Journal articles: 'Gitern'

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Gan, Xiaoxia, Xiaoke Feng, Lei Gu, Wenfeng Tan, Xiaoxuan Sun, Chengyin Lv, and Miaojia Zhang. "Correlation of Increased Blood Levels of GITR and GITRL with Disease Severity in Patients with Primary Sjögren’s Syndrome." Clinical and Developmental Immunology 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/340751.

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Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is a type I transmembrane protein belonging to the TNFR superfamily. After activated by its ligand GITRL, GITR could influence the activity of effector and regulatory T cells, participating in the development of several autoimmune and inflammatory diseases included rheumatoid arthritis and autoimmune thyroid disease. We previously reported that serum GITRL levels are increased in systemic lupus erythematosus (SLE) patients compared with healthy controls (HC). Here, we tested serum soluble GITR (sGITR) and GITRL levels in 41 primary Sjögren’s syndrome (pSS) patients and 29 HC by ELISA and correlated sGITR and GITRL levels with clinical and laboratory variables. GITR and GITRL expression in labial salivary glands was detected by immunohistochemistry. pSS patients had significantly increased serum levels of sGITR and GITRL compared with controls (GITR: 5.66 ± 3.56 ng/mL versus 0.50 ± 0.31 ng/mL;P<0.0001; GITRL: 6.17 ± 7.10 ng/mL versus 0.36 ± 0.28 ng/mL;P<0.0001). Serum sGITR and GITRL levels were positively correlated with IgG (GITRL:r=0.6084,P<0.0001; sGITR:r=0.6820,P<0.0001) and ESR (GITRL:r=0.8315,P<0.0001; sGITR:r=0.7448,P<0.0001). Moreover, GITR and GITRL are readily detected in the lymphocytic foci and periductal areas of the LSGs. In contrast, the LSGs of HC subjects did not express GITR or GITRL. Our findings indicate the possible involvement of GITR-GITRL pathway in the pathogenesis of pSS. Further studies may facilitate the development of targeting this molecule pathway for the treatment of pSS.

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Krausz, Ludovic Tibor, Rodolfo Bianchini, Simona Ronchetti, Katia Fettucciari, Giuseppe Nocentini, and Carlo Riccardi. "GITR-GITRL System, A Novel Player in Shock and Inflammation." Scientific World JOURNAL 7 (2007): 533–66. http://dx.doi.org/10.1100/tsw.2007.106.

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Glucocorticoid-induced TNFR-Related (GITR) protein is a member of the tumor necrosis factor receptor superfamily that modulates acquired and natural immune response. It is expressed in several cells and tissues, including T cells, natural killer cells, and, at lower levels, in cells of innate immunity. GITR is activated by its ligand, GITRL, mainly expressed on antigen presenting and endothelial cells. Recent evidence suggests that the GITR/GITRL system participates in the development of inflammatory responses, including shock, either due to early response of neutrophils and macrophages, or together with autoimmune/allergic pathogenesis. The pro-inflammatory role of the GITR/GITRL system is due to: 1) modulation of the extravasation process, 2) activation of innate immunity cells, 3) activation of effector T cells also favored by partial inhibition of suppressor T cells and modulation of dendritic function. This review summarizes thein vivorole of the GITR/GITRL system in inflammation and shock, explaining the mechanisms responsible for their effects, considering the interplay among the different cells of the immune system and transduction pathways activated by GITR and GITRL triggering. The hidden aspects about GITR/GITRL function, crucial for treatment planning of inflammatory diseases and shock by modulation of this system is stressed.

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Krusch, Matthias, Katrin M. Baltz, Tina Baessler, Mercedes Kloss, Ingrid Kumbier, Andrea Peterfi, Lothar Kanz, and Helmut R. Salih. "Expression of Glucocorticoid-Induced TNF Receptor Ligand on Acute Myeloid Leukemia Cells Mediates the Release of Immunosuppressive Cytokines and Impairs NK Cell-Mediated Immune Surveillance." Blood 108, no. 11 (November 16, 2006): 1941. http://dx.doi.org/10.1182/blood.v108.11.1941.1941.

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Abstract NK cells play an important role in the reciprocal interaction of tumor cells with the immune system and participate in the surveillance of hematological malignancies including acute myeloid leukemia (AML). Among the molecules influencing host-tumor interaction are many members of the TNF superfamily, which mediate multiple cellular functions including cellular proliferation, differentiation and cell death. The TNF family member Glucocorticoid-induced TNF Receptor (GITR) costimulates effector T cells, modulates apoptosis and nuclear factor kappa B and abrogates suppression of murine but not human regulatory T cells. Its cognate ligand GITRL has been found in various healthy tissues. Recently we reported that NK cells express GITR, while solid tumors express GITR ligand (GITRL), and GITR/GITRL interaction downregulates NK cell cytotoxicity and IFN-γ production. Here we analyzed the role of GITR and its ligand in AML. We report for the first time that GITRL is expressed on primary AML cells in 18 of 30 patients as determined by FACS and RT-PCR analysis. Reverse signaling through GITRL using a recombinant GITR-Ig fusion protein induces the release of the immunoregulatory cytokines IL-10 and TNF as determined by ELISA. GITRL-mediated cytokine production of AML cells is abrogated by inhibition of mitogen activated protein kinase (MAPK) pathways as demonstrated by addition of the specific p38 MAPK inhibitor SB202190, the specific JNK inhibitor SP600125 and the specific ERK Inhibitor II. Furthermore, binding of AML-expressed GITRL to GITR on NK cells downregulates cellular cytotoxicity and IFN-γ production in AML-NK cell cocultures, which can be overcome by addition of GITR-blocking antibodies as determined by cytotoxicity assays and ELISA. Thus, our data indicate that GITRL expression in AML substantially influences tumor immunoediting and enables the escape of leukemia cells from NK cell-mediated immunosurveillance.

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Baltz, Katrin M., Matthias Krusch, Radsak P. Markus, Frank Mayer, Lothar Kanz, and Helmut R. Salih. "Human GITR Ligand Is Expressed on Tumor Cells and Reduces Cytokine Production and Cellular Cytotoxicity of NK Cells Identified to Express GITR." Blood 106, no. 11 (November 16, 2005): 3310. http://dx.doi.org/10.1182/blood.v106.11.3310.3310.

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Abstract Members of the tumor necrosis factor (TNF) superfamily mediate multiple cellular functions including cellular proliferation, differentiation, and cell death. Human Glucocorticoid-induced TNF Receptor (GITR) has been shown to be expressed on T cells, is upregulated following activation and mediates costimulatory signals. The human GITR ligand (GITRL) has been reported to be expressed on antigen presenting cells and various healthy nonlymphoid tissues including small intestine, ovary, testis, kidney and endothelial cells. We analyzed multiple tumor cell lines of hematopoietic and epithelial origin as well as of germ cell lineage and various gliomas by RT-PCR and FACS analysis. Both GITRL m-RNA and protein are expressed in various carcinomas, gliomas and tumor cells of germ cell lineage, but not in hematopoietic tumor cells. Furthermore, we demonstrate that human NK cells constitutively express low levels of GITR, and this expression is upregulated following activation by, e.g., IL-2 or IL-15 as detected by quantitative PCR and FACS analysis. To address the functional interaction of GITRL with its receptor on NK cells, we generated a GITRL-IgG fusion protein (GITRL-Ig). Stimulation of activated NK cells with GITRL-Ig lead to significantly reduced IFN-g production of NK cells as measured by ELISA. Similarly, a significant reduction of IFN-g release was observed following coculture of GITR expressing NK cells with C1R cells transfected with GITRL but not with the respective mock transfectants. Furthermore, ligation of GITR on NK cells lead to significantly decreased killing of target cells as demonstrated by cellular cytotoxicity assays. Taken together, our data demonstrate that GITR not only plays an important role in adaptive immunity but is also involved in the regulation of NK cell effector functions. Since tumor cells express significant levels of GITRL, and ligation of GITR on NK cells markedly reduces cytokine production and cellular cytotoxicity, our data indicate that GITR-GITRL interactions play an important role in the escape of tumor cells from innate immune surveillance.

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Kondo, Yukio, Takamasa Katagiri, Kinya Ohata, and Shinji Nakao. "GITR Ligand on Leukemic Myeloid Dendritic Cells Suppresses Induction of Leukemia-Associated Antigen-Specific CTLs from Naïve CD8+ T Cells." Blood 112, no. 11 (November 16, 2008): 2347. http://dx.doi.org/10.1182/blood.v112.11.2347.2347.

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Abstract Glucocorticoid-induced TNFR-related protein (GITR), a member of the TNF receptor superfamily, is expressed at low levels on resting T cells and is up-regulated following activation. Triggering of GITR with its ligand (GITRL) has been described to abrogate the function of CD4+CD25+ regulatory T cells and stimulate effector T cells in mice, but little is known about roles of GITR-GITRL interaction in humans. Recent evidence suggests that the interaction between GITR on NK cell and GITRL, which is constitutively expressed on tumor cells, negatively regulates NK cell-mediated anti-tumor activity in cancer patients. Leukemic myeloid dendritic cells (mDCs) can induce cyclin-dependent kinase (CDK2)- specific cytotoxic T lymphocytes (CTLs) from naïve T cells and CDK2-specific CTLs are detectable in MRD+ patients with leukemia after allo-SCT (Blood. 110 (11): a3228. 2007). The GITR-GITRL interaction may affect this process and a modification of the interaction may improve the efficiency of inducing CDK2-specific CTLs. Therefore, the expression of GITRL on leukemic cells and leukemic mDCs was examined to determine whether an engagement of GITR controls the priming of leukemia-associated-antigen (LAA)-specific CD8+ T cells. When cryopreserved BMMCs obtained at diagnosis from 5 patients with AML were assessed using flow cytometry, GITRL expression was detectable on leukemic cells in 3 patients. Leukemic mDCs were enriched from PBMCs of HLA-A24+ patients with anti-CD1c mAb-conjugated magnetic beads and were assessed for their ability to stimulate HLA-A24+ naïve CD8+ T cells to acquire cytotoxicity specific to CDK2-peptides (CDK2 158–166, CDK2 178–186). A three days culture of immature leukemic mDCs in the presence of TNFα up-regulated the expression of GITRL along with CD83 and CD40 expression. Naïve CD8+ T cells isolated from healthy individuals and cord blood were cultured with the GITRL-expressing leukemic mDCs in the presence or absence of anti- GITR monoclonal antibodies (mAbs) for 14 days and stained for CDK2 158–166/A24, CDK2 178–186/A24 pentamers. Blocking of GITR with the mAbs augmented induction of CDK2 158–166- and CDK2 178–186- specific CD8+ T cells from 0.37% to 1.17% and from 0.45% to 1.64%, respectively (Fig). Anti-GITR mAbs did not enhance induction of CDK2-specific T cells by peptide-pulsed monocyte-derived DCs which do not express GITRL. These data suggest that the expression of GITRL on circulating leukemic mDCs may suppress induction of CTLs specific to LAAs and induce cancer immunoediting in patients with leukemia. Administration of anti-GITR mAb after allo-SCT may enhance graft versus leukemia effect by CDK2-specific CTLs without vaccination of CDK2-peptides. Fig Blocking of GITR on T cells augments induction of CDK2-specific CTLs Fig. Blocking of GITR on T cells augments induction of CDK2-specific CTLs

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Buechele, Corina, Tina Baessler, Benjamin J. Schmiedel, Lothar Kanz, and Helmut R. Salih. "Glucocorticoid-Induced TNFR-Related Protein (GITR) Ligand Mediates Tumor Immunoediting in Chronic Lymphocytic Leukemia and Impairs Direct and Rituximab-Induced NK Cell Anti-Leukemia Reactivity." Blood 114, no. 22 (November 20, 2009): 4403. http://dx.doi.org/10.1182/blood.v114.22.4403.4403.

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Abstract Abstract 4403 Members of the TNF/TNF receptor (TNFR) family of proteins govern differentiation, proliferation, activation, and death of both tumor and immune effector cells and thus play an important role in tumor immunoediting, the reciprocal interaction of tumor cells and anti-tumor immunity. Activation of the TNFR family member GITR has recently been shown to stimulate T cell-mediated anti-tumor immunity in mice. However, available data suggest that GITR mediates different effects in mice and men, and may impair anti-tumor immunity of human NK cells. Here we studied the expression and function of GITR ligand (GITRL) in patients with chronic lymphocytic leukemia (CLL) and the consequences of GITR-GITRL interaction for NK cell reactivity against CLL cells. Substantial GITRL expression was detected on primary B-CLL cells in 38 of 48 (79%) investigated patients. Upon interaction with its cognate receptor, GITRL induced the release of immunoregulatory cytokines like TNF by the leukemia cells, which demonstrated that CLL-expressed GITRL is functional and capable to transduce bidirectional signals. Moreover, disruption of GITR-GITRL interaction in cultures of allogenic NK cells with patient CLL cells by addition of blocking antibody caused a significant increase in NK cell granule mobilization, cytotoxicity and IFN-γ production. The inhibitory effect of tumor-expressed GITRL on the reactivity of human NK cells was also confirmed in cocultures of C1R lymphoma cells transfected to express GITRL with mock transfectants serving as control. In addition, blocking GITR-GITRL interaction also considerably augmented both antibody-dependent cellular cytotoxicity (ADCC) and antibody-induced IFN-γ production of NK cells in cultures with allogenic CLL cells upon Rituximab exposure. Of note, GITR blockade also significantly enhanced anti-leukemia reactivity of autologous NK cells among PBMC of B-CLL patients, and this reinforcement of NK cell effector functions was observed both regarding the direct and, more pronounced, Rituximab-induced anti-leukemia reactivity (both n=10, p<0.01, Student's T test). Thus, expression of functional GITRL by CLL cells potently influences tumor immunoediting and impairs anti-tumor immunity by diminishing both direct and Rituximab-dependent anti-leukemia reactivity of NK cells. Modulation of the GITR-GITRL system might therefore serve to enhance the efficacy of therapeutic approaches in CLL which, like Rituximab-induced ADCC or stem cell transplantation, rely on a sufficient NK cell anti-tumor response. Disclosures: No relevant conflicts of interest to declare.

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Steinbacher, Julia, Benjamin J. Schmiedel, Antje Werner, Tina Nuebling, Corina Buechele, Ludger Grosse-Hovest, Lothar Kanz, and Helmut R. Salih. "Bimodal Induction of NK Cell Reactivity Against Acute Myeloid (AML) and Chronic Lymphoid Leukemia (CLL) by Fc-Engineered GITR-Fc Fusion Proteins." Blood 120, no. 21 (November 16, 2012): 2143. http://dx.doi.org/10.1182/blood.v120.21.2143.2143.

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Abstract Abstract 2143 NK cells play an important role in anti-tumor immunity and largely contribute to the efficacy of therapeutic strategies like allogenic stem cell transplantation in AML and application of Rituximab that induces antibody-dependent cellular cytotoxicity (ADCC) in CLL. Recently, we demonstrated that the TNF family member GITR ligand (GITRL) is expressed on leukemia cells in a high proportion of AML and CLL patients and impairs direct and Rituximab-induced reactivity of NK cells which constitutively express its counterpart GITR (e.g., Buechele et al., Leukemia 2012). Here we developed a strategy to reinforce NK anti-leukemia reactivity by combining disruption of NK-inhibitory GITR-GITRL interaction with induction of ADCC against the GITRL-expressing leukemia cells using GITR-Ig fusion proteins with modified Fc moieties. Fc parts were engineered by amino acid exchange as previously described (Lazar et al., PNAS 2006; Armour et al., Eur. J. Immunol. 1999). Compared to wild type GITR-Ig (GITR-Fc-WT), our mutants (S239D/I332E and E233P/L234V/L235A/deltaG236/A327G/A330S) displayed highly enhanced (GITR-Fc-ADCC) and abrogated (GITR-Fc-KO) affinity to the Fc(gamma)RIIIa receptor (CD16) expressed on NK cells, respectively. In functional analyses of NK cells and primary leukemia cells, GITR-Fc-KO, which does not induce ADCC, already increased NK reactivity due to disruption of GITR-GITRL interaction. Treatment with GITR-Fc-WT further enhanced NK reactivity due to modest induction of ADCC, while GITR-Fc-ADCC induced highly increased NK-mediated target cell lysis, degranulation and cytokine production in a target-antigen dependent manner. With CLL cells, combined treatment with GITR-Fc-ADCC fusion protein and Rituximab caused additive effects, resulting in significantly enhanced NK cell ADCC. Notably, the effects of our fusion proteins were observed both in an allogenic setting and when employing NK cells of patients with autologous leukemia cells as targets. Our results demonstrate that Fc-engineered GITR-Fc-ADCC fusion protein may combine both neutralization of the NK-inhibitoryeffects of GITR-GITRL interaction and targeting GITRL-expressing malignant cells for NK anti-tumor reactivity and thus constitute an attractive immunotherapeutic means for the treatment of AML and CLL. Disclosures: No relevant conflicts of interest to declare.

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Schilling, Susanne R., Jörn R. Sparfeldt, Detlef H. Rost, and Grete Nickels. "Schulische Selbstkonzepte - Zur Validität einer erweiterten Version des Differentiellen Selbstkonzept Gitters (DISK-Gitter)." Diagnostica 51, no. 1 (January 2005): 21–28. http://dx.doi.org/10.1026/0012-1924.51.1.21.

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Zusammenfassung. Die Validität des erweiterten Differentiellen Selbstkonzept Gitters (DISK-Gitter; Rost & Sparfeldt, 2002 ) - ein Verfahren zur Erfassung schulfachspezifischer Selbstkonzepte - wird an N = 999 Schülern der 7. bis 10. Klassenstufe überprüft. Das DISK-Gitter mit den hier betrachteten sechs Facetten “Mathematik“, “Deutsch“, “Physik“, “Geschichte“, “Englisch“ und “Biologie“ erweist sich konfirmatorisch als faktoriell valide. Konvergente und divergente Validitätsaspekte können anhand der Beziehungen zu ausgewählten Skalen des Self-Description Questionnaire II (SDQ II; Marsh, 1990a ), zur Skala zur Erfassung schulischer Leistungen und Fähigkeiten (SKSLF; Rost & Lamsfuß, 1992 ), zu Schulzensuren sowie in Bezug auf Geschlechtsunterschiede belegt werden. Es ergeben sich hypothesenkonforme Korrelationsmuster und Mittelwertsunterschiede. Insgesamt erweist sich das erweiterte DISK-Gitter als ökonomisches, reliables und valides Instrument zur Messung schulfachspezifischer Selbstkonzepte.

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Baltz, Katrin M., Matthias Krusch, Tina Baessler, Mercedes Kloss, Ingrid Kumbier, Andrea Peterfi, Lothar Kanz, and Helmut R. Salih. "Down-Regulation of Glucocorticoid-Induced TNF Receptor (GITR) Ligand on Human Tumors by Proteolytic Shedding Increases Anti-Tumor Reactivity of NK Cells." Blood 108, no. 11 (November 16, 2006): 926. http://dx.doi.org/10.1182/blood.v108.11.926.926.

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Abstract Members of the TNF superfamily mediate multiple cellular functions, including cellular proliferation, differentiation and cell death. Many members of this protein family are shed from the cell surface as soluble forms, which affects cell-cell interactions by reduction of ligand densities and distally modulates effector cells bearing the respective receptor. The TNF family member Glucocorticoid-induced TNF Receptor (GITR) costimulates effector T cells, modulates apoptosis and NFkappaB and abrogates suppression of murine but not human regulatory T cells. Its cognate ligand GITRL has been found in various healthy tissues. Recently we reported that NK cells express GITR, while tumor cells express GITR ligand (GITRL), and GITR/GITRL interaction downregulates NK cell-mediated anti-tumor effector mechanisms like cytotoxicity and IFN-gamma production. Here we report that human tumor cells spontaneously release a soluble form of GITRL (sGITRL) detectable in culture supernatants by ELISA. Furthermore, we found elevated levels of sGITRL in sera of patients with various malignancies compared to healthy controls. We demonstrate that the release of GITRL from tumor cells can be blocked by inhibition of metalloproteinases, concomitantly causing accumulation of GITRL on the tumor cell surface as determined by FACS analysis. Upregulated GITRL surface expression further increased inhibition of NK cell anti-tumor effector mechanisms, while, in contrast, presence of sGITRL in cocultures of GITRL-expressing tumor cells and GITR-positive NK cells enhanced NK cell cytotoxicity and IFN-gamma production. Thus, in line with the results obtained with other TNF family members, conversion of membrane bound GITRL to its soluble form is associated with downregulation of its function, potentially due to blocking its cognate receptor. Thus, release of sGITRL substantially influences the interaction of tumor cells with NK cells. In addition, determination of sGITRL levels may be implemented as a diagnostic marker in patients with malignancies. Further prospective studies are currently being conducted addressing the value of GITRL as a tumor marker in different tumor entities.

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Placke, Theresa, Hans-Georg Kopp, and Helmut Rainer Salih. "Glucocorticoid-Induced TNFR-Related (GITR) Protein and Its Ligand in Antitumor Immunity: Functional Role and Therapeutic Modulation." Clinical and Developmental Immunology 2010 (2010): 1–10. http://dx.doi.org/10.1155/2010/239083.

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The ability of the tumor necrosis factor receptor (TNFR) family member GITR to modulate immune responses has been the subject of multiple studies. Initially thought to be critically involved in governing functions of regulatory T cells, GITR and its ligand GITRL have meanwhile been found to modulate the reactivity of various different cell types and to influence a broad variety of immunological conditions including the immune response against tumors. Not only GITR, but also GITRL is capable of transducing signals, and the consequences of GITR-GITRL interaction may vary among different effector cell types, differ upon signal transduction via the receptor, the ligand, or both, depend on the level of an ongoing immune response, and even differ among mice and men. In this paper, we address available data on GITR and its ligand in immune responses and discuss the role and potential therapeutic modulation of this molecule system in antitumor immunity.

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Kondo, Yukio, Luis Espinoza, Takamasa Katagiri, Zhirong Qi, and Shinji Nakao. "GITR Ligation with GITR Ligand On Leukemic Cells Suppresses Induction of Leukemia-Associated Antigen Specific T Cells by Increasing Indoleamine 2, 3-Dioxygenase (IDO) Activity Leading to Kynurenine Secretion." Blood 114, no. 22 (November 20, 2009): 3557. http://dx.doi.org/10.1182/blood.v114.22.3557.3557.

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Abstract Abstract 3557 Poster Board III-494 Immunization of allogeneic stem cell transplant (SCT) recipients with leukemia-associated antigens (LAAs) is an attractive approach to the augmentation of graft-versus-leukemia (GVL) effect. However, the induction of CTLs specific to LAAs is hampered by various inhibitory molecules expressed on leukemic cells that restrain the T cell function in connection with their receptors on T cells. Even if the cellular immunity is rebuilt after SCT by T cells of the donor origin, overcoming such an escape mechanism is required to effectively induce the CTLs specific to TAAs by vaccination after allogeneic SCT. Glucocorticoid-induced TNFR-related protein (GITR) belongs to the TNF receptor superfamily and is expressed on NK cells, CD25+ regulatory T cells and activated T cells. The binding of GITR ligand (GITRL) on leukemic cells to GITR on NK cells restrains NK cell activity but the influence on T cells of the GITR/GITRL binding has not been clarified. Myeloid dendritic cells derived from myeloid leukemic cells express GITRL which inhibits induction of LAA-specific CTLs (Blood 2008; 112:817a). The mechanisms of the negative effect on the induction of LAA-specific T cells through the GITR/GITRL interaction was investigated to improve the efficiency of the CTL induction. The expression of GITRL was observed on leukemic cells from 9 of 16 patients with myeloid leukemia and a monocytic leukemia cell line THP-1, and soluble GITRL (sGITRL) was detectable in the serum from 3 of 5 patients as well as in the culture supernatant of THP-1 cells. CFSE-labeled pan T cell, CD4+ T cell and CD8+ T cell proliferation in response to microbeads coated with anti-CD3 and anti-CD28 monoclonal antibodies (CD3/CD28 microbeads) was suppressed to 55.0%, 63.6%, 65.8% of the controls in a culture supernatant of THP-1 cells, and was restored to 86.9%, 65.1% and 76.8% respectively by addition of sGITR to block the binding of sGITRL in the supernatant and GITR on T cells. Flow cytometry detected GITRL in exosomes, which express HLA class II, purified from the culture supernatant of THP-1 with anti-HLA class II antibody-coated microbeads, and CFSE-labeled pan T cell, CD4+ T cell and CD8+ T cell proliferation was restrained as well by the addition of GITRL+ exosomes in a dose dependent manner (27.6%, 54.1%, 27.9% reduction of proliferation with 10 μl exosome, respectively). Indoleamine 2, 3-dioxygenase (IDO) activity in plasmacytoid DC (pDC) is negatively correlated with the activity of CD4+ T cells induced by their interaction with the pDC through the GITR/GITRL interaction in a mouse model. Kynurenine (Kyn), a metabolite of tryptophan in leukemic cells that is broken down by IDO, suppressed CFSE-labeled pan T cell, CD4+ T cell and CD8+ T cell proliferation in response to CD3/CD28 microbeads in a dose dependent manner (24.5%, 12.3%, 18.3% reduction in the proliferation at 100 μM, respectively). Significantly higher concentrations of Kyn were detected in the supernatant of THP-1 cells after incubation in the presence of sGITR than a control, and the production of Kyn was suppressed by the addition of an IDO inhibitor, 1-Methyl Tryptophan (1MT) (Fig). Moreover, the addition of sGITR to leukemic cells from five patients with AML induced Kyn (Fig). These findings indicate that GITRL on leukemic cells and sGITRL secreted by leukemic cells as an exosome protein suppress the induction of LAA-specific CTLs by directly binding GITR on LAA-specific CTLs, increasing the IDO activity in leukemic cells and inducing Kyn secretion from leukemic cells. The administration of anti-IDO agents or anti-GITRL blocking Abs combined with LAA vaccination may therefore effectively induce LAA-specific T cells in SCT recipients. Fig GITR/GITRL binding induces kyn secretion from THP-1 cell and primary AML cells. Fig. GITR/GITRL binding induces kyn secretion from THP-1 cell and primary AML cells. Disclosures: No relevant conflicts of interest to declare.

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Krusch, Matthias, Katrin M. Baltz, Tina Baessler, Lothar Kanz, and Helmut R. Salih. "Role of Glucocorticoid-Induced TNF-Related Protein (GITR) Ligand in the Interaction of Acute Myeloid Leukemia with NK Cells." Blood 110, no. 11 (November 16, 2007): 18. http://dx.doi.org/10.1182/blood.v110.11.18.18.

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Abstract NK cells play an important role in the reciprocal interaction of tumor cells with the immune system and participate in the surveillance and eradication of hematological malignancies. The activity of NK cells is governed by a balance of activating and inhibitory surface receptors. Glucocorticoid-induced TNF-related protein (GITR) and its ligand (GITRL) are members of the TNF/TNF receptor (TNFR) superfamily, which mediates multiple cellular functions including proliferation, differentiation, and cell death. Recently we reported that NK cells express GITR while cancer cells express GITRL and GITR-GITRL interaction down regulates NK cell-mediated anti-tumor immunity (Baltz et al., FASEB J 2007). Here we demonstrate that GITRL is expressed on 6 of 7 investigated acute myeloid leukemia (AML) cell lines and on primary AML cells in 30 of 52 (59%) patients, while no GITRL expression was detected on CD34+ cells of healthy donors (n=5). GITRL expression was not restricted to a specific French-American-British (FAB) subtype, but was significantly (p<0.05, one-way ANOVA) associated with monocytic (FAB M4, M5) differentiation. In addition, no association with a particular cytogenetic abnormality or with expression of MHC class I was observed. Reverse signaling via GITRL led to phosphorylation of ERK and JNK resulting in significantly (p<0.05, Mann-Whitney U-test) enhanced production of IL-10 and TNF by patient AML cells (n=10). In line, specific inhibitors for JNK and ERK1/2 blocked the cytokine release by AML cells demonstrating that activation of MAP kinases is responsible for the production of the immunoregulatory cytokines following GITRL stimulation. Importantly, blocking GITR-GITRL interaction in cocultures of AML and NK cells significantly (both <0.05 Mann-Whitney U-test) increased cellular cytotoxicity about 70% and IFN-γ production about 60%, and this was due to restored NK cell NF-κB activity. Thus, GITRL substantially influences immunoediting by AML cells and enables the escape of AML cells from NK cell-mediated immune surveillance. The correlation found between GITRL expression and NK cell susceptibility may provide useful information for NK cell-based immunotherapy.

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Placke, Theresa, Lothar Kanz, Helmut R. Salih, and Hans-Georg Kopp. "Pseudoexpression of Glucocorticoid-Induced TNF-Related (GITR) Ligand Upon Coating of Cancer Cells by Platelets Impairs NK Cell Anti-Tumor Reactivity." Blood 116, no. 21 (November 19, 2010): 3193. http://dx.doi.org/10.1182/blood.v116.21.3193.3193.

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Abstract Abstract 3193 NK cells as part of the innate immune system substantially contribute to cancer immune surveillance. They prevent tumor progression and metastasis due to their ability to mediate cellular cytotoxicity and to produce cytokines like IFN-γ, which, among others, stimulates subsequent adaptive immune responses. NK reactivity results from an integrative response emerging upon recognition of multiple ligands for activating and inhibitory NK cell receptors including various members of the TNFR family. Apart from the direct interaction with their target cells, NK cell activity is further influenced by the reciprocal interplay with various other hematopoietic cells like e.g. dendritic cells. Metastatic tumor spread in experimental animals is dramatically reduced in thrombopenic mice. Additional depletion of NK cells reverses this effect, indicating that platelets may impair NK anti-tumor reactivity. However, the underlying mechanisms have not been fully elucidated, especially in humans. Recently, we demonstrated that NK anti-tumor immunity is impaired by platelet-derived TGF-β, which is released upon interaction of platelets with tumor cells (Kopp et al., Cancer Res. 2009). Here we report that the ligand for the TNFR family member GITR (GITRL) is upregulated on megakaryocytes during maturation resulting in substantial GITRL expression by platelets. Since we recently identified GITR as inhibitory NK receptor involved in tumor immune escape (e.g., Baltz et al., Blood 2008, Baessler et al., Cancer Res. 2009) we investigated how platelet-derived GITRL influences platelet function and NK immune surveillance. Signaling via GITRL into platelets upon interaction with NK-expressed GITR or recombinant GITR-Ig fusion protein did not alter platelet activation as revealed by analysis of the activation marker CD62P and release of TGF-β. Interestingly, we found that GITRL-negative tumor cells rapidly get coated by platelets, which confers a seemingly GITRL-positive phenotype. “GITRL pseudoexpression” on tumor cells caused a substantial reduction of NK cell cytotoxicity and cytokine production. This reduced NK reactivity was not due to induction of apoptosis via GITR and could be restored by addition of a blocking GITR antibody. Thus, coating of tumor cells by platelets inhibits NK reactivity, which is in part mediated by platelet-derived GITRL. Our data provide a functional basis for the previously observed finding that platelets increase metastasis i.e. by enabling evasion of tumor cells from NK-mediated immune surveillance. Disclosures: No relevant conflicts of interest to declare.

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Kaban, Kübra, Sarah M. Greiner, Samuel Holzmayer, Claudia Tandler, Sophie Meyer, Clemens Hinterleitner, Helmut R. Salih, Melanie Märklin, and Jonas S. Heitmann. "Immunoprofiling of 4-1BB Expression Predicts Outcome in Chronic Lymphocytic Leukemia (CLL)." Diagnostics 11, no. 11 (November 4, 2021): 2041. http://dx.doi.org/10.3390/diagnostics11112041.

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Recent success of novel therapies has improved treatment of chronic lymphocytic leukemia (CLL) patients, but most of them still require several treatment regimes. To improve treatment choice, prognostic markers suitable for prediction of disease outcome are required. Several molecular/genetic markers have been established, but accessibility for the entirety of all patients is limited. We here evaluated the relevance of GITR/4-1BB as well as their ligands for the prognosis of CLL patients. Surface expression of GITR/GITRL and 4-1BB/4-1BBL was correlated with established prognostic markers. Next, we separated our patient population according to GITR/GITRL and 4-1BB/4-1BBL expression in groups with high/low expression levels and performed Kaplan-Meier analyses. Interestingly, no correlation was observed with the defined prognostic markers. Whereas no significant difference between high and low expression of GITR, GITRL and 4-1BBL was observed, high 4-1BB levels on leukemic cells were associated with significantly shorter survival. Thereby we identify 4-1BB as prognostic marker for CLL.

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Hanabuchi, Shino, Norihiko Watanabe, Yi-Hong Wang, Yui-Hsi Wang, Tomoki Ito, Joanne Shaw, Wei Cao, F. Xiao-Feng Qin, and Yong-Jun Liu. "Human plasmacytoid predendritic cells activate NK cells through glucocorticoid-induced tumor necrosis factor receptor-ligand (GITRL)." Blood 107, no. 9 (May 1, 2006): 3617–23. http://dx.doi.org/10.1182/blood-2005-08-3419.

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Plasmacytoid dendritic cell precursors (pDCs) are professional type I interferon-producing cells, a critical cell type in regulating innate and adaptive immune responses. By microarray gene expression analysis, we found that pDCs activated by virus or CpG-ODN preferentially express the ligand for the glucocorticoid-induced tumor necrosis factor receptor (GITRL), which was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry analysis. Using the same approaches, we found GITR is expressed by activated natural killer (NK) cells and T cells. We show that pDCs activated by CpG-ODN promote NK cell cytotoxicity and interferon (IFN)-γ production through type I IFNs and GITRL. Using a GITRL-transfected cell line, we further demonstrate that GITRL promotes NK cell cytotoxicity and IFN-γ production in synergy with interleukin-2 (IL-2), IFN-α, and NKG2D triggering. We also demonstrated that pDCs localized in close contact to NK cells in T-cell areas of the tonsils, and a subpopulation of the pDCs expressed GITRL. This study reveals a novel function of GITR/GITRL in pDC-mediated coactivation of NK cells.

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Erak, Dušan. "The importance of guitar handbooks by Georgije Milanovich and Ivan padovec in music education and methodology of guitar teaching in South Slavic region." Zbornik Akademije umetnosti, no. 6 (2018): 148–57. http://dx.doi.org/10.5937/zbakum1801148e.

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Baltz, Katrin M., Matthias Krusch, Tina Baessler, Anita Bringmann, Lothar Kanz, Peter Brossart, and Helmut R. Salih. "Neutralization of Tumor-Derived Soluble Glucocorticoid-Induced TNF-Related Protein (GITR) Ligand Present in Cancer Patient Sera Increases Anti-Tumor Reactivity of NK Cells." Blood 110, no. 11 (November 16, 2007): 314. http://dx.doi.org/10.1182/blood.v110.11.314.314.

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Abstract Glucocorticoid-induced TNF-related protein (GITR) and its ligand (GITRL) are members of the TNF/TNF receptor (TNFR) superfamily, which mediates multiple cellular functions including proliferation, differentiation, and cell death. Recently we reported that NK cells express GITR while tumor cells express GITRL, and GITR-GITRL interaction downregulates NK cell-mediated anti-tumor immunity (Baltz et al., FASEB J 2007). Many TNF family members are released as soluble forms, which affects cell-cell interactions by reduction of ligand density and distally modulates effector cells bearing the respective receptor. Here we report that human tumor cells spontaneously release a soluble form of GITRL (sGITRL), which can be detected in tumor cell culture supernatants by ELISA (detection limit 0.01ng/ml). We demonstrated that NK cell cytotoxicity and IFN-γ production in cocultures with the tumor cell lines SK-Mel (Melanoma), PC-3 (prostate), HCT116 (colon), and LX-1 (lung) were significantly (both p<0.01, Mann-Whitney U-test) and concentration dependently reduced (up to 50%) by tumor-derived sGITRL, and NK cell effector functions could be restored by neutralization of sGITRL using a GITR-Fc fusion protein. While tumor-derived GITRL did not induce apoptosis in NK cells, it diminished nuclear localized RelB indicating that sGITRL negatively modulates NK cell NF-κB activity. Furthermore, we demonstrate that significantly elevated sGITRL levels (mean 0.4ng/ml, range from 0.01 to 3.5ng/ml) were contained in 40 out of 50 sera of patients with various cancers (colon, lung and germ line), while sera of healthy volunteers (n=8) contained no detectable levels of sGITRL. Addition of sGITRL containing patient sera to cocultures of NK cells and GITRL-negative tumor cells significantly reduced NK cell cytotoxicity and IFN-γ production about 30% and 45%, respectively (both p<0.05, Mann-Whitney U-test). Again the inhibitory effects of sGITRL on NK cell effector functions could be completely restored by neutralization of sGITRL with GITR-Fc. The strong correlation of tumor incidence and elevated sGITRL levels clearly suggests that sGITRL is released at significant amounts from malignant cells in vivo and may reduce immune surveillance of human tumors. Our data indicate that determination of sGITRL levels may be implemented as an immunological diagnostic marker in tumor patients, and GITRL-neutralization may be employed in therapeutic strategies like adoptive NK cell transfer.

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Pascutti, Fernanda M., Tomasz Poplonski, René A. W. Van Lier, Claudia Brandao, and Martijn A. Nolte. "Costimulation Through GITR Increases Follicular Helper T Cell Formation and Leads To Control Of A Chronic Viral Infection." Blood 122, no. 21 (November 15, 2013): 3496. http://dx.doi.org/10.1182/blood.v122.21.3496.3496.

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Abstract The glucocorticoid-induced TNF receptor family-related protein (GITR) is an important costimulatory receptor on T cells. We have previously shown that enhanced costimulation through GITR increases the formation of both effector and regulatory CD4+ T cells. Here we explored whether it could also affect humoral immunity and T cell help to B cells. Although development of mature B cells was not affected in GITRL transgenic (tg) mice, we found that the number of follicular helper T cells (CXCR5+ PD1+ CD4+ T cells, Tfh) was significantly increased, including the absolute number of Tfh-B cell conjugates, as revealed by ImageStream analysis. Tfh from GITRL tg mice had normal expression levels of ICOS, SLAM and CD44 and slightly lower levels of CD62L and CCR7 compared to wild-type (WT) littermates. Interestingly, Tfh from GITRL tg mice produced more IFN-g and IL-10, which was accompanied by a biased antibody repertoire (decreased IgG3 and increased IgA, IgG2a and IgG2b). Since Tfh have been implicated in the late control of viral replication, we infected WT and GITRL tg mice with LCMV Clone 13. Surprisingly, at day 30 after infection, we could not detect viral genome in spleen and liver from GITRL tg mice, while WT mice were still infected. Also, PD-1 expression was strongly decreased on virus-specific CD8+ T cells, which correlated with faster viral clearance. All in all, these results indicate that GITR-mediated costimulation enhances the control of chronic viral infections, by boosting and modulating Tfh cell responses. Disclosures: No relevant conflicts of interest to declare.

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Feng, Xiaoli, Jin-Liang Wang, and Detlef H. Rost. "Akademische Selbstkonzepte bei chinesischen Studenten und Studentinnen der Germanistik sowie Schülern und Schülerinnen." Diagnostica 63, no. 4 (October 2017): 269–84. http://dx.doi.org/10.1026/0012-1924/a000183.

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Zusammenfassung. Mit dem acht Items umfassenden deutschsprachigen Differentiellen Schulischen Selbstkonzept Gitter (DISK-Gitter; Rost, Sparfeldt & Schilling, 2007 ) lassen sich mehrere fachspezifisch-akademische Selbstkonzepte simultan und sehr ökonomisch messen. Die Struktur und psychometrischen Kennwerte einer chinesischen Adaptation des DISK-Gitters wurden anhand zweier Studien überprüft (Studie 1, Universitätsstichprobe mit N1 = 601 Studenten und Studentinnen des Studienfachs „Deutsche Sprache“; Selbstkonzepte: Chinesisch, Englisch, Deutsch und Mathematik; Studie 2, Schulstichprobe mit N2 = 441 Mittelschulschülern und Mittelschulschülerinnen; Selbstkonzepte: Chinesisch, Englisch, Geschichte und Politik). Die Fachspezifität akademischer Selbstkonzepte konnte mit explorativen (Studie 1, Teilstichprobe 1A, n1A = 239) und konfirmatorischen (Studie 1, Teilstichprobe 1B, n1B = 367 sowie Studie 2) Dimensionsanalysen bestätigt werden. Die psychometrischen Kennwerte aller Selbstkonzeptskalen waren gut, ihre konvergenten und divergenten Validitäten hinsichtlich der Beziehungen zu Leistungen in einem Deutschtest (Studie 1) und zu fachspezifisch-akademischen Selbstwirksamkeiten (Studie 2) ließen sich belegen.

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Zhou, Yanjun, Jonas S. Heitmann, Kim L. Clar, Korbinian N. Kropp, Martina Hinterleitner, Tobias Engler, André Koch, et al. "Platelet-expressed immune checkpoint regulator GITRL in breast cancer." Cancer Immunology, Immunotherapy 70, no. 9 (February 4, 2021): 2483–96. http://dx.doi.org/10.1007/s00262-021-02866-y.

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AbstractOwing to their key role in several diseases including cancer, activating and inhibitory immune checkpoint molecules are increasingly exploited as targets for immunotherapy. Recently, we demonstrated that platelets, which largely influence tumor progression and immune evasion, functionally express the ligand of the checkpoint molecule GITR. This immunoreceptor modulates effector functions of T cells and NK cells with its function varying dependent on cellular context and activation state. Here, we provide a comparative analysis of platelet-derived GITRL (pGITRL) in breast cancer patients and healthy volunteers. The levels of pGITRL were found to be higher on platelets derived from cancer patients and appeared to be specifically regulated during tumor progression as exemplified by several clinical parameters including tumor stage/grade, the occurrence of metastases and tumor proliferation (Ki67) index. In addition, we report that pGITRL is upregulated during platelet maturation and particularly induced upon exposure to tumor-derived soluble factors. Our data indicate that platelets modulate the GITR/GITRL immune checkpoint in the context of malignant disease and provide a rationale to further study the GITR/GITRL axis for exploitation for immunotherapeutic intervention in cancer patients.

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Agostini, Massimiliano, Elio Cenci, Eva Pericolini, Giuseppe Nocentini, Giovanni Bistoni, Anna Vecchiarelli, and Carlo Riccardi. "The Glucocorticoid-Induced Tumor Necrosis Factor Receptor-Related Gene Modulates the Response to Candida albicans Infection." Infection and Immunity 73, no. 11 (November 2005): 7502–8. http://dx.doi.org/10.1128/iai.73.11.7502-7508.2005.

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ABSTRACT The glucocorticoid-induced tumor necrosis factor (TNF) receptor-related gene (GITR; TNFRSF18) modulates immune response activating coaccessory signals in T cells and is expressed at high levels in CD4+CD25+ cells. Its ligand (GITRL) is expressed in antigen-presenting cells, where it is capable of promoting signaling. We investigated the role of GITR/GITRL interaction during disseminated candidiasis in GITR knockout (GITR−/−) mice. GITR−/− mice survived longer and had a significantly decreased yeast load in kidneys and brain compared to GITR+/+ mice. Since protective immunity to the fungus is mediated by antigen-specific T helper (Th) 1 cells, we studied in vitro cytokine production following infection. CD4+ T cells of GITR−/− mice demonstrated a more efficient Th1 polarization as suggested by a two- to threefold decreased production of interleukin- (IL-)4 and IL-10 and a four- to fivefold increased production of gamma interferon compared to GITR+/+ mice. This effect was not due to differences in lymphocyte and dendritic cell (DC) subpopulations in infected mice as demonstrated by flow cytometric studies. To verify whether DC activity was differently modulated, DCs were cocultured with CD4+ T cells in the presence of heat-inactivated Candida albicans. DCs, cocultured with GITR+/+ CD4+CD25+ cells produced a lower amount of IL-12 than DCs cocultured with GITR−/− CD4+CD25+ T cells. These results suggest that GITR regulates susceptibility to systemic candidiasis by negatively modulating IL-12 production and promoting polarization of CD4+ T cells towards Th2 by analogy with OX40, another TNF receptor superfamily member.

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Kloss, Mercedes, Matthias Krusch, Katrin M. Baltz, Andrea Peterfi, Ingrid Kumbier, Lothar Kanz, and Helmut R. Salih. "The Ligand of Glucocorticoid-Induced TNF Receptor Is Expressed on Human Macrophages and Stimulates Proinflammatory and Anti-Tumor Effector Functions." Blood 108, no. 11 (November 16, 2006): 1649. http://dx.doi.org/10.1182/blood.v108.11.1649.1649.

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Abstract Macrophages are involved in inflammatory and anti-tumor responses by antigen presentation, release of immunoregulatory cytokines and cellular cytotoxicity. Among the molecules influencing macrophage functions are many members of the TNF superfamily. The TNF receptor family member Glucocorticoid-induced TNF Receptor (GITR) costimulates effector T cells, modulates apoptosis and nuclear factor kappa B and abrogates suppression of murine but not human regulatory T cells. Expression of its cognate ligand GITRL has, in humans, been detected in dendritic cells and various healthy nonlymphoid tissues. Up to now, nothing is known regarding the function of human GITRL, while in mice, reverse signaling through GITRL has been shown to influence the activation and survival of macrophages. Here we report for the first time that GITRL is expressed in human macrophages as determined by FACS and RT-PCR analysis. Reverse signaling through GITRL using a recombinant GITR-Ig fusion protein differentially affects expression of costimulatory molecules like CD80, CD86 and B7-H1, death ligands like TNF, CD178 and TRAIL as well as MHC class I and II on the macrophage surface. Furthermore, stimulation of GITRL enhances phagocytosis and respiratory burst of macrophages as determined by analysis of ingestion of PE-labeled polystyrene microspheres and oxidation of dichlor-fluorescein diacetate, respectively by FACS. Interaction of GITRL with its receptor also leads to significantly increased production of proinflammatory cytokines like TNF, IL-6 and IL-8 as determined by ELISA. In addition, stimulation of GITRL significantly increases the killing of various human tumor cell lines by macrophages as determined by cytotoxicity assays. Taken together, our data demonstrate that GITRL plays an important role in the stimulation of macrophage-mediated inflammatory responses and immune responses against tumors.

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Nocentini, Giuseppe, Simona Ronchetti, Maria Grazia Petrillo, and Carlo Riccardi. "Pharmacological modulation of GITRL/GITR system: therapeutic perspectives." British Journal of Pharmacology 165, no. 7 (March 9, 2012): 2089–99. http://dx.doi.org/10.1111/j.1476-5381.2011.01753.x.

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Rakké, Yannick, Lucia Campos Carrascosa, Adriaan van Beek, Valeska de Ruiter, Michael Doukas, Susan ter Borg, Pascal Doornebosch, et al. "588 Targeting GITR enhances human tumour-infiltrating T cell functionality in mismatch repair proficient primary colorectal carcinoma and liver metastases." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A623. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0588.

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BackgroundImmune checkpoint blockade (ICB; e.g. anti-PD-1/-CTLA-4) has been proven to be clinically effective in mismatch repair deficient (dMMR) colorectal carcinoma (CRC). Yet, the majority of patients carry mismatch repair proficient (pMMR) CRC, especially those with liver metastasis, and do not respond to ICB. Here, we studied the effect of immune checkpoint stimulation via GITR targeting on human tumour-infiltrating lymphocyte (TIL) functionality in pMMR primary CRC and liver metastases (CRLM).MethodsHuman TIL were isolated from freshly resected pMMR tumours of patients with primary CRC (stage 1–3) or liver metastases (table 1). GITR expression on TIL was determined using flow cytometry and compared to leukocytes isolated from blood (PBMC) and tumour-free surrounding tissues (tumour-free colon/liver, resp. TFC and TFL). Ex vivo functional assays were used to assess TIL expansion, activation and cytokine/cytotoxic mediator secretion upon CD3/CD28 bead activation and co-stimulation using an antibody-crosslinked recombinant trimeric GITR ligand (GITRL).ResultsGITR was overexpressed on TIL when compared to other stimulatory immune checkpoints (4-1BB, OX40). GITR expression was enhanced on CD4+ and CD8+ TIL compared to PBMC and TFC or TFL compartments in both primary CRC and CRLM. Among CD4+ TIL, GITR was increasingly expressed on CD45RA± FoxP3- helper T (Th), CD45RA- FoxP3int activated helper T (aTh), and CD45RA- FoxP3hi activated regulatory T cells (aTreg), respectively. Within CD8+ TIL, GITR expression was higher on TOX+ PD1Hi and putatively tumour-reactive CD103+ CD39+ TIL.1 Impaired effector cytokine production upon ex vivo PMA/ionomycin stimulation was observed in CD4+ and CD8+ GITR-expressing TIL, hinting to functional exhaustion of the target population. However, recombinant GITRL reinvigorated ex vivo TIL responses by significantly enhancing CD4+ and CD8+ TIL numbers and proinflammatory cytokine secretion in a dose-dependent manner (figure 1). Treg depletion did not fully abrogate the stimulatory effect of GITR ligation on CD4+ and CD8+ T cell expansion, demonstrating that the stimulatory effect was partly exerted via direct targeting GITR on effector T cells. Importantly, GITR-ligation also enhanced expansion of purified CD8+CD39+ TIL. Dual treatment with GITR ligand and nivolumab (anti-PD-1) further enhanced CD8+ TIL responses compared to GITR ligand monotherapy, whereas nivolumab alone did not show any effect.Abstract 588 Table 1Patient characteristicsPatient characteristics of patients included for FACS analysis and/or functional assays. † Pathologic staging was performed according to the AJCC 8th edition criteriaAbstract 588 Figure 1GITR ligation enhances CD4+ and CD8+ TIL expansionTIL were isolated from CRC or CRLM and cultured upon CD3/CD28 activation with or without GITRL (0.1–1.0 ug/mL) for 8 days. TIL numbers were acquired by flow cytometry and normalized to counting beads. Indicated is fold change relative to ctrl-treated TIL (n=10).ConclusionsAgonistic targeting of GITR enhances ex vivo human TIL functionality in pMMR CRC and might therefore be a promising approach for novel mono- or combinatorial immunotherapies in primary CRC and CRLM.AcknowledgementsN/ATrial RegistrationN/AEthics ApprovalThe study was approved by the medical ethics committee of the Erasmus Medical Center (MEC-2012-331).ConsentN/AReferenceDuhen T, Duhen R, Montler R, et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat Commun 2018;9(1):2724. doi: 10.1038/s41467-018-05072-0.

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Erbe, Barbara. "Freiheit hinter Gittern." DMW - Deutsche Medizinische Wochenschrift 140, no. 08 (April 16, 2015): 626–27. http://dx.doi.org/10.1055/s-0041-101382.

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Drach, Volker. "Solarzellen ‚hinter Gittern’." Physik in unserer Zeit 27, no. 2 (1996): 92. http://dx.doi.org/10.1002/piuz.19960270212.

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应, 亚萍. "Recent Advance in GITR/GITRL Signaling Pathway and Bronchial Asthma." Asian Case Reports in Pediatrics 01, no. 02 (2013): 23–29. http://dx.doi.org/10.12677/acrp.2013.12006.

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Krausz, L. T., E. Fischer-Fodor, Z. Zs Major, and B. Fetica. "Gitr-Expressing Regulatory T-Cell Subsets are Increased in Tumor-Positive Lymph Nodes from Advanced Breast Cancer Patients as Compared to Tumor-Negative Lymph Nodes." International Journal of Immunopathology and Pharmacology 25, no. 1 (January 2012): 59–66. http://dx.doi.org/10.1177/039463201202500108.

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Lymph node (LN) infiltration by neoplastic process involves important changes in lymph node immune microenvironment. In particular, regulatory T cells (Treg) seem to have a key role in altering the immunoediting function of the immune system which leads to the elusion of the tumor from immune surveillance. In this study, we evaluate the expression of T-cell markers in CD4+ and CD8+ subsets from tumor-positive and tumor-negative lymph nodes from the same, advanced stage breast cancer patient. The study was carried out on 3 patients and similar results were obtained. Flow cytometric analysis of CD8+ cells demonstrated a significant difference in the expression of CD25, CD45RA, CD45RO, and GITRL (Glucocorticoid-Induced TNF receptor-Related ligand). Flowcytometric analysis of CD4+ cells demonstrated a significant difference in the expression of GITR (Glucocorticoid-Induced TNF receptor-Related), CD25, FoxP3 (Forkhead box P3), CD28, and CD45RA. Multiple staining allowed the identification of two Treg subpopulations, CD4+CD25highGITR+CD127−/low and CD4+CD25lowGITR+CD127+ cells, proving that both are increased in the positive nodes in comparison with the negative nodes from the same patient. We identified for the first time the CD4+CD25lowGITR+CD127+ Treg subpopulation in cancer, and the 2.6 fold increase in positive LN suggests that this Treg subpopulation could be a key player in metastasis. We also found GITRL expression in the CD8 lymphocytes, which may also contribute to the changes of metastatic lymph node microenvironment. These findings make both GITR and GITRL good possible co-candidates for future therapeutical intervention against metastasis and perhaps also as disease evolution biomarkers.

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Harriman, J. E. "From gittern to citole." Early Music 39, no. 1 (January 27, 2011): 139–40. http://dx.doi.org/10.1093/em/caq135.

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Müller, Thomas. "Mit Psychose hinter Gittern." MMW - Fortschritte der Medizin 160, no. 2 (February 2018): 16. http://dx.doi.org/10.1007/s15006-018-0127-7.

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Simon, Jens. "Kristalle: Phänomene hinter Gittern." Physik in unserer Zeit 28, no. 5 (1997): 194–200. http://dx.doi.org/10.1002/piuz.19970280503.

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O'Keeffe, Gerard W., Humberto Gutierrez, Pier Paolo Pandolfi, Carlo Riccardi, and Alun M. Davies. "NGF-promoted axon growth and target innervation requires GITRL-GITR signaling." Nature Neuroscience 11, no. 2 (January 6, 2008): 135–42. http://dx.doi.org/10.1038/nn2034.

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Nocentini, Giuseppe, Simona Ronchetti, Salvatore Cuzzocrea, and Carlo Riccardi. "GITR/GITRL: More than an effector T cell co-stimulatory system." European Journal of Immunology 37, no. 5 (May 2007): 1165–69. http://dx.doi.org/10.1002/eji.200636933.

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Shevach, Ethan M., and Geoffrey L. Stephens. "The GITR–GITRL interaction: co-stimulation or contrasuppression of regulatory activity?" Nature Reviews Immunology 6, no. 8 (August 2006): 613–18. http://dx.doi.org/10.1038/nri1867.

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König, Simon. "Therapie hinter Gittern – Forensische Psychiatrie." ergopraxis 12, no. 02 (February 2019): 22–26. http://dx.doi.org/10.1055/a-0770-4878.

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Psychisch erkrankte Straftäter, die schuldunfähig oder vermindert schuldfähig gesprochen wurden, erhalten ihre Behandlung im Maßregelvollzug. Sie unterstützt Patienten dabei, ein eingegliedertes Mitglied der Gesellschaft zu werden. Simon König berichtet von seiner Arbeit in der LVR-Klinik Viersen und wie er als Ergotherapeut trotz des fremd-bestimmten Umfelds die Betätigung im Blick behält.

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Bolte, Walter. "Zur Optimierung von Turbinen-Gittern." Forschung im Ingenieurwesen 54, no. 6 (November 1988): 180. http://dx.doi.org/10.1007/bf02574564.

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Müller, Thomas. "Opioidsubstitution klappt auch hinter Gittern." MMW - Fortschritte der Medizin 160, no. 5 (March 2018): 16. http://dx.doi.org/10.1007/s15006-018-0266-x.

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cs. "Hinter Gittern altert man schneller." Heilberufe 70, no. 5 (April 23, 2018): 20. http://dx.doi.org/10.1007/s00058-018-3443-5.

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Kim, James I., Samsher B. Sonawane, Major K. Lee, Seoung‐Hoon Lee, Patrick E. Duff, Daniel J. Moore, Matthew R. O'Connor, et al. "Blockade of GITR–GITRL interaction maintains Treg function to prolong allograft survival." European Journal of Immunology 40, no. 5 (April 29, 2010): 1369–74. http://dx.doi.org/10.1002/eji.200940046.

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Fu, Zhuo, Shuang Wang, Jinhua Li, Yunfeng Zhang, Han Li, Guangquan Li, Xue Wan, and Yu Zhang. "Biological role of GITR/GITRL in attributes and immune responses of macrophage." Journal of Leukocyte Biology 107, no. 2 (December 13, 2019): 309–21. http://dx.doi.org/10.1002/jlb.3a0919-387rr.

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Schmohl, Joerg U., Tina Nuebling, Julia Wild, Tanja Kroell, Lothar Kanz, Helmut R. Salih, and Helga Schmetzer. "Expression of 4-1BB and its ligand on blasts correlates with prognosis of patients with AML." Journal of Investigative Medicine 64, no. 8 (July 7, 2016): 1252–60. http://dx.doi.org/10.1136/jim-2016-000081.

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Costimulatory ligands (COLs) and their receptors (COR) regulate immune reactions and cellular survival and might be relevant in acute myeloid leukemia (AML). This study evaluated the clinical relevance of 4-1BBL, glucocorticoid-induced TNFR-related protein (GITR) and ligand (GITRL), CD80, and CD86 in case of expression on AML blasts. 98 patients were evaluated at initial diagnosis. Immunophenotypically evaluated specific fluorescence index (SFI) levels of COR and COL on blasts were correlated with morphological, cytogenetic, and several prognostic parameters. Significantly higher COR expression was seen in monocytic versus non-monocytic AML subtypes; GITR, p=0.05; GITRL, p=0.005; CD86, p=0.001). Cut-off values for two COR and their ligands were evaluated: cases presenting with 4-1BB values above cut-off 1.2 SFI levels correlated (tendentially) significantly with a higher probability for disease-free survival (DFS, p=0.06) and a favorable HR of 0.2; p=0.04 for relapse. HR for death was also significantly lower in this group (0.12; p=0.04). In contrast, a lower probability for DFS and overall survival was seen in cases with 4-1BBL expression above 2.2 SFI levels (p=0.08 and p=0.09). In addition, multivariate analysis showed a significantly higher probability of death in this group (HR 10.3, p=0.04). Expression of CD80 and CD86 did not show significant prognostic relevance. On initial diagnosis, 4-1BB and 4-1BBL qualify as markers for prediction of patients’ course and represent a valuable screening target for patients with AML at initial diagnosis.

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Stone, Geoffrey W., Suzanne Barzee, Victoria Snarsky, Celsa A. Spina, Jeffrey D. Lifson, Vinod Kumar Bhaskara Pillai, Rama Rao Amara, François Villinger, and Richard S. Kornbluth. "Macaque Multimeric Soluble CD40 Ligand and GITR Ligand Constructs Are Immunostimulatory Molecules In Vitro." Clinical and Vaccine Immunology 13, no. 11 (September 20, 2006): 1223–30. http://dx.doi.org/10.1128/cvi.00198-06.

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ABSTRACT CD40 ligand (CD40L) and GITR ligand (glucocorticoid-induced tumor necrosis factor receptor-related protein ligand [GITRL]) are tumor necrosis factor superfamily molecules that can be used as vaccine adjuvants. In a previous human immunodeficiency virus (HIV) DNA vaccine study in mice, we found that plasmids expressing multimeric soluble forms of trimeric CD40L (i.e., many trimers) were stronger activators of CD8+ T-cell responses than were single-trimer soluble forms or the natural membrane-bound molecule. This report describes similar multimeric soluble molecules that were constructed for studies in macaques. Both two-trimer and four-trimer forms of macaque CD40L were active in B-cell proliferation assays using macaque and human cells. With human cells, four-trimer macaque GITRL costimulated CD4+ T-cell proliferation and abrogated the immunosuppressive effects of CD4+ CD25+ regulatory T cells on a mixed leukocyte reaction. These molecular adjuvants provide new tools for vaccine development in the simian immunodeficiency virus system and other macaque models.

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Lorizio, Daniela, Michael Weller, Manuela Silginer, Alan Epstein, and Patrick Roth. "IMMU-13. COMBINED MODULATION OF THE TGF-Β PATHWAY AND GITR IMMUNE CHECKPOINT SIGNALING PROMOTES ANTI-TUMOR IMMUNITY IN SYNGENEIC GLIOMA MODELS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi94. http://dx.doi.org/10.1093/neuonc/noab196.372.

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Abstract The profound local immunosuppressive microenvironment is one hallmark of glioblastoma, which results in resistance to most immunotherapeutic strategies that have been explored so far. Reverting this condition in order to reinvigorate anti-glioma immunity might be a promising therapeutic approach. Transforming growth factor (TGF)-β signaling is deregulated in different cancer types and contributes to the malignant phenotype of glioma cells. Glioma-derived TGF-β is also a major immunosuppressive factor in the tumor microenvironment. Furthermore, intratumoral regulatory T (Treg) cells and activated T effector cells express high levels of the co-stimulatory immune checkpoint glucocorticoid-induced tumor necrosis factor receptor (GITR). Agonistic anti-GITR antibodies have been explored in preclinical tumor models and are under investigation in clinical trials for the treatment of solid tumors. We evaluated the effect of TGF-β and GITR targeting on anti-tumor immune responses in syngeneic mouse glioma models. In co-culture settings, GITR modulation with a GITR ligand (GITRL)-Fc fusion protein, given alone or in combination with a pharmacological TGF-β receptor inhibitor, led to increased T cell activation. Furthermore, the combined targeting of the two pathways resulted in significantly higher immune cell-mediated tumor cell killing than either treatment alone. In vivo, TGF-β inhibition and GITR signaling modulation resulted in a higher fraction of long-term surviving glioma-bearing mice than single-agent treatment. Surviving mice were resistant to tumor re-challenge, suggesting adaptive immunity as an underlying mechanism. These data support the assumption that combined immunotherapeutic strategies may represent a promising approach for the treatment of glioma.

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Stone, Geoffrey W., Suzanne Barzee, Victoria Snarsky, Kristin Kee, Celsa A. Spina, Xiao-Fang Yu, and Richard S. Kornbluth. "Multimeric Soluble CD40 Ligand and GITR Ligand as Adjuvants for Human Immunodeficiency Virus DNA Vaccines." Journal of Virology 80, no. 4 (February 15, 2006): 1762–72. http://dx.doi.org/10.1128/jvi.80.4.1762-1772.2006.

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ABSTRACT For use in humans, human immunodeficiency virus (HIV) DNA vaccines may need to include immunostimulatory adjuvant molecules. CD40 ligand (CD40L), a member of the tumor necrosis factor (TNF) superfamily (TNFSF), is one candidate adjuvant, but it has been difficult to use because it is normally expressed as a trimeric membrane molecule. Soluble trimeric forms of CD40L have been produced, but in vitro data indicate that multimeric, many-trimer forms of soluble CD40L are more active. This multimerization requirement was evaluated in mice using plasmids that encoded either 1-trimer, 2-trimer, or 4-trimer soluble forms of CD40L. Fusion with the body of Acrp30 was used to produce the 2-trimer form, and fusion with the body of surfactant protein D was used to produce the 4-trimer form. Using plasmids for secreted HIV-1 antigens Gag and Env, soluble CD40L was active as an adjuvant in direct proportion to the valence of the trimers (1 < 2 < 4). These CD40L-augmented DNA vaccines elicited strong CD8+ T-cell responses but did not elicit significant CD4+ T-cell or antibody responses. To test the applicability of the multimeric fusion protein approach to other TNFSFs, a 4-trimer construct for the ligand of glucocorticoid-induced TNF family-related receptor (GITR) was also prepared. Multimeric soluble GITR ligand (GITRL) augmented the CD8+ T-cell, CD4+ T-cell, and antibody responses to DNA vaccination. In summary, multimeric CD40L and GITRL are new adjuvants for DNA vaccines. Plasmids for expressing multimeric TNFSF fusion proteins permit the rapid testing of TNFSF molecules in vivo.

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Chan, M., L. Wu, Z. Yun, Y. Zhao, M. Kohno, and M. De Perrot. "P2.06-06 Role of GITRL-GITR System in Promoting Proliferation of Malignant Mesothelioma." Journal of Thoracic Oncology 13, no. 10 (October 2018): S744. http://dx.doi.org/10.1016/j.jtho.2018.08.1261.

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Vecchiarelli, Anna, Eva Pericolini, Elena Gabrielli, Massimiliano Agostini, Francesco Bistoni, Giuseppe Nocentini, Elio Cenci, and Carlo Riccardi. "The GITRL–GITR system alters TLR-4 expression on DC during fungal infection." Cellular Immunology 257, no. 1-2 (2009): 13–22. http://dx.doi.org/10.1016/j.cellimm.2009.02.001.

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Matschnig, Teresa, Stefan Frühwald, and Patrick Frottier. "Suizide hinter Gittern im internationalen Vergleich." Psychiatrische Praxis 33, no. 01 (2006): 6–13. http://dx.doi.org/10.1055/s-2004-834784.

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Beneker, Christian. "Patienten in Handschellen: Klinikalltag hinter Gittern." Heilberufe 68, no. 5 (April 28, 2016): 44–45. http://dx.doi.org/10.1007/s00058-016-2163-y.

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Baumgartner-Nielsen, J., C. Vestergaard, K. Thestrup-Pedersen, M. Deleuran, and B. Deleuran. "Glucocorticoid-induced Tumour Necrosis Factor Receptor (GITR) and its Ligand (GITRL) in Atopic Dermatitis." Acta Dermato-Venereologica 86, no. 5 (2006): 393–98. http://dx.doi.org/10.2340/00015555-0118.

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Fleischmann, R., T. Geisel, R. Ketzmerick, and G. Petschel. "Chaos und fraktale Energiespektren in Antidot-Gittern." Physik Journal 51, no. 3 (March 1995): 177–81. http://dx.doi.org/10.1002/phbl.19950510308.

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Journal articles on the topic 'Gitern'

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