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51. PLGA nanoparticles enhance the expression of retinaldehyde dehydrogenase enzymes in dendritic cells and induce FoxP3(+) T-cells in vitro.

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Keijzer, C., Spiering, R., Silva, A.L., van Eden, W., Jiskoot, W., Vervelde, L., Broere, F., Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Keijzer, C., Spiering, R., Silva, A.L., van Eden, W., Jiskoot, W., Vervelde, L., and Broere, F.

Published
2013

53. Peritoneal cavity B-1a cells promote peripheral CD4(+) T-cell activation.

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, Dep Infectieziekten Immunologie, Margry, B., Wieland, W.H., van Kooten, P., van Eden, W., Broere, F., Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, Dep Infectieziekten Immunologie, Margry, B., Wieland, W.H., van Kooten, P., van Eden, W., and Broere, F.

Published
2013

54. Tandem repeats modify the structure of the canine CD1D gene

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Geneeskunde van gezelschapsdieren, Dep Infectieziekten Immunologie, Looringh van Beeck, F.A., Leegwater, P.A.J., Herrmann, T., Broere, F., Rutten, V.P.M.G., Willemse, T., van Rhijn, I., Risk Assessment of Toxic and Immunomodulatory Agents, Geneeskunde van gezelschapsdieren, Dep Infectieziekten Immunologie, Looringh van Beeck, F.A., Leegwater, P.A.J., Herrmann, T., Broere, F., Rutten, V.P.M.G., Willemse, T., and van Rhijn, I.

Published
2013

55. APL-1, an altered peptide ligand derived from human heat-shock protein 60, selectively induces apoptosis in activated CD4+ CD25+ T cells from peripheral blood of rheumatoid arthritis patients

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Barberá, A., Lorenzo, N., Mazola, Y., Falcón, V., Torres, A.M., Hernández, M.I., Hernández, M.V., Margry, B., de Groot, A.M., van Roon, J.A.G., van der Zee, R., Broere, F., van Eden, W., Padrón, G., Domínguez, M.D.C., Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Barberá, A., Lorenzo, N., Mazola, Y., Falcón, V., Torres, A.M., Hernández, M.I., Hernández, M.V., Margry, B., de Groot, A.M., van Roon, J.A.G., van der Zee, R., Broere, F., van Eden, W., Padrón, G., and Domínguez, M.D.C.

Published
2013

56. The anti-inflammatory mechanisms of Hsp70

Author

Borges, T.J., Wieten, L., van Herwijnen, M.J.C., Broere, F., van der Zee, R., Bonorino, C., van Eden, W., Borges, T.J., Wieten, L., van Herwijnen, M.J.C., Broere, F., van der Zee, R., Bonorino, C., and van Eden, W.

Published
2012

59. Tolerogenic dendritic cells that inhibit autoimmune arthritis can be induced by a combination of carvacrol and thermal stress

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Spiering, R., van der Zee, R., Wagenaar, J.P.A., Kapetis, F., Zolezzi, F., van Eden, W., Broere, F., Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Spiering, R., van der Zee, R., Wagenaar, J.P.A., Kapetis, F., Zolezzi, F., van Eden, W., and Broere, F.

Published
2012

60. Regulatory T cells that recognize a ubiquitous stress-inducible self-antigen are long-lived suppressors of autoimmune arthritis

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, Dep Infectieziekten Immunologie, van Herwijnen, M.J.C., Wieten, L., van der Zee, R., van Kooten, P.J., Wagenaar, J.P.A., Hoek, A., den Braber, A.J., Anderton, S.M., Singh, M., Meiring, H.D., van Els, C.A.C.M., van Eden, W., Broere, F., Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, Dep Infectieziekten Immunologie, van Herwijnen, M.J.C., Wieten, L., van der Zee, R., van Kooten, P.J., Wagenaar, J.P.A., Hoek, A., den Braber, A.J., Anderton, S.M., Singh, M., Meiring, H.D., van Els, C.A.C.M., van Eden, W., and Broere, F.

Published
2012

62. The anti-inflammatory mechanisms of Hsp70

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Borges, T.J., Wieten, L., van Herwijnen, M.J.C., Broere, F., van der Zee, R., Bonorino, C., van Eden, W., Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Borges, T.J., Wieten, L., van Herwijnen, M.J.C., Broere, F., van der Zee, R., Bonorino, C., and van Eden, W.

Published
2012

63. A case of mistaken identity: HSPs are no DAMPs but DAMPERs

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, van Eden, W., Spiering, R., Broere, F., van der Zee, R., Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, van Eden, W., Spiering, R., Broere, F., and van der Zee, R.

Published
2012

64. PLGA, PLGA-TMC and TMC-TPP nanoparticles differentially modulate the outcome of nasal vaccination by inducing tolerance or enhancing humoral immunity

Author

Advanced drug delivery systems/drug targeting, Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Dep Farmaceutische wetenschappen, Keijzer, C., Slutter, B., van der Zee, R., Jiskoot, W., van Eden, W., Broere, F., Advanced drug delivery systems/drug targeting, Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Dep Farmaceutische wetenschappen, Keijzer, C., Slutter, B., van der Zee, R., Jiskoot, W., van Eden, W., and Broere, F.

Published
2011

65. Improving solubitity and chemical stability of natural compounds for medicinal use by incorporation into liposomes.

Author

Advanced drug delivery systems/drug targeting, Biomolecular Analysis, Farmaceutische Analyse, Pharmaceutics, Risk Assessment of Toxic and Immunomodulatory Agents, Dep Farmaceutische wetenschappen, Sub Drug targeting, Afd Pharmaceutics, Sub Biomolecular analysis, Dep Infectieziekten Immunologie, Gomes Coimbra, M.J., Isacchi, B., van Bloois, L., Sastre Torano, J., Ket, A., Wu, X., Broere, F., Metselaar, J.M., Rijcken, C.J.F., Storm, G., Bilia, R., Schiffelers, R.M., Advanced drug delivery systems/drug targeting, Biomolecular Analysis, Farmaceutische Analyse, Pharmaceutics, Risk Assessment of Toxic and Immunomodulatory Agents, Dep Farmaceutische wetenschappen, Sub Drug targeting, Afd Pharmaceutics, Sub Biomolecular analysis, Dep Infectieziekten Immunologie, Gomes Coimbra, M.J., Isacchi, B., van Bloois, L., Sastre Torano, J., Ket, A., Wu, X., Broere, F., Metselaar, J.M., Rijcken, C.J.F., Storm, G., Bilia, R., and Schiffelers, R.M.

Published
2011

66. CD62LnegCD38+ expression on circulating CD4+ T cells identifies mucosally differentiated cells in protein fed mice and in human celiac disease patients and controls.

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Fleur du Pre, M., van Berkel, L.A., Raki, M., van Leeuwen, M., de Ruiter, L.F., Broere, F., ter Borg, M.N.D., Lund, F.E., Escher, J.C., Lundin, K.E.A., Sollid, L.M., Kraal, G., Nieuwenhuis, E.E.S., Samson, J.N., Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Fleur du Pre, M., van Berkel, L.A., Raki, M., van Leeuwen, M., de Ruiter, L.F., Broere, F., ter Borg, M.N.D., Lund, F.E., Escher, J.C., Lundin, K.E.A., Sollid, L.M., Kraal, G., Nieuwenhuis, E.E.S., and Samson, J.N.

Published
2011

67. Critical proinflammatory role of thymic stromal lymphopoietin and its receptor in experimental autoimmune arthritis.

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Hartgring, S.A.Y., Willis, C.R., Dean, C.E., Broere, F., van Eden, W., Bijlsma, J.W.J., Lafeber, F.P.J.G., van Roon, J.A.G., Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Hartgring, S.A.Y., Willis, C.R., Dean, C.E., Broere, F., van Eden, W., Bijlsma, J.W.J., Lafeber, F.P.J.G., and van Roon, J.A.G.

Published
2011

68. Heat shock proteins are no DAMPs, rather 'DAMPERs'

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Broere, F., van der Zee, R., van Eden, W., Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Broere, F., van der Zee, R., and van Eden, W.

Published
2011

69. Hsp70 expression and induction as a readout for detection of immune modulatory components in food.

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Wieten, L., van der Zee, R., Goedemans, R., Sijtsma, J., Serafini, M., Lubsen, N.H., van Eden, W., Broere, F., Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Wieten, L., van der Zee, R., Goedemans, R., Sijtsma, J., Serafini, M., Lubsen, N.H., van Eden, W., and Broere, F.

Published
2010

70. Nasal vaccination with N-trimethyl chitosan and PLGA based nanoparticles: Nanoparticle characteristics determine quality and strength of the antibody response in mice against the encapsulated antigen.

Author

Advanced drug delivery systems/drug targeting, Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Dep Farmaceutische wetenschappen, Slutter, B., Bal, S., Keijzer, C., Mallants, R., Hagenaars, N., Que, I., Kaijzel, E.L., van Eden, W., Augustijns, P., Lowik, C., Bouwstra, J.A., Broere, F., Jiskoot, W., Advanced drug delivery systems/drug targeting, Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Dep Farmaceutische wetenschappen, Slutter, B., Bal, S., Keijzer, C., Mallants, R., Hagenaars, N., Que, I., Kaijzel, E.L., van Eden, W., Augustijns, P., Lowik, C., Bouwstra, J.A., Broere, F., and Jiskoot, W.

Published
2010

71. A novel heat-shock protein coinducer boosts stress protein Hsp70 to activate T cell regulation of inflammation in autoimmune arthritis.

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Wieten, L., van der Zee, R., Spiering, R., Wagenaar-Hilbers, J.P.A., van Kooten, P.J., Broere, F., van Eden, W., Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Wieten, L., van der Zee, R., Spiering, R., Wagenaar-Hilbers, J.P.A., van Kooten, P.J., Broere, F., and van Eden, W.

Published
2010

72. IL-10 is critically involved in mycobacterial HSP70 induced suppression of proteoglycan-induced arthritis.

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Wieten, L., Berlo, S.E., ten Brink, C.B.M., van Kooten, P.J., Singh, M., van der Zee, R., Glant, T., Broere, F., van Eden, W., Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Wieten, L., Berlo, S.E., ten Brink, C.B.M., van Kooten, P.J., Singh, M., van der Zee, R., Glant, T., Broere, F., and van Eden, W.

Published
2009

73. Cartilage proteoglycan-specific T cells as vectors of immunomodulatory biologicals in chronic proteoglycan-induced arthritis.

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, Dep Infectieziekten Immunologie, Guichelaar, T., ten Brink, C.B.M., van Kooten, P.J., Berlo, S.E., Lafeber, F.P.J.G., Broeren, C.P.M., van Eden, W., Hauet-Broere, F., Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, Dep Infectieziekten Immunologie, Guichelaar, T., ten Brink, C.B.M., van Kooten, P.J., Berlo, S.E., Lafeber, F.P.J.G., Broeren, C.P.M., van Eden, W., and Hauet-Broere, F.

Published
2008

74. Autoantigen-specific IL-10-transduced T cells suppress chronic arthritis by promoting the endogenous regulatory IL-10 response.

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, Dep Infectieziekten Immunologie, Guichelaar, T., ten Brink, C.B.M., van Kooten, P.J., Berlo, S.E., Broeren, C.P.M., van Eden, W., Hauet-Broere, F., Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, Dep Infectieziekten Immunologie, Guichelaar, T., ten Brink, C.B.M., van Kooten, P.J., Berlo, S.E., Broeren, C.P.M., van Eden, W., and Hauet-Broere, F.

Published
2008

75. Two canine CD1a proteins are differentially expressed in skin.

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, Dep Infectieziekten Immunologie, Looringh van Beeck, F.A., Zajonc, D.M., Moore, P.F., Schlotter, Y.M., Broere, F., Rutten, V.P.M.G., Willemse, A., van Rhijn, I., Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, Dep Infectieziekten Immunologie, Looringh van Beeck, F.A., Zajonc, D.M., Moore, P.F., Schlotter, Y.M., Broere, F., Rutten, V.P.M.G., Willemse, A., and van Rhijn, I.

Published
2008

76. Targeting inflammation with autoantigen-specific T cells.

Author

Strategic Infection Biology, Dep Infectieziekten Immunologie, van Eden, Willem, Broere, F., Guichelaar, T., Prakken, A.B.J., Strategic Infection Biology, Dep Infectieziekten Immunologie, van Eden, Willem, Broere, F., Guichelaar, T., and Prakken, A.B.J.

Published
2008

79. Cell stress induced HSP are targets of regulatory T cells: a role for HSP inducing compounds as anti-inflammatory immuno-modulators?

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Wieten, L., Hauet-Broere, F., van der Zee, R., Klein Koerkamp, E., Wagenaar-Hilbers, J.P.A., van Eden, W., Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Wieten, L., Hauet-Broere, F., van der Zee, R., Klein Koerkamp, E., Wagenaar-Hilbers, J.P.A., and van Eden, W.

Published
2007

81. Heat shock proteins induce T cell regulation of chronic inflammation.

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, Dep Infectieziekten Immunologie, Hauet-Broere, F., Wieten, L., Guichelaar, T., van Berlo, J., van der Zee, R., van Eden, W., Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, Dep Infectieziekten Immunologie, Hauet-Broere, F., Wieten, L., Guichelaar, T., van Berlo, J., van der Zee, R., and van Eden, W.

Published
2006

82. Increased arthritis susceptibility in cartilage proteoglycan-specific T cell receptor-transgenic mice.

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, Dep Infectieziekten Immunologie, Berlo, S.E., Guichelaar, T., ten Brink, C.B.M., van Kooten, P.J., Hauet-Broere, F., Ludanyi, K., van Eden, W., Broeren, C.P.M., Glant, T., Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, Dep Infectieziekten Immunologie, Berlo, S.E., Guichelaar, T., ten Brink, C.B.M., van Kooten, P.J., Hauet-Broere, F., Ludanyi, K., van Eden, W., Broeren, C.P.M., and Glant, T.

Published
2006

83. Stress proteins are used by the immune system for cognate interactions with anti-inflammatory regulatory T cells

Author

van Eden, W., van Herwijnen, M.J.C., Wagenaar, J, van Kooten, P., Broere, F., van der Zee, R., Advances in Veterinary Medicine, Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Faculteit Diergeneeskunde, Advances in Veterinary Medicine, Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, and Faculteit Diergeneeskunde

Subjects
T cell, Molecular Sequence Data, Biophysics, Arthritis, Autoimmunity, chemical and pharmacologic phenomena, Biology, medicine.disease_cause, Major histocompatibility complex, T-Lymphocytes, Regulatory, Biochemistry, Epitopes, 03 medical and health sciences, 0302 clinical medicine, Immune system, Structural Biology, Genetics, medicine, Animals, Humans, HSP, Amino Acid Sequence, IL-2 receptor, Molecular Biology, Heat-Shock Proteins, HSP70, 030304 developmental biology, Inflammation, 0303 health sciences, MHC class II, Stress protein, FOXP3, Cell Biology, medicine.disease, 3. Good health, Treg, medicine.anatomical_structure, Immunology, biology.protein, Inflammation Mediators, HSP60, 030215 immunology
Abstract

Since the initial discovery of the protective role of heat shock protein (HSP) 60 in arthritis, T cell recognition of endogenous HSP was found to be one of the possible underlying mechanisms. Recently we have uncovered potent disease-suppressive Tregs (anti-inflammatory immunosuppressive T cells) recognizing HSP70 self-antigens, and enabling selective targeting of such Tregs to inflamed tissues. HSP70 is a major contributor to the major histocompatibility complex (MHC) Class II ligandome and we have shown that a conserved HSP70-epitope (B29) is abundantly present in murine MHC Class II. Upon transfer, B29-induced CD4+CD25+Foxp3+T cells suppressed established proteoglycan-induced arthritis (PGIA) in mice. These self-antigen specific Tregs were activated in vivo and as little as 4.000 cells sufficed to fully inhibit arthritis. Furthermore, in vivo depletion of transferred Tregs abrogated disease suppression. Given that B29 can be presented by most human MHC class II molecules and that B29 inhibited arthritis in HLA-DQ8 (human MHC) transgenic mice, we feel that therapeutic vaccination with selected HSP peptides can be an effective route for induction of anti-inflammatory Tregs as a novel intervention in chronic inflammatory diseases.

Published
2013

84. New cohorts of naive T cells exacerbate ongoing allergy but can be suppressed by regulatory T cells

Author

Immunofarmacologie van het respiratoire en gastrointestinale systemen, Faculteit Diergeneeskunde, Dep Farmaceutische wetenschappen, Hauet-Broere, F., Unger, W.W.J., van Berkel, L.A., Garssen, J., Hoijer, M.A., Kraal, G., Samsom, J.N., Immunofarmacologie van het respiratoire en gastrointestinale systemen, Faculteit Diergeneeskunde, Dep Farmaceutische wetenschappen, Hauet-Broere, F., Unger, W.W.J., van Berkel, L.A., Garssen, J., Hoijer, M.A., Kraal, G., and Samsom, J.N.

Published
2005

87. Heat shock proteins are therapeutic targets in autoimmune diseases and other chronic inflammatory conditions

Author

Keijzer, C., Wieten, L., van Herwijnen, M.J.C., van der Zee, R., van Eden, W., Broere, F., Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Risk Assessment of Toxic and Immunomodulatory Agents, and Dep Infectieziekten Immunologie

Subjects
Clinical Biochemistry, Disease, medicine.disease_cause, T-Lymphocytes, Regulatory, Autoimmune Diseases, Autoimmunity, 03 medical and health sciences, 0302 clinical medicine, Heat shock protein, Drug Discovery, medicine, Humans, Stress Proteins, Heat-Shock Proteins, 030304 developmental biology, Inflammation, Pharmacology, 0303 health sciences, business.industry, 3. Good health, Chronic disease, Gene Expression Regulation, Expert opinion, Chronic Disease, Immunology, Molecular Medicine, business, 030215 immunology
Abstract

Exploitation of antigen-specific regulatory T cells (Tregs) as critical regulators in the control of chronic inflammatory diseases is hampered by the obscure nature of most disease-relevant autoantigens. Heat shock proteins (Hsp) are possible targets for Tregs due to their enhanced expression in inflamed (stressed) tissues and there is evidence that Hsp can induce anti-inflammatory immunoregulatory T-cell responses.Recent publications showing that exogenous administration of stress proteins has induced immunoregulation in various models of inflammatory disease have also been shown to be effective in first clinical trials in humans. Now, in the light of a growing interest in T-cell regulation, it is of interest to further explore the mechanisms through which Hsp can be utilized to trigger immunoregulatory pathways, capable of suppressing such a wide and diversified spectrum of inflammatory diseases.Therapeutic approaches via exploitation of antigen-specific Tregs will benefit from tailor-made combination therapies. Combining current therapeutic approaches with Hsp-specific therapies thereby enhancing natural immune regulation might expedite the entry of antigen-specific regulatory T cells into the therapeutic arsenal of the anti-inflammatory therapeutics.

Published
2012
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88. Heat shock proteins are no DAMPs, rather 'DAMPERs'

Author

Broere, F., van der Zee, R., van Eden, W., Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Risk Assessment of Toxic and Immunomodulatory Agents, and Dep Infectieziekten Immunologie

Subjects
0303 health sciences, 03 medical and health sciences, History, 0302 clinical medicine, Chemistry, 030220 oncology & carcinogenesis, Heat shock protein, Innate immunology, Computational biology, 030304 developmental biology, Computer Science Applications, Education, Damper
Published
2011
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90. A novel heat-shock protein coinducer boosts stress protein Hsp70 to activate T cell regulation of inflammation in autoimmune arthritis

Author

Wieten, L., van der Zee, R., Spiering, R., Wagenaar-Hilbers, J.P.A., van Kooten, P.J., Broere, F., van Eden, W., Risk Assessment of Toxic and Immunomodulatory Agents, Dep Infectieziekten Immunologie, Risk Assessment of Toxic and Immunomodulatory Agents, and Dep Infectieziekten Immunologie

Subjects
CD4-Positive T-Lymphocytes, T cell, T-Lymphocytes, Immunology, Arthritis, Inflammation, Biology, Lymphocyte Activation, Polymerase Chain Reaction, 03 medical and health sciences, Mice, Peyer's Patches, 0302 clinical medicine, Immune system, Rheumatology, Heat shock protein, medicine, Immunology and Allergy, Animals, Humans, Pharmacology (medical), HSP70 Heat-Shock Proteins, IL-2 receptor, RNA, Messenger, 030304 developmental biology, 0303 health sciences, Mice, Inbred BALB C, Macrophages, FOXP3, Dendritic Cells, medicine.disease, Arthritis, Experimental, 3. Good health, Hsp70, Cell biology, Interleukin-10, medicine.anatomical_structure, 030220 oncology & carcinogenesis, CD4 Antigens, Monoterpenes, Cymenes, Female, medicine.symptom
Abstract

Objective Stress proteins, such as members of the heat-shock protein (HSP) family, are up-regulated by cells in inflamed tissue and can be viewed functionally as “biomarkers” for the immune system to monitor inflammation. Exogenous administration of stress proteins has induced immunoregulation in various models of inflammation and has also been shown to be effective in clinical trials in humans. This study was undertaken to test the hypothesis that boosting of endogenous HSP expression can restore effective immunoregulation through T cells specific for stress proteins. Methods Stress protein expression was manipulated in vivo and in vitro with a food component (carvacrol), and immune recognition of stress proteins was studied. Results Carvacrol, a major compound in the oil of many Origanum species, had a notable capacity to coinduce cellular Hsp70 expression in vitro and, upon intragastric administration, in Peyer's patches of mice in vivo. As a consequence, carvacrol specifically promoted T cell recognition of endogenous Hsp70, as demonstrated in vitro by the activation of an Hsp70-specific T cell hybridoma and in vivo by amplified T cell responses to Hsp70. Carvacrol administration also increased the number of CD4+CD25+FoxP3+ T cells, systemically in the spleen and locally in the joint, and almost completely suppressed proteoglycan-induced experimental arthritis. Furthermore, protection against arthritis could be transferred with T cells isolated from carvacrol-fed mice. Conclusion These findings illustrate that a food component can boost protective T cell responses to a self stress protein and down-regulate inflammatory disease, i.e., that the immune system can respond to diet.

Published
2010

92. Tandem repeats modify the structure of the canine CD1 D gene.

Author

Looringh van Beeck, F. A., Leegwater, P. A. J., Herrmann, T., Broere, F., Rutten, V. P. M. G., Willemse, T., and Rhijn, I.

Subjects
ANTIGENS, T cells, NUCLEOTIDES, SIGNAL peptides, PEPTIDES
Abstract

Among the CD1 proteins that present lipid antigens to T cells, CD1d is the only one that stimulates a population of T cells with an invariant T-cell receptor known as NKT cells. Sequencing of a 722 nucleotide gap in the dog ( Canis lupus familiaris) genome revealed that the canine CD1 D gene lacks a sequence homologous to exon 2 of human CD1 D, coding for the start codon and signal peptide. Also, the canine CD1D gene contains three different short tandem repeats that disrupt the expected gene structure. Because canine CD1 D cDNA lacks sequences homologous to human exon 2 and 3, the functionality of canine CD1d protein may be affected, and this could have consequences for the development and activation of canine NKT cells. [ABSTRACT FROM AUTHOR]

Published
2013
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94. Regulation of inflammation in canine species: a role for macrophages and Hsp70

Author

Qingkang Lyu, Eden, W. van, Broere, F., Sijts, E.J.A.M., and University Utrecht

Subjects
Chemistry, Macrophage polarization, medicine, Inflammation, Canine Species, medicine.symptom, Nf κb activation, Leucinostatin, health care economics and organizations, humanities, Hsp70, Cell biology, leucinostatin, canine retinal pigment epithelial cells, NF-κB activation, canine macrophage, M1 and M2 macrophages, macrophage polarization, 030D monocyte-like cell line
Abstract

Summary This thesis can be roughly divided into two parts. In the first three chapters, we discussed and studied the role of Hsp70 in retinal pigment epithelial (RPE) cells, and the innate and adaptive immune response. We reviewed the relationship of T cell-mediated diseases and HSPs, and pointed out that the induction of Hsp70 may contribute to therapeutic tolerance (chapter 2). Then, we explored a new Hsp70 co-inducer, leucinostatin, and its role in canine RPE cells (chapter 3). Further, we studied the anti-inflammatory effects of Hsp70 in canine macrophages (chapter 4). In the last two chapters, we focus on various differently activated canine macrophage subsets originating from both primary monocytes and a monocyte-like cell line (030D cell) (chapter 5 and 6). We successfully polarized canine monocyte-derived macrophages (MDMs) into M1 and M2 cells and thoroughly characterized their features (chapter 5). Meanwhile, we demonstrated that 030D cells can be differentiated into M1 and M2 macrophages and that each subset shares the characteristics of the corresponding canine monocyte-derived macrophage subset.

Published
2021

95. Targeting inflammation with autoantigen-specific T cells

Author

Guichelaar, T., Prakken, A.B.J., Strategic Infection Biology, Dep Infectieziekten Immunologie, van Eden, Willem, Broere, F., and University Utrecht

Abstract

Chronic autoimmune diseases are driven by cells that respond to tissue components of the body. Inflammation in diseases like rheumatoid arthritis, diabetes or multiple sclerosis, can be suppressed by drug therapy. However, the broad range of immunosuppressive action of these drugs often does not restrict to the autoimmune response, but increases the risk of serious infection. Therefore, therapies that restrict to suppression of only the auto-immune response need to be developed. CD4+ T cells that recognize cartilage are responsible for induction of arthritis because they direct their actions to cartilage in the joints. Such T cells are present in the joints of arthritis patients. Therefore, we hypothesized that T cells specific for the cartilage-derived antigen proteoglycan can be used to target arthritis with suppressive agents after introduction of genes that express suppressive agents in these T cells. For our studies we used cartilage proteoglycan-induced arthritis, which is a chronic arthritis in mice. This arthritis represents many features of rheumatoid arthritis, and is mediated by Th1 cells, B cells and antibodies. To enable studies on cartilage-specific T cells, we generated a transgenic mouse expressing a proteoglycan-specific T cell receptor on its T cells. Due to the high number of cartilage-specific T cells, transgenic mice were highly susceptible for arthritis. Moreover, the T cell response of transgenic mice with arthritis shifted to an excessive Th1-phenotype. Therefore, these transgenic mice were useful donors for arthritogenic CD4+ T cells. To explore gene therapy of inflammation with T cells, we provided proteoglycan-specific T cells with different genes encoding immunosuppressive proteins. The genes were isolated from mouse cells and inserted into T cells by retroviruses. Retroviral transduction of T cells resulted in up to 80% of cells expressing the transgenes (IL-4, IL-10, TNF-alpha-Receptor-Ig, IL-1 receptor antagonist). T cells expressing the inserted genes were sorted by flow cytometry and transferred to mice with arthritis. Especially T cells that were manipulated to express IL-10 were able to induce significant suppression of joint inflammation. Moreover, only the IL-10-producing T cells that expressed the cartilage-specific T cell receptor suppressed arthritis, indicating specificity of therapy. In addition, manipulated T cells suppressed production of pro-inflammatory proteins like TNF-alpha, IL-17, IL-2 and PG-specific IgG2a antibodies. Strikingly, we discovered that propagation of IL-10 production in cells of the treated recipient was the mechanism that was used by the transferred IL-10-producing T cells to suppress arthritis. Among the recipient’s cells, T cells and B cells were found to express increased levels of IL-10. Because interleukin-10 is an immunomodulatory cytokine expressed by cells in order to naturally prevent exacerbation of inflammation in healthy individuals, these results indicate that T cells producing IL-10 restore natural immunosuppressive immune responses in arthritis. In conclusion, manipulation of pro-inflammatory T cells that recognize tissue components is a powerful approach to specifically target inflammation in chronic autoimmune diseases. In addition, moving focus from suppression of pro-inflammatory mediators to propagation of immunosuppressive functions of cells may provide a more comprehensive insight in mechanisms that support specific regulatory capacities of the immune system.

Published
2008

96. Antiviral activity of cathelicidins against porcine epidemic diarrhea virus (PEDV): Mechanisms, and efficacy.

Author

Pashaie F, Hoornweg TE, Bikker FJ, Veenendaal T, Broere F, and Veldhuizen EJA

Abstract

Porcine epidemic diarrhea virus (PEDV) is a harmful coronavirus infecting pigs, which is resulting in substantial financial losses in the global pig industry. The lack of effective vaccines or treatments underscores the pressing need for new antiviral strategies. Antimicrobial peptides (AMPs), specifically cathelicidins such as LL-37, have demonstrated promising activity against a range of viruses. This study aims to elucidate the antiviral mechanisms of cathelicidins by examining their inhibitory capabilities against PEDV in vitro. Four pig-derived antimicrobial peptides (PMAP-36, PMAP-23, PR-39, and PG-1), together with chicken-derived CATH-B1 and human-derived LL-37 were analyzed for their anti-PEDV activity. Flow cytometry and fluorescent microscopy confirmed that LL-37 and CATH-B1 had strong inhibitory effects at non-toxic concentrations of 5 and 10 µM, significantly reducing GFP-PEDV infection of Vero cells both in co- and pre-incubation setups. In contrast, none of the porcine peptides exhibited any inhibitory effects, even at higher doses. Fluorogenic LL-37 was shown to enter VERO cells, indicative of a possible immunomodulatory antiviral mode of action. However, transmission electron microscopy clearly indicated that both LL-37 and CATH-B1 affected virus morphology and caused aggregation of viral particles, showing that peptide-virus interaction caused reduced virus infectivity. In conclusion, this analysis highlights the potential of LL-37 and CATH-B1 as inhibitors against PEDV, suggesting promising directions for innovative therapeutic antiviral strategies., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Published
2024
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97. Design of TOLERANT: phase I/II safety assessment of intranodal administration of HSP70/mB29a self-peptide antigen-loaded autologous tolerogenic dendritic cells in patients with rheumatoid arthritis.

Author

Stoppelenburg AJ, Schreibelt G, Koeneman B, Welsing P, Breman EJ, Lammers L, de Goede A, Duiveman-de Boer T, van Eden W, Leufkens P, de Vries IJM, Broere F, and van Laar JM

Subjects
Humans, Immune Tolerance, HSP70 Heat-Shock Proteins immunology, Male, Female, Clinical Trials, Phase I as Topic, Adult, Middle Aged, Clinical Trials, Phase II as Topic, Transplantation, Autologous, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid drug therapy, Arthritis, Rheumatoid therapy, Dendritic Cells immunology, Autoantigens immunology
Abstract

Introduction: In rheumatoid arthritis (RA), immunosuppressive therapies may achieve symptomatic relief, but do not induce long-term, drug-free remission. Meanwhile, the lifelong use of immunosuppressive drugs confers increased risk for malignancy and infections. As such, there is an unmet need for novel treatments that selectively target the pathogenic immune response in RA by inducing tolerance to autoantigens. Autologous cell therapy using antigen-loaded tolerogenic dendritic cells (tolDCs) aims to reinstate autoantigen-specific immunological tolerance in RA and could potentially meet this need., Methods and Analysis: We report here the design of the phase I/II, investigator-initiated, open-label, dose-escalation trial TOLERANT. In this study, we will evaluate the intranodal administration of tolDCs in patients with RA that are in remission under immunosuppressive therapy. The tolDCs in this trial are loaded with the heat shock protein 70-derived peptide mB29a, which is an effective surrogate autoantigen in animal models of arthritis. Within this study, three dose-escalation cohorts (two intranodal injections of 5×10 6 , 10×10 6 and 15×10 6 tolDCs), each consisting of three patients, are evaluated to identify the highest safe dose (recommended dose), and an extension cohort of nine patients will be treated with the recommended dose. The (co-)primary endpoints of this study are safety and feasibility, which we assess by the number of AEs and the successful production of tolDCs. The secondary endpoints include the immunological effects of the treatment, which we assess with a variety of high-dimensional and antigen-specific immunological assays. Clinical effects are exploratory outcomes., Ethics and Dissemination: Ethical approval for this study has been obtained from the Netherlands Central Committee on Research Involving Human Subjects. The outcomes of the trial will be disseminated through publications in open-access, peer-reviewed scientific journals, scientific conferences and to patient associations., Trial Registration Numbers: NCT05251870; 2019-003620-20 (EudraCT); NL71296.000.20 (CCMO register)., Competing Interests: Competing interests: Trajectum Pharma B.V. has licensed IP relating to the B29 antigen from Utrecht University. AJS, FB, WvE and PL have a financial interest in Trajectum Pharma B.V. The other authors declare that they have no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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98. Antimicrobial and immunomodulatory activities of porcine cathelicidin Protegrin-1.

Author

Javed A, Oedairadjsingh T, Ludwig IS, Wood TM, Martin NI, Broere F, Weingarth MH, and Veldhuizen EJA

Subjects
Animals, Mice, Anti-Infective Agents pharmacology, Immunologic Factors pharmacology, RAW 264.7 Cells, Swine, Antimicrobial Cationic Peptides pharmacology, Cathelicidins, Lipopolysaccharides metabolism, Macrophages immunology, Macrophages drug effects, Phagocytosis drug effects
Abstract

Antimicrobial peptides (AMPs) are a promising alternative to antibiotics in the fight against multi-drug resistant and immune system-evading bacterial infections. Protegrins are porcine cathelicidins which have been identified in porcine leukocytes. Protegrin-1 is the best characterized family member and has broad antibacterial activity by interacting and permeabilizing bacterial membranes. Many host defense peptides (HDPs) like LL-37 or chicken cathelicidin 2 (CATH-2) have also been shown to have protective biological functions during infections. In this regard, it is interesting to study if Protegrin-1 has the immune modulating potential to suppress unnecessary immune activation by neutralizing endotoxins or by influencing the macrophage functionality in addition to its direct antimicrobial properties. This study showed that Protegrin-1 neutralized lipopolysaccharide- (LPS) and bacteria-induced activation of RAW macrophages by binding and preventing LPS from cell surface attachment. Furthermore, the peptide treatment not only inhibited bacterial phagocytosis by murine and porcine macrophages but also interfered with cell surface and intracellular bacterial survival. Lastly, Protegrin-1 pre-treatment was shown to inhibit the amastigote survival in Leishmania infected macrophages. These experiments describe an extended potential of Protegrin-1's protective role during microbial infections and add to the research towards clinical application of cationic AMPs., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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99. Deciphering metabolic crosstalk in context: lessons from inflammatory diseases.

Author

Verheijen FWM, Tran TNM, Chang JC, Broere F, Zaal EA, and Berkers CR

Subjects
Humans, Animals, Metabolomics methods, Single-Cell Analysis, Energy Metabolism, Inflammation metabolism, Inflammation pathology
Abstract

Metabolism plays a crucial role in regulating the function of immune cells in both health and disease, with altered metabolism contributing to the pathogenesis of cancer and many inflammatory diseases. The local microenvironment has a profound impact on the metabolism of immune cells. Therefore, immunological and metabolic heterogeneity as well as the spatial organization of cells in tissues should be taken into account when studying immunometabolism. Here, we highlight challenges of investigating metabolic communication. Additionally, we review the capabilities and limitations of current technologies for studying metabolism in inflamed microenvironments, including single-cell omics techniques, flow cytometry-based methods (Met-Flow, single-cell energetic metabolism by profiling translation inhibition (SCENITH)), cytometry by time of flight (CyTOF), cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq), and mass spectrometry imaging. Considering the importance of metabolism in regulating immune cells in diseased states, we also discuss the applications of metabolomics in clinical research, as well as some hurdles to overcome to implement these techniques in standard clinical practice. Finally, we provide a flowchart to assist scientists in designing effective strategies to unravel immunometabolism in disease-relevant contexts., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Published
2024
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100. Owners' experiences of administering meglumine antimoniate injections to dogs with leishmaniosis: An online questionnaire study.

Author

de Jong MK, van Eijk D, Broere F, and Piek CJ

Subjects
Dogs, Animals, Surveys and Questionnaires, Humans, Male, Female, Ownership, Meglumine therapeutic use, Meglumine administration & dosage, Organometallic Compounds administration & dosage, Organometallic Compounds therapeutic use, Injections, Subcutaneous veterinary, Meglumine Antimoniate therapeutic use, Meglumine Antimoniate administration & dosage, Dog Diseases drug therapy, Leishmaniasis veterinary, Leishmaniasis drug therapy, Antiprotozoal Agents therapeutic use, Antiprotozoal Agents administration & dosage
Abstract

Background: This study examined the experiences of owners of dogs with leishmaniosis who treated their dogs with daily subcutaneous meglumine antimoniate injections. The owners' perceived ease of administering the injections, the occurrence of problems and the effects on the owners and on the dog‒owner bond were evaluated., Methods: Dogs prescribed meglumine antimoniate as a treatment for leishmaniosis were identified using the database of the veterinary pharmacy of the Faculty of Veterinary Medicine, Utrecht University. An online questionnaire was sent to the owners of these dogs to evaluate the perceived ease of administering the injections, the occurrence of problems and the effects on the owner and the dog-owner bond., Results: Responses were received from 64 dog owners. Most respondents (78%) reported that administering the injections was not difficult. Pain or the development of nodules at the injection site was reported in 50% and 40% of the dogs, respectively. Polyuria was reported in 44% of the dogs. Some owners reported that administering the injections had a negative impact on their psychological wellbeing (20%), and some would have liked more veterinary support (11%)., Limitations: Some questions were answered by a limited number of people, and their responses may not be representative., Conclusion: Dog owners remain highly motivated to persevere with meglumine antimoniate treatment and are willing to administer the injections themselves. The availability of active support when needed during the therapy cycle may further improve their acceptance of and confidence in giving the injections., (© 2024 British Veterinary Association.)

Published
2024
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