Publications by authors named "Yu-Hwa Huang"

20 Publications

  • Page 1 of 1

Neutrophil Extracellular Trap-Associated CEACAM1 as a Putative Therapeutic Target to Prevent Metastatic Progression of Colon Carcinoma.

J Immunol 2020 04 13;204(8):2285-2294. Epub 2020 Mar 13.

Cancer Research Program and the LD MacLean Surgical Research Laboratories, Department of Surgery, Research Institute of the McGill University Health Center, Montreal, Quebec H4A 3J1, Canada;

Neutrophils promote tumor growth and metastasis at multiple stages of cancer progression. One mechanism through which this occurs is via release of neutrophil extracellular traps (NETs). We have previously shown that NETs trap tumor cells in both the liver and the lung, increasing their adhesion and metastasis following postoperative complications. Multiple studies have since shown that NETs play a role in tumor progression and metastasis. NETs are composed of nuclear DNA-derived web-like structures decorated with neutrophil-derived proteins. However, it is unknown which, if any, of these NET-affiliated proteins is responsible for inducing the metastatic phenotype. In this study, we identify the NET-associated carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) as an essential element for this interaction. Indeed, blocking CEACAM1 on NETs, or knocking it out in a murine model, leads to a significant decrease in colon carcinoma cell adhesion, migration and metastasis. Thus, this work identifies NET-associated CEACAM1 as a putative therapeutic target to prevent the metastatic progression of colon carcinoma.
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http://dx.doi.org/10.4049/jimmunol.1900240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534954PMC
April 2020

CEACAM1 structure and function in immunity and its therapeutic implications.

Semin Immunol 2019 04;42:101296

Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA. Electronic address:

The type I membrane protein receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) distinctively exhibits significant alternative splicing that allows for tunable functions upon homophilic binding. CEACAM1 is highly expressed in the tumor environment and is strictly regulated on lymphocytes such that its expression is restricted to activated cells where it is now recognized to function in tolerance pathways. CEACAM1 is also an important target for microbes which have co-opted these attributes of CEACAM1 for the purposes of invading the host and evading the immune system. These properties, among others, have focused attention on CEACAM1 as a unique target for immunotherapy in autoimmunity and cancer. This review examines recent structural information derived from the characterization of CEACAM1:CEACAM1 interactions and heterophilic modes of binding especially to microbes and how this relates to CEACAM1 function. Through this, we aim to provide insights into targeting CEACAM1 for therapeutic intervention.
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http://dx.doi.org/10.1016/j.smim.2019.101296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814268PMC
April 2019

SLAM-ing the brakes on iNKT cell selection.

Nat Immunol 2019 04;20(4):378-379

Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41590-019-0355-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444350PMC
April 2019

Dual normative commitments mediating the relationship between perceived investment in employees' development and intention to leave among the healthcare workforce in underserviced areas of Taiwan.

Rural Remote Health 2019 02 7;19(1):4837. Epub 2019 Feb 7.

Department of Hematology-Oncology, E-Da Cancer Hospital, No. 21, Yi-Da Road, Jiao-Su Village, Yan-Chao District, 824, Kaohsiung City, Taiwan, Republic of China

Introduction: To study the factors affecting the intent to leave of healthcare workers who serve in underserviced areas of Taiwan, the authors tested the mediating role of both professional and organizational commitment in the relationship between perceived investment of employee development and intention to leave among these healthcare workers.

Method: This study was designed as a cross-sectional study using a well-organized questionnaire with major study variables consisting of perceived investment in employees' development (PIED), Meyer's occupational and organizational normative commitment, and intent to leave. In total, 692 healthcare workers from 48 health centers were enrolled for study; 616 people, including 415 (68.9%) from mountainous areas and 187 (31.1%) from isolated islands, responded and were valid for analysis. The response rate was 87%.

Results: The healthcare worker's PIED was positively correlated with both professional normative commitment and organizational normative commitment and negatively correlated with an individual's intent to leave. The dual normative commitments mediate completely the relationship between PIED and intention to leave in those health workers with government subsidy, while no such effect was noted in those without.

Conclusion: The employee's dual commitments of professional and organizational normative commitment mediated the relationship between perceived investment of employee development and intention to leave. The government's investment in on-the-job training and career planning for the healthcare workers in both remote areas and isolated islands is important to enforce their professional and organizational normative commitment, and to retain the workforce in these underserviced areas.
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http://dx.doi.org/10.22605/RRH4837DOI Listing
February 2019

High resolution X-ray and NMR structural study of human T-cell immunoglobulin and mucin domain containing protein-3.

Sci Rep 2018 11 30;8(1):17512. Epub 2018 Nov 30.

Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.

T-cell immunoglobulin and mucin domain containing protein-3 (TIM-3) is an important immune regulator. Here, we describe a novel high resolution (1.7 Å) crystal structure of the human (h)TIM-3 N-terminal variable immunoglobulin (IgV) domain with bound calcium (Ca) that was confirmed by nuclear magnetic resonance (NMR) spectroscopy. Significant conformational differences were observed in the B-C, C'-C″ and C'-D loops of hTIM-3 compared to mouse (m)TIM-3, hTIM-1 and hTIM-4. Further, the conformation of the C-C' loop of hTIM-3 was notably different from hTIM-4. Consistent with the known metal ion-dependent binding of phosphatidylserine (PtdSer) to mTIM-3 and mTIM-4, the NMR spectral analysis and crystal structure of Ca-bound hTIM-3 revealed that residues in the hTIM-3 F-G loop coordinate binding to Ca. In addition, we established a novel biochemical assay to define hTIM-3 functionality as determined by binding to human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1). These studies provide new insights useful for understanding and targeting hTIM-3.
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http://dx.doi.org/10.1038/s41598-018-35754-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269442PMC
November 2018

New Insights Into the Regulation of Natural-Killer Group 2 Member D (NKG2D) and NKG2D-Ligands: Endoplasmic Reticulum Stress and CEA-Related Cell Adhesion Molecule 1.

Front Immunol 2018 18;9:1324. Epub 2018 Jun 18.

Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

Natural-killer group 2 member D (NKG2D) is a well-characterized activating receptor expressed by natural killer (NK) cells, NKT cells, activated CD8 T cells, subsets of γδ T cells, and innate-like T cells. NKG2D recognizes multiple ligands (NKG2D-ligands) to mount an innate immune response against stressed, transformed, or infected cells. NKG2D-ligand surface expression is tightly restricted on healthy cells through transcriptional and post-transcriptional mechanisms, while transformed or infected cells express the ligands as a danger signal. Recent studies have revealed that unfolded protein response pathways during endoplasmic reticulum (ER) stress result in upregulation of ULBP-related protein the protein kinase RNA-like ER kinase-activating factor 4-C/EBP homologous protein (PERK-ATF4-CHOP) pathway, which can be linked to the pathogenesis of autoimmune diseases. Transformed cells, however, possess mechanisms to escape NKG2D-mediated immune surveillance, such as upregulation of carcinoembryonic antigen (CEA)-related cell adhesion molecule 1 (CEACAM1), a negative regulator of NKG2D-ligands. In this review, we discuss mechanisms of NKG2D-ligand regulation, with a focus on newly discovered mechanisms that promote NKG2D-ligand expression on epithelial cells, including ER stress, and mechanisms that suppress NKG2D-ligand-mediated killing of cancer cells, namely by co-expression of CEACAM1.
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http://dx.doi.org/10.3389/fimmu.2018.01324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020765PMC
June 2018

Blockade of Tim-3 binding to phosphatidylserine and CEACAM1 is a shared feature of anti-Tim-3 antibodies that have functional efficacy.

Oncoimmunology 2018;7(2):e1385690. Epub 2017 Nov 9.

Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.

Both data in preclinical cancer models and data with T cells from patients with advanced cancer support a role for Tim-3 blockade in promoting effective anti-tumor immunity. Consequently, there is considerable interest in the clinical development of antibody-based therapeutics that target Tim-3 for cancer immunotherapy. A challenge to this clinical development is the fact that several ligands for Tim-3 have been identified: galectin-9, phosphatidylserine, HMGB1, and most recently, CEACAM1. These observations raise the important question of which of these multiple receptor:ligand relationships must be blocked by an anti-Tim-3 antibody in order to achieve therapeutic efficacy. Here, we have examined the properties of anti-murine and anti-human Tim-3 antibodies that have shown functional efficacy and find that all antibodies bind to Tim-3 in a manner that interferes with Tim-3 binding to both phosphatidylserine and CEACAM1. Our data have implications for the understanding of Tim-3 biology and for the screening of anti-Tim-3 antibody candidates that will have functional properties .
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http://dx.doi.org/10.1080/2162402X.2017.1385690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749620PMC
November 2017

CEACAM1 as a multi-purpose target for cancer immunotherapy.

Oncoimmunology 2017;6(7):e1328336. Epub 2017 May 16.

Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.

CEACAM1 is an extensively studied cell surface molecule with established functions in multiple cancer types, as well as in various compartments of the immune system. Due to its multi-faceted role as a recently appreciated immune checkpoint inhibitor and tumor marker, CEACAM1 is an attractive target for cancer immunotherapy. Herein, we highlight CEACAM1's function in various immune compartments and cancer types, including in the context of metastatic disease. This review outlines CEACAM1's role as a therapeutic target for cancer treatment in light of these properties.
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http://dx.doi.org/10.1080/2162402X.2017.1328336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543821PMC
May 2017

CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.

Nature 2015 01 26;517(7534):386-90. Epub 2014 Oct 26.

Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.

T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in cis through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-specific CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity.
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http://dx.doi.org/10.1038/nature13848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297519PMC
January 2015

CEACAM1 on activated NK cells inhibits NKG2D-mediated cytolytic function and signaling.

Eur J Immunol 2013 Sep 18;43(9):2473-83. Epub 2013 Jun 18.

Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed on activated natural killer (NK) cells wherein it inhibits lysis of CEACAM1-bearing tumor cell lines. The mechanism for this is unknown. Here, we show that interleukin-2-induced expression of CEACAM1 on both mouse and primary human NK cells impairs the ability of NK gene complex group 2 member D (NKG2D) to stimulate cytolysis of CEACAM1-bearing cells. This process requires the expression of CEACAM1 on the NK cells and on the tumor cells, which is consistent with the involvement of trans-homophilic interactions between CEACAM1. Mechanistically, co-engagement of NKG2D and CEACAM1 results in a biochemical association between these two surface receptors and the recruitment of Src homology phosphatase 1 by CEACAM1 that leads to dephosphorylation of the guanine nucleotide exchange factor Vav1 and blockade of downstream signaling that is associated with the initiation of cytolysis. Thus, CEACAM1 on activated NK cells functions as an inhibitory receptor for NKG2D-mediated cytolysis, which has important implications for understanding the means by which CEACAM1 expression adversely affects tumor immunity.
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http://dx.doi.org/10.1002/eji.201242676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775953PMC
September 2013

The short isoform of the CEACAM1 receptor in intestinal T cells regulates mucosal immunity and homeostasis via Tfh cell induction.

Immunity 2012 Nov 1;37(5):930-46. Epub 2012 Nov 1.

Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Carcinoembryonic antigen cell adhesion molecule like I (CEACAM1) is expressed on activated T cells and signals through either a long (L) cytoplasmic tail containing immune receptor tyrosine based inhibitory motifs, which provide inhibitory function, or a short (S) cytoplasmic tail with an unknown role. Previous studies on peripheral T cells show that CEACAM1-L isoforms predominate with little to no detectable CEACAM1-S isoforms in mouse and human. We show here that this was not the case in tissue resident T cells of intestines and gut associated lymphoid tissues, which demonstrated predominant expression of CEACAM1-S isoforms relative to CEACAM1-L isoforms in human and mouse. This tissue resident predominance of CEACAM1-S expression was determined by the intestinal environment where it served a stimulatory function leading to the regulation of T cell subsets associated with the generation of secretory IgA immunity, the regulation of mucosal commensalism, and defense of the barrier against enteropathogens.
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http://dx.doi.org/10.1016/j.immuni.2012.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516394PMC
November 2012

CEACAM1 dampens antitumor immunity by down-regulating NKG2D ligand expression on tumor cells.

J Exp Med 2011 Dec 5;208(13):2633-40. Epub 2011 Dec 5.

Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Although carcinoembryonic antigen (CEA)-related cell adhesion molecule 1 (CEACAM1) has been viewed as a tumor suppressor, increasing clinical evidence shows that high levels of CEACAM1 expression on tumors correlates with poor prognosis and high risk of metastasis. Here, we examined the consequences of CEACAM1 expression on tumor cells. We show that tumor cell-associated CEACAM1 causes intracellular retention of various NKG2D ligands in mouse and human tumor cells. CEACAM1-silenced tumor cells expressed more cell surface NKG2D ligands and exhibited greater sensitivity to natural killer cell-mediated cytolysis in vitro and rejection in vivo. Our studies reveal a novel mechanism through which CEACAM1-bearing tumor cells may escape immune-surveillance.
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http://dx.doi.org/10.1084/jem.20102575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244030PMC
December 2011

Mediating effects of emotional exhaustion on the relationship between job demand–control model and mental health.

Stress Health 2011 Apr;27(2):e94-109

Institute of Human Resource Management, National Sun Yat-Sen University, Kaohsiung, Taiwan.

This study attempted to investigate the role of emotional exhaustion as a mediator on the relationship between job demands-control (JDC) model and mental health. Three-wave data from 297 employees were collected. The results showed that job demands were positively related to emotional exhaustion, and increasing job demands will increase the level of emotional exhaustion. Job control was negatively associated with emotional exhaustion; therefore, increasing job control will decrease the level of emotional exhaustion. Emotional exhaustion was negatively related to mental health. Emotional exhaustion fully mediated the relationship between job demands and mental health, and partially mediated the positive relationship between job control and mental health. In addition, job control was positively associated with mental health directly. The remarkable finding of the present study was that emotional exhaustion served as the key mediator between the JDC model and mental health. Theoretical and managerial implications and limitations were discussed.
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http://dx.doi.org/10.1002/smi.1340DOI Listing
April 2011

Janus head: the dual role of HLA-G in CNS immunity.

Cell Mol Life Sci 2011 Feb 18;68(3):407-16. Epub 2010 Nov 18.

Department of Neurology, Inflammatory Disorders of Nervous System and Neurooncology, University of Müenster, Domagkstr. 13, 48149 Müenster, Germany.

The central nervous system (CNS) is considered an immune-privileged organ that maintains an adaptable immune surveillance system. Dysregulated immune function within the CNS contributes to the development of brain tumor growth, and robust immune activation results in excessive inflammation. Human lymphocyte antigen-G (HLA-G) proteins with tolerogenic immunoreactivity have been implicated in various pathophysiological processes including immune surveillance, governing homeostasis and immune regulation. In this review, we describe the wealth of evidence for the involvement of HLA-G in the CNS under physiological and pathological conditions. Further, we review regulatory functions that may be applicable as beneficial strategies in the therapeutic manipulation of immune-mediated CNS immune responses. Additionally, we try to understand how this molecule cooperates with other CNS-resident cells to maintain normal immune homeostasis, while still facilitating the development of the appropriate immune responses.
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http://dx.doi.org/10.1007/s00018-010-0582-5DOI Listing
February 2011

Specific central nervous system recruitment of HLA-G(+) regulatory T cells in multiple sclerosis.

Ann Neurol 2009 Aug;66(2):171-83

Department of Neurology, University of Würzburg, Würzburg, Germany.

Objective: We have recently described a novel population of natural regulatory T cells (T(reg)) that are characterized by the expression of HLA-G and may be found at sites of tissue inflammation (HLA-G(pos) T(reg)). Here we studied the role of these cells in multiple sclerosis (MS), a prototypic autoimmune inflammatory disorder of the central nervous system (CNS).

Methods: Sixty-four patients with different types of MS, 9 patients with other neurological diseases, and 20 healthy donors were included in this study. Inflamed brain lesions from 5 additional untreated MS patients were examined. HLA-G(pos) T(reg) were analyzed in the cerebrospinal fluid (CSF) by flow cytometry and in inflammatory demyelinating lesions of MS brain specimens by immunohistochemistry. Functional capacity was accessed and transmigration was determined using an in vitro model of the human blood-brain barrier (BBB).

Results: HLA-G(pos) T(reg) were found enriched in the inflamed CSF of MS patients and in inflammatory demyelinating lesions of MS brain specimens. HLA-G(pos) T(reg) showed a strong propensity to transmigrate across BBB, which was vigorously driven by inflammatory chemokines, and associated with a gain of suppressive capacity upon transmigration. CSF-derived HLA-G(pos) T(reg) of MS patients represented a population of activated central memory activated T cells with an upregulated expression of inflammatory chemokine receptors and exhibiting full suppressive capacity. Unlike natural FoxP3-expressing T(reg), HLA-G(pos) T(reg) derived from peripheral blood were functionally unimpaired in MS.

Interpretation: In MS, HLA-G(pos) T(reg) may serve to control potentially destructive immune responses directly at the sites of CNS inflammation and to counterbalance inflammation once specifically recruited to the CNS.
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http://dx.doi.org/10.1002/ana.21705DOI Listing
August 2009

T cell suppression by naturally occurring HLA-G-expressing regulatory CD4+ T cells is IL-10-dependent and reversible.

J Leukoc Biol 2009 Aug 28;86(2):273-81. Epub 2009 Apr 28.

Department of Neurology, University of Wuerzburg, Wuerzburg, Germany.

CD4(+) T cells constitutively expressing the immune-tolerogenic HLA-G have been described recently as a new type of nT(reg) (HLA-G(pos) T(reg)) in humans. HLA-G(pos) T(reg) accumulate at sites of inflammation and are potent suppressors of T cell proliferation in vitro, suggesting their role in immune regulation. We here characterize the mechanism of how CD4(+) HLA-G(pos) T(reg) influence autologous HLA-G(neg) T(resp) function. Using a suppression system free of APC, we demonstrate a T-T cell interaction, resulting in suppression of HLA-G(neg) T(resp), which is facilitated by TCR engagement on HLA-G(pos) T(reg). Suppression is independent of cell-cell contact and is reversible, as the removal of HLA-G(pos) T(reg) from the established coculture restored the proliferative capability of responder cells. Further, HLA-G(pos) T(reg)-mediated suppression critically depends on the secretion of IL-10 but not TGF-beta.
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http://dx.doi.org/10.1189/jlb.1008649DOI Listing
August 2009

Postpartum-activation of multiple sclerosis is associated with down-regulation of tolerogenic HLA-G.

J Neuroimmunol 2007 Jul 11;187(1-2):205-11. Epub 2007 Jun 11.

Department of Neurology and MediCity Research Laboratory, University of Turku, PO Box 52, 20521Turku, Finland.

We used microarray analysis to obtain insights into the immuno-regulatory mechanisms controlling pregnancy-associated MS disease activity. We studied expression levels of 5000 immune-related genes in peripheral blood mononuclear cells in patients with relapsing-remitting MS during pregnancy and postpartum and in comparison to controls. In the microarray analysis, HLA-G, a non-classical major histocompatibility molecule mainly attributed with immune-tolerogenic functions, was found differentially regulated between MS patients and controls. The finding was corroborated and extended by real-time PCR, flow-cytometry and ELISA in a larger patient sample. The results delineate an important role for the immune-tolerogenic molecule HLA-G in modulating disease activity and pregnancy-related changes in MS patients.
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http://dx.doi.org/10.1016/j.jneuroim.2007.05.008DOI Listing
July 2007

HLA-G expression defines a novel regulatory T-cell subset present in human peripheral blood and sites of inflammation.

Blood 2007 Jul 19;110(2):568-77. Epub 2007 Mar 19.

Department of General Neurology, Hertie-Institute for Clinical Brain Research, Eberhard-Karls-University Tuebingen, Tuebingen, Germany.

Regulatory T cells can inhibit harmful immunopathologic responses directed against self and foreign antigens and play a major role in controlling autoimmunity. Here we have identified and characterized a subpopulation of CD4 and CD8 T cells in human peripheral blood expressing the immune tolerizing molecule HLA-G. HLA-G-expressing T cells are hypoproliferative, are CD25- and FOXP3-negative, and exhibit potent suppressive properties that are partially mediated by HLA-G. HLA-G-positive (HLA-G(pos)) T cells are found at low percentages among CD4 and CD8 single-positive thymocytes, suggesting a thymic origin. The presence of HLA-G(pos) T cells at sites of inflammation such as inflamed skeletal muscle in myositis or the cerebrospinal fluid of patients with acute neuroinflammatory disorders suggests an important function in modulating parenchymal inflammatory responses in vivo.
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http://dx.doi.org/10.1182/blood-2006-11-057125DOI Listing
July 2007

The role of leukemia-derived B7-H1 (PD-L1) in tumor-T-cell interactions in humans.

Exp Hematol 2006 Jul;34(7):888-94

Department of Hematology/Oncology II, University of Tuebingen, Germany.

Objective: Expression of the B7 homolog B7-H1 (PD1-Ligand) has been proposed to enable tumor cells to evade immune surveillance. Recently, B7-H1 on murine leukemia cells was reported to mediate resistance to cytolytic T-cell destruction. We here investigate the expression and function of the B7 homolog B7-H1 in human leukemia.

Patients And Methods: Leukemia cells from 30 patients and 9 human leukemia cell lines were investigated for B7-H1 expression by flow cytometry. Functional relevance of B7-H1 for tumor-immune interactions was assessed by coculture experiments using purified, alloreactive CD4 and CD8 T cells in the presence of a neutralizing anti-B7-H1 antibody.

Results: Significant B7-H1 expression levels on leukemia cells were detected in 17 of 30 patients and in eight of nine cell lines. In contrast to various other tumor entities and the data reported from a murine leukemia system, no significant inhibitory effect of leukemia-derived B7-H1 on CD4 and CD8 cytokine production (IFN-gamma, IL-2), proliferation or expression of T-cell activation markers (ICOS, CD69) was observed. Furthermore, in the presence of neutralizing B7-H1 antibody (mAb 5H1) occurred no significant changes in T cell IFN-gamma or IL-2 production or proliferation.

Conclusions: Our data demonstrate that leukemia-derived B7-H1 seems to have no direct influence on T-cell activation, proliferation, and cytokine production in humans. Further experiments are warranted to delineate factors and characterize yet-unidentified B7-H1 receptor(s) that determine inhibitory and stimulatory functions of B7-H1 in human leukemia.
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http://dx.doi.org/10.1016/j.exphem.2006.03.006DOI Listing
July 2006