genes and immune cells for >15,000 complex diseases; (2) study pleiotropy between various phenotypically distinct rheumatic and other non-rheumatic diseases; and (3) identify novel targets for drug repurposing and discovery. We implemented DIME as a tool (https://bitbucket.org/systemsimmunology/dime) that allows users to explore disease-immune-cell associations and disease drug networks to pave way for future (pre-) clinical research.

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Sitagliptin: a potential drug for the treatment of SARS-CoV-2?

10.31222/osf.io/78mbt ◽

2020 ◽

Author(s):

Sanaa Bardaweel

Keyword(s):

Clinical Trials ◽

Drug Discovery ◽

Antimalarial Drug ◽

Drug Repurposing ◽

Spike Protein ◽

Diabetic Patients ◽

Potential Drug ◽

Chemokine Production ◽

Drug Discovery And Development ◽

Sequence Identity

Recently, an outbreak of fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. As the coronavirus pandemic rages, drug discovery and development become even more challenging. Drug repurposing of the antimalarial drug chloroquine and its hydroxylated form had demonstrated apparent effectiveness in the treatment of COVID-19 associated pneumonia in clinical trials. SARS-CoV-2 spike protein shares 31.9% sequence identity with the spike protein presents in the Middle East Respiratory Syndrome Corona Virus (MERS-CoV), which infects cells through the interaction of its spike protein with the DPP4 receptor found on macrophages. Sitagliptin, a DPP4 inhibitor, that is known for its antidiabetic, immunoregulatory, anti-inflammatory, and beneficial cardiometabolic effects has been shown to reverse macrophage responses in MERS-CoV infection and reduce CXCL10 chemokine production in AIDS patients. We suggest that Sitagliptin may be beneficial alternative for the treatment of COVID-19 disease especially in diabetic patients and patients with preexisting cardiovascular conditions who are already at higher risk of COVID-19 infection.

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Innate Lymphoid Cells Type 2 Attenuate Inflammatory Arthritis and Protect from Bone Destruction

SSRN Electronic Journal ◽

10.2139/ssrn.3155751 ◽

2018 ◽

Author(s):

Yasunori Omata ◽

SSbastien Lucas ◽

Kerstin Sarter ◽

Darja Andreev ◽

Tatjana Primbs ◽

...

Keyword(s):

Inflammatory Arthritis ◽

Bone Destruction ◽

Innate Lymphoid Cells ◽

Lymphoid Cells

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Sialic Acids and Their Influence on Human NK Cell Function

Cells ◽

10.3390/cells10020263 ◽

2021 ◽

Vol 10 (2) ◽

pp. 263

Author(s):

Philip Rosenstock ◽

Thomas Kaufmann

Keyword(s):

Nk Cells ◽

Immune Cells ◽

Cell Function ◽

Nk Cell ◽

Sialic Acids ◽

Innate Immune ◽

Target Cells ◽

Carbon Backbone ◽

Nk Cell Receptors ◽

Cell Inhibition

Sialic acids are sugars with a nine-carbon backbone, present on the surface of all cells in humans, including immune cells and their target cells, with various functions. Natural Killer (NK) cells are cells of the innate immune system, capable of killing virus-infected and tumor cells. Sialic acids can influence the interaction of NK cells with potential targets in several ways. Different NK cell receptors can bind sialic acids, leading to NK cell inhibition or activation. Moreover, NK cells have sialic acids on their surface, which can regulate receptor abundance and activity. This review is focused on how sialic acids on NK cells and their target cells are involved in NK cell function.

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Microfluidic tumor-on-a-chip model to evaluate the role of tumor environmental stress on NK cell exhaustion

Science Advances ◽

10.1126/sciadv.abc2331 ◽

2021 ◽

Vol 7 (8) ◽

pp. eabc2331 ◽

Cited By ~ 1

Author(s):

Jose M. Ayuso ◽

Shujah Rehman ◽

Maria Virumbrales-Munoz ◽

Patrick H. McMinn ◽

Peter Geiger ◽

...

Keyword(s):

Nk Cells ◽

Immune Cells ◽

Molecular Mechanisms ◽

Nk Cell ◽

Checkpoint Inhibitors ◽

Waste Product ◽

Extended Period ◽

Cell Exhaustion

Solid tumors generate a suppressive environment that imposes an overwhelming burden on the immune system. Nutrient depletion, waste product accumulation, hypoxia, and pH acidification severely compromise the capacity of effector immune cells such as T and natural killer (NK) cells to destroy cancer cells. However, the specific molecular mechanisms driving immune suppression, as well as the capacity of immune cells to adapt to the suppressive environment, are not completely understood. Thus, here, we used an in vitro microfluidic tumor-on-a-chip platform to evaluate how NK cells respond to the tumor-induced suppressive environment. The results demonstrated that the suppressive environment created by the tumor gradually eroded NK cell cytotoxic capacity, leading to compromised NK cell surveillance and tumor tolerance. Further, NK cell exhaustion persisted for an extended period of time after removing NK cells from the microfluidic platform. Last, the addition of checkpoint inhibitors and immunomodulatory agents alleviated NK cell exhaustion.

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Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

Biomolecules ◽

10.3390/biom11060901 ◽

2021 ◽

Vol 11 (6) ◽

pp. 901

Author(s):

Ramiz S. Ahmad ◽

Timothy D. Eubank ◽

Slawomir Lukomski ◽

Brian A. Boone

Keyword(s):

Pancreatic Cancer ◽

Extracellular Matrix ◽

Immune Cells ◽

Immune Cell ◽

Treatment Strategies ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Cellular Mechanisms ◽

Novel Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

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Biology and pathology of the uterine microenvironment and its natural killer cells

Cellular and Molecular Immunology ◽

10.1038/s41423-021-00739-z ◽

2021 ◽

Author(s):

Fuyan Wang ◽

Anita Ellen Qualls ◽

Laia Marques-Fernandez ◽

Francesco Colucci

Keyword(s):

Natural Killer ◽

Fetal Growth ◽

Immune Cells ◽

Smooth Muscle Actin ◽

Lymphoid Cells ◽

Unk Cells ◽

New Frontier ◽

Uterine Mucosa ◽

Blastocyst Implantation ◽

And Function

AbstractTissues are the new frontier of discoveries in immunology. Cells of the immune system are an integral part of tissue physiology and immunity. Determining how immune cells inhabit, housekeep, and defend gut, lung, brain, liver, uterus, and other organs helps revealing the intimate details of tissue physiology and may offer new therapeutic targets to treat pathologies. The uterine microenvironment modulates the development and function of innate lymphoid cells [ILC, largely represented by natural killer (NK) cells], macrophages, T cells, and dendritic cells. These immune cells, in turn, contribute to tissue homeostasis. Regulated by ovarian hormones, the human uterine mucosa (endometrium) undergoes ~400 monthly cycles of breakdown and regeneration from menarche to menopause, with its fibroblasts, glands, blood vessels, and immune cells remodeling the tissue into the transient decidua. Even more transformative changes occur upon blastocyst implantation. Before the placenta is formed, the endometrial glands feed the embryo by histiotrophic nutrition while the uterine spiral arteries are stripped of their endothelial layer and smooth muscle actin. This arterial remodeling is carried out by invading fetal trophoblast and maternal immune cells, chiefly uterine NK (uNK) cells, which also assist fetal growth. The transformed arteries no longer respond to maternal stimuli and meet the increasing demands of the growing fetus. This review focuses on how the everchanging uterine microenvironment affects uNK cells and how uNK cells regulate homeostasis of the decidua, placenta development, and fetal growth. Determining these pathways will help understand the causes of major pregnancy complications.

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