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1. Corrigendum: NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22

Author

Spalinger, Marianne R., Kasper, Stephanie, Gottier, Claudia, Lang, Silvia, Atrott, Kirstin, Vavricka, Stephan R., Scharl, Sylvie, Gutte, Petrus M., Grutter, Markus G., Beer, Hans-Dietmar, Contassot, Emmanuel, Chan, Andrew C., Dai, Xuezhi, Rawlings, David J., Mair, Florian, Becher, Burkhard, Falk, Werner, Fried, Michael, Rogler, Gerhard, and Scharl, Michael

Subjects
Health care industry
Abstract

Original citation: J Clin Invest. 2016;126(5):1783-1800. https://doi.org/10.1172/JCI83669. https://doi.org/10.1172/JCI169304 The authors recently became aware of errors in Figure 8, A and B. In Figure 8A, the WT/[H.sub.2]O and WT/DSS pictures were [...]

Published
2023
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6. NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22

Author

Spalinger, Marianne R, Kasper, Stephanie, Gottier, Claudia, Lang, Silvia, Atrott, Kirstin, Vavricka, Stephan R, Scharl, Sylvie, Gutte, Petrus M, Grütter, Markus G, Beer, Hans-Dietmar, Contassot, Emmanuel, Chan, Andrew C, Dai, Xuezhi, Rawlings, David J, Mair, Florian, Becher, Burkhard, Falk, Werner, Fried, Michael, Rogler, Gerhard, Scharl, Michael, Spalinger, Marianne R, Kasper, Stephanie, Gottier, Claudia, Lang, Silvia, Atrott, Kirstin, Vavricka, Stephan R, Scharl, Sylvie, Gutte, Petrus M, Grütter, Markus G, Beer, Hans-Dietmar, Contassot, Emmanuel, Chan, Andrew C, Dai, Xuezhi, Rawlings, David J, Mair, Florian, Becher, Burkhard, Falk, Werner, Fried, Michael, Rogler, Gerhard, and Scharl, Michael

Abstract

Erratum for: NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase N22

Published
2023

7. NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22

Author

Spalinger, Marianne R., primary, Kasper, Stephanie, additional, Gottier, Claudia, additional, Lang, Silvia, additional, Atrott, Kirstin, additional, Vavricka, Stephan R., additional, Scharl, Sylvie, additional, Gutte, Petrus M., additional, Grütter, Markus G., additional, Beer, Hans-Dietmar, additional, Contassot, Emmanuel, additional, Chan, Andrew C., additional, Dai, Xuezhi, additional, Rawlings, David J., additional, Mair, Florian, additional, Becher, Burkhard, additional, Falk, Werner, additional, Fried, Michael, additional, Rogler, Gerhard, additional, and Scharl, Michael, additional

Published
2023
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9. NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22

Author

Spalinger, Marianne R., Kasper, Stephanie, Gottier, Claudia, Lang, Silvia, Atrott, Kirstin, Vavricka, Stephan R., Scharl, Sylvie, Gutte, Petrus M., Grutter, Markus G., Beer, Hans-Dietmar, Contassot, Emmanuel, Chan, Andrew C., Dai, Xuezhi, Rawlings, David J., Mair, Florian, Becher, Burkhard, Falk, Werner, Fried, Michael, Rogler, Gerhard, and Scharl, Michael

Subjects
Tyrosine -- Research, Phosphorylation -- Analysis, Health care industry
Abstract

Inflammasomes form as the result of the intracellular presence of danger-associated molecular patterns and mediate the release of active IL-1β, which influences a variety of inflammatory responses. Excessive inflammasome activation results in severe inflammatory conditions, but physiological IL-1β secretion is necessary for intestinal homeostasis. Here, we have described a mechanism of NLRP3 inflammasome regulation by tyrosine phosphorylation of NLRP3 at Tyr861. We demonstrated that protein tyrosine phosphatase non-receptor 22 (PTPN22), variants in which are associated with chronic inflammatory disorders, dephosphorylates NLRP3 upon inflammasome induction, allowing efficient NLRP3 activation and subsequent IL-1β release. In murine models, PTPN22 deficiency resulted in pronounced colitis, increased NLRP3 phosphorylation, but reduced levels of mature IL-1β. Conversely, patients with inflammatory bowel disease (IBD) that carried an autoimmunity-associated PTPN22 variant had increased IL-1β levels. Together, our results identify tyrosine phosphorylation as an important regulatory mechanism for NLRP3 that prevents aberrant inflammasome activation., Introduction Inflammasomes are large, multiprotein complexes that form upon cytosolic or nuclear presence of damage- or pathogen-associated molecular patterns, ultimately leading to the secretion of IL-1β and IL-18. Inflammasomes consist [...]

Published
2016
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11. Phosphodiesterase-4 Inhibition Reduces Cutaneous Inflammation and IL-1β Expression in a Psoriasiform Mouse Model but Does Not Inhibit Inflammasome Activation

Author

Meier-Schiesser, Barbara, Mellett, Mark, Ramirez-Fort, Marigdalia K, Maul, Julia-Tatjana, Klug, Annika, Winkelbeiner, Nicola, Fenini, Gabriele, Schafer, Peter, Contassot, Emmanuel, French, Lars E, University of Zurich, and Meier-Schiesser, Barbara

Subjects
QH301-705.5, Inflammasomes, 1503 Catalysis, PDE4 inhibition, Interleukin-1beta, Drug Evaluation, Preclinical, 1607 Spectroscopy, Mice, Transgenic, 610 Medicine & health, Article, Catalysis, Inorganic Chemistry, inflammasome, 1312 Molecular Biology, 1706 Computer Science Applications, Animals, Humans, Psoriasis, Biology (General), Physical and Theoretical Chemistry, QD1-999, Molecular Biology, Spectroscopy, 1604 Inorganic Chemistry, Organic Chemistry, 10177 Dermatology Clinic, General Medicine, cytokines, Immunity, Innate, Thalidomide, Computer Science Applications, Chemistry, Phosphodiesterase 4 Inhibitors, 1606 Physical and Theoretical Chemistry, 1605 Organic Chemistry
Abstract

Apremilast (Otezla®) is an oral small molecule phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of psoriasis, psoriatic arthritis, and oral ulcers associated with Behçet’s disease. While PDE4 inhibition overall is mechanistically understood, the effect of apremilast on the innate immune response, particularly inflammasome activation, remains unknown. Here, we assessed the effect of apremilast in a psoriasis mouse model and primary human cells. Psoriatic lesion development in vivo was studied in K5.Stat3C transgenic mice treated with apremilast for 2 weeks, resulting in a moderate (2 mg/kg/day) to significant (6 mg/kg/day) resolution of inflamed plaques after 2-week treatment. Concomitantly, epidermal thickness dramatically decreased, the cutaneous immune cell infiltrate was reduced, and proinflammatory cytokines were significantly downregulated. Additionally, apremilast significantly inhibited lipopolysaccharide- or anti-CD3-induced expression of proinflammatory cytokines in peripheral mononuclear cells (PBMCs). Notably, inflammasome activation and secretion of IL-1β were not inhibited by apremilast in PBMCs and in human primary keratinocytes. Collectively, apremilast effectively alleviated the psoriatic phenotype of K5.Stat3 transgenic mice, further substantiating PDE4 inhibitor-efficiency in targeting key clinical, histopathological and inflammatory features of psoriasis. Despite lacking direct effect on inflammasome activation, reduced priming of inflammasome components upon apremilast treatment reflected the indirect benefit of PDE4 inhibition in reducing inflammation.

Published
2021

12. Phosphodiesterase-4 Inhibition Reduces Cutaneous Inflammation and IL-1β Expression in a Psoriasiform Mouse Model but Does Not Inhibit Inflammasome Activation

Author

Meier-Schiesser, Barbara, primary, Mellett, Mark, additional, Ramirez-Fort, Marigdalia K., additional, Maul, Julia-Tatjana, additional, Klug, Annika, additional, Winkelbeiner, Nicola, additional, Fenini, Gabriele, additional, Schafer, Peter, additional, Contassot, Emmanuel, additional, and French, Lars E., additional

Published
2021
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15. Folate hydrolase‐1 (FOLH1) is a novel target for antibody‐based brachytherapy in Merkel cell carcinoma

Author

Ramirez‐Fort, Marigdalia K; https://orcid.org/0000-0002-1918-7114, Meier‐Schiesser, Barbara, Lachance, Kristina, Mahase, Sean S, Church, Candice D, Niaz, Muhammad J; https://orcid.org/0000-0001-7995-2415, Liu, Huixian, Navarro, Vicente, Nikolopoulou, Anastasia, Kazakov, Dmitry V, Contassot, Emmanuel, Nguyen, Daniel P, Sach, J, Hadravsky, L, Sheng, Yinxiangzi, Tagawa, Scott T, Wu, Xianwei, Lange, Christopher S, French, Lars E; https://orcid.org/0000-0002-4629-1486, Nghiem, Paul T, Bander, Neil H, Ramirez‐Fort, Marigdalia K; https://orcid.org/0000-0002-1918-7114, Meier‐Schiesser, Barbara, Lachance, Kristina, Mahase, Sean S, Church, Candice D, Niaz, Muhammad J; https://orcid.org/0000-0001-7995-2415, Liu, Huixian, Navarro, Vicente, Nikolopoulou, Anastasia, Kazakov, Dmitry V, Contassot, Emmanuel, Nguyen, Daniel P, Sach, J, Hadravsky, L, Sheng, Yinxiangzi, Tagawa, Scott T, Wu, Xianwei, Lange, Christopher S, French, Lars E; https://orcid.org/0000-0002-4629-1486, Nghiem, Paul T, and Bander, Neil H

Abstract

Backgrounds: Folate Hydrolase-1 (FOLH1; PSMA) is a type II transmembrane protein, luminally expressed by solid tumour neo-vasculature. Monoclonal antibody (mAb), J591, is a vehicle for mAb-based brachytherapy in FOLH1+ cancers. Brachytherapy is a form of radiotherapy that involves placing a radioactive material a short distance from the target tissue (e.g., on the skin or internally); brachytherapy is commonly accomplished with the use of catheters, needles, metal seeds and antibody or small peptide conjugates. Herein, FOLH1 expression in primary (p) and metastatic (m) Merkel cell carcinoma (MCC) is characterized to determine its targeting potential for J591-brachytherapy. Materials & Methods: Paraffin sections from pMCC and mMCC were evaluated by immunohistochemistry for FOLH1. Monte Carlo simulation was performed using the physical properties of conjugated radioisotope lutetium-177. Kaplan–Meier survival curves were calculated based on patient outcome data and FOLH1 expression. Results: Eighty-one MCC tumours were evaluated. 67% (54/81) of all cases, 77% (24/31) pMCC and 60% (30/50) mMCC tumours were FOLH1+. Monte Carlo simulation showed highly localized ionizing tracks of electrons emitted from the targeted neo-vessel. 42% (34/81) of patients with FOLH1+/− MCC had available survival data for analysis. No significant differences in our limited data set were detected based on FOLH1 status (p = 0.4718; p = 0.6470), staining intensity score (p = 0.6966; p = 0.9841) or by grouping staining intensity scores (− and + vs. ++, +++, +++) (p = 0.8022; p = 0.8496) for MCC-specific survival or recurrence free survival, respectively. Conclusions: We report the first evidence of prevalent FOLH1 expression within MCC-associated neo-vessels, in 60-77% of patients in a large MCC cohort. Given this data, and the need for alternatives to immune therapies it is appropriate to explore the safety and efficacy of FOLH1-targeted brachytherapy for MCC.

Published
2021

16. IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes

Author

Satoh, Takashi K., primary, Mellett, Mark, additional, Meier-Schiesser, Barbara, additional, Fenini, Gabriele, additional, Otsuka, Atsushi, additional, Beer, Hans-Dietmar, additional, Rordorf, Tamara, additional, Maul, Julia-Tatjana, additional, Hafner, Jürg, additional, Navarini, Alexander A., additional, Contassot, Emmanuel, additional, and French, Lars E., additional

Published
2020
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19. Divergent LAG-3 versus BTLA, TIGIT, and FCRL3 expression in Sézary syndrome

Author

Anzengruber, Florian, Ignatova, Desislava, Schlaepfer, Tanja, Chang, Yun-Tsan, French, Lars E, Pascolo, Steve, Contassot, Emmanuel, Bobrowicz, Malgorzata, Hoetzenecker, Wolfram, Guenova, Emmanuella; https://orcid.org/0000-0001-5478-8735, Anzengruber, Florian, Ignatova, Desislava, Schlaepfer, Tanja, Chang, Yun-Tsan, French, Lars E, Pascolo, Steve, Contassot, Emmanuel, Bobrowicz, Malgorzata, Hoetzenecker, Wolfram, and Guenova, Emmanuella; https://orcid.org/0000-0001-5478-8735

Published
2019

23. T cell tolerance to the skin: a central role for central tolerance

Author

Schuler, Prisca, Contassot, Emmanuel, Huard, Bertrand, Schuler, Prisca, Contassot, Emmanuel, and Huard, Bertrand

Abstract

T cell tolerance to self-antigens is believed to be achieved in a two-step process. The first step, called central tolerance, takes place in the thymus. The second step takes place outside the thymus in secondary lymphoid organs. One may ask why two mechanisms are needed to insure T cell tolerance. These two mechanisms share redundant functions and dysfunctions, leading to T cell-mediated autoimmune syndromes. By reviewing the literature on relevant animal models for T cell tolerance and our own recent findings, we are providing evidences that only central tolerance is acting for the skin

Published
2018

25. Expression of CD164 on malignant T Cells in Sézary syndrome

Author

Guenova, Emmanuella, Ignatova, Desislava, Chang, Yun-Tsan, Contassot, Emmanuel, Mehra, Tarun, Saulite, Ieva, Navarini, Alexander A, Mitev, Vanyo, Dummer, Reinhard, Kazakov, Dmitry V, French, Lars E, Hötzenecker, Wolfram, Cozzio, Antonio, University of Zurich, and Guenova, Emmanuella

Subjects
2708 Dermatology, 10177 Dermatology Clinic, 610 Medicine & health
Published
2016

26. Corrigendum - NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22

Author

Spalinger, Marianne R, Kasper, Stephanie, Gottier, Claudia, Lang, Silvia, Atrott, Kirstin, Vavricka, Stephan R, Scharl, Sylvie, Raselli, Tina, Frey-Wagner, Isabelle, Gutte, Petrus M, Grütter, Markus G, Beer, Hans-Dietmar, Contassot, Emmanuel, Chan, Andrew C, Dai, Xuezhi, Rawlings, David J, Mair, Florian, Becher, Burkhard, Falk, Werner, Fried, Michael, Rogler, Gerhard, Scharl, Michael, and University of Zurich

Subjects
10219 Clinic for Gastroenterology and Hepatology, 10076 Center for Integrative Human Physiology, 10019 Department of Biochemistry, 570 Life sciences, biology, 610 Medicine & health, 2700 General Medicine, 10263 Institute of Experimental Immunology
Published
2016

27. Abstract 1905: Possible cancer stem cells: Folate hydrolase-1 is expressed in a subset of Oct4-positive melanoma cells

Author

Ramirez-Fort, Marigdalia K., primary, Liu, He, additional, Navarro, Vicente, additional, Meier, Barbara, additional, Levesque, Mitch, additional, Moy, Jonathan, additional, Vissicchio, Jessica, additional, Contassot, Emmanuel, additional, Kim, Sae, additional, Syed, Talal, additional, Zhang, Michael, additional, Tem, Vincent, additional, Christos, Paul J., additional, Tagawa, Scott T., additional, Bander, Neil H., additional, Lange, Christopher S., additional, and French, Lars E., additional

Published
2017
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29. Tumour hypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1 and M2-like macrophages

Author

00362484, Huber, Roman, Meier, Barbara, Otsuka, Atsushi, Fenini, Gabriele, Satoh, Takashi, Gehrke, Samuel, Widmer, Daniel, Levesque, Mitchell P., Mangana, Joanna, Kerl, Katrin, Gebhardt, Christoffer, Fujii, Hiroko, Nakashima, Chisa, Nonomura, Yumi, Kabashima, Kenji, Dummer, Reinhard, Contassot, Emmanuel, French, Lars E., 00362484, Huber, Roman, Meier, Barbara, Otsuka, Atsushi, Fenini, Gabriele, Satoh, Takashi, Gehrke, Samuel, Widmer, Daniel, Levesque, Mitchell P., Mangana, Joanna, Kerl, Katrin, Gebhardt, Christoffer, Fujii, Hiroko, Nakashima, Chisa, Nonomura, Yumi, Kabashima, Kenji, Dummer, Reinhard, Contassot, Emmanuel, and French, Lars E.

Abstract

Hypoxia is a hallmark of cancer that is strongly associated with invasion, metastasis, resistance to therapy and poor clinical outcome. Tumour hypoxia affects immune responses and promotes the accumulation of macrophages in the tumour microenvironment. However, the signals linking tumour hypoxia to tumour-associated macrophage recruitment and tumour promotion are incompletely understood. Here we show that the damage-associated molecular pattern High-Mobility Group Box 1 protein (HMGB1) is released by melanoma tumour cells as a consequence of hypoxia and promotes M2-like tumour-associated macrophage accumulation and an IL-10 rich milieu within the tumour. Furthermore, we demonstrate that HMGB1 drives IL-10 production in M2-like macrophages by selectively signalling through the Receptor for Advanced Glycation End products (RAGE). Finally, we show that HMGB1 has an important role in murine B16 melanoma growth and metastasis, whereas in humans its serum concentration is significantly increased in metastatic melanoma. Collectively, our findings identify a mechanism by which hypoxia affects tumour growth and metastasis in melanoma and depict HMGB1 as a potential therapeutic target.

Published
2016

30. Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy

Author

Goldinger, Simone M, Stieger, Pascale, Meier, Barbara, Micaletto, Sara, Contassot, Emmanuel, French, Lars E, Dummer, Reinhard, Goldinger, Simone M, Stieger, Pascale, Meier, Barbara, Micaletto, Sara, Contassot, Emmanuel, French, Lars E, and Dummer, Reinhard

Abstract

PURPOSE: Immunotherapy experienced impressive progresses in cancer treatment. Antibodies against PD-1 improved survival in different types of cancer including melanoma. They are generally well tolerated. However, skin toxicities including pruritus, rashes and vitiligo are reported. Although frequent, they are have not been further characterized yet. In this analysis we aimed to systematically assess and characterize the adverse cutaneous reactions observed in melanoma patients treated with anti-PD-1 antibodies. EXPERIMENTAL DESIGN: Melanoma patients were treated with anti-PD-1 antibodies within clinical trials and early access program. Adverse cutaneous eruptions emerged in our melanoma patient cohort were systematically investigated and classified using histology and gene expression profiling in comparison to maculopapular drug rash, cutaneous graft versus host disease and the severe drug eruption toxic epidermal necrolysis. RESULTS: Between Feb 2013 and Sept 2015, 68 stage IV melanoma patients were treated at the University Hospital Zurich; 15 patients (22%) developed cutaneous reactions and 10 (15%) vitiligo. The cutaneous reactions ranged from small erythematous papules with mild pruritus to disseminated erythematous maculopapular rashes without signs of epidermal involvement to severe maculopapular rashes including epidermal detachment and mucosal involvement. Although skin involvement varied from mild rash to bullous drug eruptions, gene expression profiling pathogenically classified all investigated cases as toxic epidermal necrolysis-like reactions. CONCLUSIONS: As predicted by the PD-1 knock out mouse, anti-PD-1 antibodies frequently cause adverse cutaneous reactions. Gene expression profiling reminds in all cases to a toxic epidermal necrolysis-like pattern suggesting that PD-1/PD-L1 interaction is required to preserve epidermal integrity during inflammatory skin reactions.

Published
2016

32. Epidermal Elafin Expression Is an Indicator of Poor Prognosis in Cutaneous Graft-versus-Host Disease

Author

Brüggen, Marie-Charlotte, primary, Petzelbauer, Peter, additional, Greinix, Hildegard, additional, Contassot, Emmanuel, additional, Jankovic, Dragana, additional, French, Lars, additional, Socié, Gérard, additional, Rabitsch, Werner, additional, Kuzmina, Zoya, additional, Kalhs, Peter, additional, Knobler, Robert, additional, Stingl, Georg, additional, and Stary, Georg, additional

Published
2015
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36. IL-1β Drives Inflammatory Responses to Propionibacterium acnes In Vitro and In Vivo

Author

Kistowska, Magdalena, primary, Gehrke, Samuel, additional, Jankovic, Dragana, additional, Kerl, Katrin, additional, Fettelschoss, Antonia, additional, Feldmeyer, Laurence, additional, Fenini, Gabriele, additional, Kolios, Antonios, additional, Navarini, Alexander, additional, Ganceviciene, Ruta, additional, Schauber, Jürgen, additional, Contassot, Emmanuel, additional, and French, Lars E., additional

Published
2014
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39. The Nlrp3 inflammasome regulates acute graft-versus-host disease

Author

Jankovic, Dragana, primary, Ganesan, Jayanthi, additional, Bscheider, Michael, additional, Stickel, Natalie, additional, Weber, Felix C., additional, Guarda, Greta, additional, Follo, Marie, additional, Pfeifer, Dietmar, additional, Tardivel, Aubry, additional, Ludigs, Kristina, additional, Bouazzaoui, Abdellatif, additional, Kerl, Katrin, additional, Fischer, Julius C., additional, Haas, Tobias, additional, Schmitt-Gräff, Annette, additional, Manoharan, Anand, additional, Müller, Leonard, additional, Finke, Jürgen, additional, Martin, Stefan F., additional, Gorka, Oliver, additional, Peschel, Christian, additional, Ruland, Jürgen, additional, Idzko, Marco, additional, Duyster, Justus, additional, Holler, Ernst, additional, French, Lars E., additional, Poeck, Hendrik, additional, Contassot, Emmanuel, additional, and Zeiser, Robert, additional

Published
2013
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40. TNF-α and IFN-γ Are Potential Inducers of Fas-Mediated Keratinocyte Apoptosis through Activation of Inducible Nitric Oxide Synthase in Toxic Epidermal Necrolysis

Author

Viard-Leveugle, Isabelle, primary, Gaide, Olivier, additional, Jankovic, Dragana, additional, Feldmeyer, Laurence, additional, Kerl, Katrin, additional, Pickard, Chris, additional, Roques, Stéphanie, additional, Friedmann, Peter S., additional, Contassot, Emmanuel, additional, and French, Lars E., additional

Published
2013
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47. Propionibacterium acnesStrains Differentially Regulate the Fate of Th17 Responses in the Skin

Author

Contassot, Emmanuel and French, Lars E.

Abstract

Agak et al. demonstrate that different strains of Propionibacterium acnes, a bacterium colonizing pilosebaceous units in healthy skin and acne, have the ability to induce T helper type 17 cells secreting either IFN-γ or IL-10 and exhibiting either pathogenic or protective properties, respectively. This work contributes to growing evidence indicating that the phenotype of T helper type 17 cells is largely dependent on their microbiological environment.

Published
2018
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49. Inflammasome activation and IL-1β target IL-lα for secretion as opposed to surface expression.

Author

Fettelschoss, Antonia, Kistowska, Magdalena, LeibundGut-Landmann, Salomé, Beer, Hans-Dietmar, Johansen, Pål, Senti, Gabriela, Contassot, Emmanuel, Bachmann, Martin F., French, Lars E., Oxenius, Annette, and Kündig, Thomas M.

Subjects
BIOLOGICAL transport, INTERLEUKINS, CELLULAR immunity, IMMUNOREGULATION, CELL membranes
Abstract

Interleukin-11α (IL-11α) and -β both bind to the same IL-1 receptor (IL-1R) and are potent proinflammatory cytokines. Production of proinflammatory (pro)-IL-11α and pro-IL-1β is induced by Toll-like receptor (TLR)-mediated NF-κ activation. Additional stimulus involving activation of the inflammasome and caspase-1 is required for proteolytic cleavage and secretion of mature IL-1β. The regulation of IL-11α maturation and secretion, however, remains elusive. IL-11α exists as a cell surface-associated form and as a mature secreted form. Here we show that both forms of IL-11α, the surface and secreted form, are differentially regulated. Surface IL-11α requires NF-κ activation only, whereas secretion of mature IL-11α requires additional activation of the inflammasome and caspase-1. Surprisingly, secretion of IL-11α also required the presence of IL-1β, as demonstrated in IL-1β-deficient mice. We further demonstrate that IL-1β directly binds IL-11α, thus identifying IL-1β as a shuttle for another proinflammatory cytokine. These results have direct impact on selective treatment modalities of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Published
2011
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50. Retrovirus-Mediated Gene Transfer in Primary T Lymphocytes: Influence of the Transduction/Selection Process and of ex Vivo Expansion on the T Cell Receptor β Chain Hypervariable Region Repertoire

Author

Ferrand, Christophe, Robinet, Eric, Contassot, Emmanuel, Certoux, Jean-Marie, Lim, Annick, Hervé, Patrick, and Tiberghien, Pierre

Abstract

We have initiated a phase I/II clinical trial, involving the use of herpes simplex thymidine kinase gene (HS-tk)-expressing donor primary T cells, in order to modulate the graft-versus-host disease (GvHD) occurring after allogeneic hematopoietic stem cell transplantation. The preparation of gene-modified T cells (TkTCs) required a 12-day ex vivo culture comprising an initial OKT3 and IL-2 stimulation, a retrovirus-mediated transduction, and a 7-day selection step in the presence of G418 and IL-2. The low transduction efficiency as well as the culture conditions may significantly alter the diversity of the T cell repertoire. We therefore examined the T cell repertoire of HS-tk-expressing T cell samples from 11 different donors by the Immunoscope method. This method analyzes the hypervariable region of the T cell receptor β chain (TCRBV) by amplifying the complementarity-determining region 3 (CDR3) and determining size diversity. In all examined samples (four of which were infused into patients), all TCRBV subfamilies were represented with, however, a significant skewing within a minority of subfamilies. Kinetic studies demonstrated that this skewing appeared between day 7 and day 12, with dates of appearance variable from one subfamily to another. In addition, the repertoire analysis of two different culture products, harvested and produced at different times from the same donors, suggested that some repertoire abnormalities could be donor specific. Quantitative analysis revealed no major modifications in gene usage, even in skewed TCRBV subfamilies, with a few clonal expansions concerning a limited number of TCRBV subfamilies. Importantly, identical abnormalities were found in control cells grown in parallel under similar conditions but not transduced or selected, thus demonstrating that these abnormalities were not related to the transduction or the selection process, but rather to the ex vivo culture. The initial stimulus used for T cell activation is a major source of TCRBV perturbation, since replacing the OKT3 + IL-2 stimulus by CD3 + CD28 monoclonal antibody-coated beads prevented the occurrence of alterations. Overall, the HS-tk-expressing T cells used in our clinical trial exhibit limited TCR repertoire skewing that is not due to the transduction/selection procedure. However, future T cell gene transfer protocols for clinical trials should be designed to take into account or possibly prevent such T cell repertoire alterations.

Published
2000
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