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290 results on '"Grohmann U"'

1. P555 Ustekinumab tissue and serum levels in patients with Crohn’s disease are closely correlated though not consistently associated with objective response after induction

Author

Proietti, E, primary, Bayoumy, A, additional, Pauwels, R, additional, van der Woude, J, additional, Doukas, M, additional, Oudijk, L, additional, Peppelenbosch, M, additional, Grohmann, U, additional, Crombag, R, additional, de Vries, A, additional, and Fuhler, G, additional

Published
2022
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3. Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation

Author

Mondanelli, G., Coletti, A., Greco, F. A., Pallotta, M. T., Orabona, C., Iacono, A., Belladonna, M. L., Albini, E., Panfili, E., Fallarino, F., Gargaro, M., Manni, G., Matino, D., Carvalho, A., Cunha, C., Maciel, P., Filippo, M. D., Gaetani, L., Bianchi, R., Vacca, C., Iamandii, I. M., Proietti, E., Boscia, F., Annunziato, L., Peppelenbosch, M., Puccetti, P., Calabresi, Paolo, Macchiarulo, A., Santambrogio, L., Volpi, C., Grohmann, U., Calabresi P. (ORCID:0000-0003-0326-5509), Mondanelli, G., Coletti, A., Greco, F. A., Pallotta, M. T., Orabona, C., Iacono, A., Belladonna, M. L., Albini, E., Panfili, E., Fallarino, F., Gargaro, M., Manni, G., Matino, D., Carvalho, A., Cunha, C., Maciel, P., Filippo, M. D., Gaetani, L., Bianchi, R., Vacca, C., Iamandii, I. M., Proietti, E., Boscia, F., Annunziato, L., Peppelenbosch, M., Puccetti, P., Calabresi, Paolo, Macchiarulo, A., Santambrogio, L., Volpi, C., Grohmann, U., and Calabresi P. (ORCID:0000-0003-0326-5509)

Abstract

L-tryptophan (Trp), an essential amino acid for mammals, is the precursor of a wide array of immunomodulatory metabolites produced by the kynurenine and serotonin pathways. The kynurenine pathway is a paramount source of several immunoregulatory metabolites, including L-kynurenine (Kyn), the main product of indoleamine 2,3-dioxygenase 1 (IDO1) that catalyzes the rate-limiting step of the pathway. In the serotonin pathway, the metabolite N-acetylserotonin (NAS) has been shown to possess antioxidant, antiinflammatory, and neuroprotective properties in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, little is known about the exact mode of action of the serotonin metabolite and the possible interplay between the 2 Trp metabolic pathways. Prompted by the discovery that NAS neuroprotective effects in EAE are abrogated in mice lacking IDO1 expression, we investigated the NAS mode of action in neuroinflammation. We found that NAS directly binds IDO1 and acts as a positive allosteric modulator (PAM) of the IDO1 enzyme in vitro and in vivo. As a result, increased Kyn will activate the ligand-activated transcription factor aryl hydrocarbon receptor and, consequently, antiinflammatory and immunoregulatory effects. Because NAS also increased IDO1 activity in peripheral blood mononuclear cells of a significant proportion of MS patients, our data may set the basis for the development of IDO1 PAMs as first-in-class drugs in autoimmune/neuroinflammatory diseases.

Published
2020

13. A Relay Pathway between Arginine and Tryptophan Metabolism Confers Immunosuppressive Properties on Dendritic Cells

Author

Mondanelli, G, Bianchi, R, Pallotta, MT, Orabona, C, Albini, E, Iacono, A, Belladonna, ML, Vacca, C, Fallarino, F, Macchiarulo, A, Ugel, S, Bronte, V, Gevi, F, Zolla, L, Verhaar, Auke, Peppelenbosch, Maikel, Mazza, EMC, Bicciato, S, Laouar, Y, Santambrogio, L, Puccetti, P, Volpi, C, Grohmann, U, Mondanelli, G, Bianchi, R, Pallotta, MT, Orabona, C, Albini, E, Iacono, A, Belladonna, ML, Vacca, C, Fallarino, F, Macchiarulo, A, Ugel, S, Bronte, V, Gevi, F, Zolla, L, Verhaar, Auke, Peppelenbosch, Maikel, Mazza, EMC, Bicciato, S, Laouar, Y, Santambrogio, L, Puccetti, P, Volpi, C, and Grohmann, U

Published
2017

14. IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII

Author

Matino, D, Gargaro, M, Santagostino, E, Di Minno, Mnd, Castaman, G, Morfini, M, Rocino, A, Mancuso, Me, Di Minno, G, Coppola, A, Talesa, Vn, Volpi, C, Vacca, C, Orabona, C, Iannitti, R, Mazzucconi, Mg, Santoro, C, Tosti, A, Chiappalupi, S, Sorci, G, Tagariello, G, Belvini, D, Radossi, P, Landolfi, Raffaele, Fuchs, D, Boon, L, Pirro, M, Marchesini, E, Grohmann, U, Puccetti, P, Iorio, A, Fallarino, F., Landolfi, Raffaele (ORCID:0000-0002-7913-8576), Matino, D, Gargaro, M, Santagostino, E, Di Minno, Mnd, Castaman, G, Morfini, M, Rocino, A, Mancuso, Me, Di Minno, G, Coppola, A, Talesa, Vn, Volpi, C, Vacca, C, Orabona, C, Iannitti, R, Mazzucconi, Mg, Santoro, C, Tosti, A, Chiappalupi, S, Sorci, G, Tagariello, G, Belvini, D, Radossi, P, Landolfi, Raffaele, Fuchs, D, Boon, L, Pirro, M, Marchesini, E, Grohmann, U, Puccetti, P, Iorio, A, Fallarino, F., and Landolfi, Raffaele (ORCID:0000-0002-7913-8576)

Abstract

The development of inhibitory antibodies to factor VIII (FVIII) is a major obstacle in using this clotting factor to treat individuals with hemophilia A. Patients with a congenital absence of FVIII do not develop central tolerance to FVIII, and therefore, any control of their FVIII-reactive lymphocytes relies upon peripheral tolerance mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulatory enzyme that supports Treg function and peripheral tolerance in adult life. Here, we investigated the association between IDO1 competence and inhibitor status by evaluating hemophilia A patients harboring F8-null mutations that were either inhibitor negative (n = 50) or positive (n = 50). We analyzed IDO1 induction, expression, and function for any relationship with inhibitor occurrence by multivariable logistic regression and determined that defective TLR9-mediated activation of IDO1 induction is associated with an inhibitor-positive status. Evaluation of experimental hemophilic mouse models with or without functional IDO1 revealed that tryptophan metabolites, which result from IDO1 activity, prevent generation of anti-FVIII antibodies. Moreover, treatment of hemophilic animals with a TLR9 agonist suppressed FVIII-specific B cells by a mechanism that involves IDO1-dependent induction of Tregs. Together, these findings indicate that strategies aimed at improving IDO1 function should be further explored for preventing or eradicating inhibitors to therapeutically administered FVIII protein.

Published
2015

18. Reinstalling immune regulatory tryptophan catabolism in juvenile diabetes via interleukin 6 receptor blockade

Author

Mondanelli, G., Orabona, C., Pallotta, Mt, Albini, E., Volpi, C., and Grohmann, U.

Subjects
Immunology, Immunology and Allergy
Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunoregulatory enzyme that catalyses the degradation of the essential amino acid tryptophan (Trp) along the kynurenines pathway. Significant changes in systemic Trp catabolism have been reported in many diseases, including cancer and autoimmunity. In female nonobese (NOD) mice, IDO1 expression and hence immune tolerance to pancreatic b-cell autoantigens are defective in conventional dendritic cells stimulated with IFN-γ, the main IDO1 inducer. Although the evidences in NOD mice suggest that IDO1 function is impaired, the existence of the IDO1 defect in human T1D (type 1 diabetes) has not been proven yet. Here we monitored the IDO1 expression and activity in peripheral blood mononuclear cells (PBMCs) of children with T1D as compare to age-matched control subject, in response to IFN- γ. Results from kynurenines assay and Western blot analysis demonstrate that the majority of patients with T1D is characterized by defective Trp catabolism. Moreover, our data indicated that this defect is mainly imputable to a SOCS3-mediated, dysregulated IL-6 signaling that would favor IDO1 proteasomal degradation in inflammatory environments, i.e. dominated by IFN-γ. To confirm this, we measured IDO1 expression and activity in PBMCs co-incubated with IFN-γ and Tocilizumab (TCZ), a licensed IL-6 receptor blocker. Results showed that TCZ is able to restore normal levels of IDO1 catalytic activity in response to IFN-γ in approximately 30% of the examined T1D population. Besides further confirming the heterogeneity of the disease, our data indicate the existence of a subset of individuals with T1D who may gain clinical benefit in restoring immunoregulatory mechanisms by treatment with tocilizumab.

Published
2016
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20. Control of immune response by amino acid metabolism

Author

Grohmann, U. and Bronte, Vincenzo

Subjects
tolerance, Adaptive Immunity, Amino Acids, Animals, Cell Survival, Humans, Immunity, Innate, Indoleamine-Pyrrole 2, 3, Dioxygenase, Lymphocytes, Phylogeny, Tryptophan, T cells, amino acid metabolism, monocytes, macrophages, dendritic cells, nitric oxide, Immunity, Innate, Indoleamine-Pyrrole 2,3,-Dioxygenase
Abstract

The interaction between pathogenic microorganisms and their hosts is regulated by reciprocal survival strategies, including competition for essential nutrients. Though paradoxical, mammalian hosts have learned to take advantage of amino acid catabolism for controlling pathogen invasion and, at the same time, regulating their own immune responses. In this way, ancient catabolic enzymes have acquired novel functions and evolved into new structures with highly specialized functions, which go beyond the struggle for survival. In this review, we analyze the evidence supporting a critical role for the metabolism of various amino acids in regulating different steps of both innate and adaptive immunity.

Published
2010

26. O6-alkylguanine-DNA alkyltransferase attenuates triazene-induced cytotoxicity and tumor cell immunogenicity in murine L1210 leukemia

Author

Graziani, G., Faraoni, I., Grohmann, U., Roberta Bianchi, Binaglia, L., Margison, G. P., Watson, A. J., Orlando, L., Bonmassar, E., and D Atri, S.

Subjects
Molecular Sequence Data, O6-alkylguanine-DNA alkyltransferase, L1210 leukemia, tumor immunogenicity, Antineoplastic Agents, Transfection, O(6)-Methylguanine-DNA Methyltransferase, Mice, Animals, Humans, Inbred DBA, Leukemia L1210, Inbred BALB C, DNA Primers, Cultured, Base Sequence, Triazines, Settore BIO/14, Dacarbazine, DNA Damage, Mice, Inbred BALB C, Mice, Inbred DBA, Tumor Cells, Cultured, Antineoplastic Agents, Alkylating, Methyltransferases, Nitrogen Mustard Compounds, Alkylating, Tumor Cells
Published
1995

29. IL-9 protects mice from Gram-negative bacterial shock : suppression of TNF-alpha, IL-12, and IFN-gamma, and induction of IL-10.

Author

UCL - MD/MIGE - Département de microbiologie, d'immunologie et de génétique, Grohmann, U, Van Snick, J, Campanile, F, Silla, S, Giampietri, A, Vacca, C, Renauld, Jean-Christophe, Fioretti, M C, Puccetti, P, UCL - MD/MIGE - Département de microbiologie, d'immunologie et de génétique, Grohmann, U, Van Snick, J, Campanile, F, Silla, S, Giampietri, A, Vacca, C, Renauld, Jean-Christophe, Fioretti, M C, and Puccetti, P

Abstract

IL-9 is a T cell-derived cytokine that, similar to the Th2 cytokines IL-4 and IL-10, has been implicated in the response to parasitic infections, allergy, and inflammatory processes. Because both IL-4 and IL-10 can confer protection to mice from septic shock, we investigated whether IL-9 may also be capable of conferring resistance on recipients of an otherwise lethal challenge with Pseudomonas aeruginosa. Prophylactic injections of rIL-9 appeared to be most effective in preventing the onset of a lethal shock, according to a pattern that was both dose dependent and time dependent. The protective effect of IL-9 was correlated with marked decreases in the production of the inflammatory mediators TNF-alpha, IL-12, and IFN-gamma, as well as the induction of the anti-inflammatory cytokine IL-10. Sustained levels of IL-9-specific transcripts could be detected in the spleens of mice recovering from sublethal P. aeruginosa infection. Therefore, IL-9 may be protective in septic shock via a rather unique mechanism involving a complex modulation of inflammatory and anti-inflammatory mediators.

Published
2000

35. T cell apoptosis by tryptophan catabolism

Author

Fallarino, F, primary, Grohmann, U, additional, Vacca, C, additional, Bianchi, R, additional, Orabona, C, additional, Spreca, A, additional, Fioretti, M C, additional, and Puccetti, P, additional

Published
2002
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45. Immunopharmacology of antitumor agents

Author

D'Atri, S., primary, Graziani, G., additional, Aquino, A., additional, Tentori, L., additional, Giuliani, A., additional, Puccetti, P., additional, Grohmann, U., additional, Fioretti, M.C., additional, and Bonmassar, E., additional

Published
1995
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