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Article: Immune-potentiating effects of the chemotherapeutic drug cyclophosphamide.

Brode, Sven / Cooke, Anne

2008 Volume 28, Issue 2, Page(s) 109–126

Abstract: Cyclophosphamide (CTX) is an alkylating cytotoxic drug that primarily affects proliferating lymphocytes. CTX has been extensively used as a chemotherapeutic and disease-modifying agent against certain solid tumors, lymphomas, and some autoimmune ... ...

Abstract	Cyclophosphamide (CTX) is an alkylating cytotoxic drug that primarily affects proliferating lymphocytes. CTX has been extensively used as a chemotherapeutic and disease-modifying agent against certain solid tumors, lymphomas, and some autoimmune conditions. Depending on its dose and timing of administration, CTX can also enhance immune responses. These opposing immune functions of CTX have been investigated in numerous animal models and recent clinical studies. Administration of CTX augments delayed type 1 hypersensitivity (DTH) reactions, can precipitate type 1 diabetes, and boosts antitumor responses in both vaccination and adoptive cell transfer models. Although the mechanisms by which CTX elicits these effects are not fully understood, CTX treatment has a differential effect on lymphocyte compartments, rapidly depleting B and T cells. This is followed by a recovery phase characterized by extensive proliferation and bone marrow mobilization. The proposed underlying mechanisms of augmentation of immune responses include the facilitation of homing and homeostatic proliferation by the creation of space, the skewing of Th2/Th1 responses due to the cytokine storm during the recovery phase, and the removal or inhibition of a suppressor cell population. With the identification of naturally occurring and peripheral regulatory T cells, recent studies have re-evaluated these hypotheses and suggest that CTX inhibits the function of Foxp3+ regulatory T cells. In this review, we critically evaluate relevant historical and recent data on CTX-mediated immunomodulation and discuss the resulting implications for immunotherapy.
MeSH term(s)	Adjuvants, Immunologic/pharmacology ; Animals ; Antineoplastic Agents, Alkylating/pharmacology ; Autoimmunity ; Cyclophosphamide/pharmacology ; Forkhead Transcription Factors/analysis ; Humans ; Lymphocyte Depletion ; Neoplasms/drug therapy ; Neoplasms/immunology ; T-Lymphocytes, Regulatory/physiology
Chemical Substances	Adjuvants, Immunologic ; Antineoplastic Agents, Alkylating ; FOXP3 protein, human ; Forkhead Transcription Factors ; Cyclophosphamide (8N3DW7272P)
Language	English
Publishing date	2008-05-13
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1353116-5
ISSN	1040-8401
ISSN	1040-8401
DOI	10.1615/critrevimmunol.v28.i2.20
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Article ; Online: Same-day or historical ESR for disease activity score measurement: does it matter?

Brode, Sven / Nisar, Muhammad K / Ostör, Andrew J K

Clinical rheumatology

2012 Volume 32, Issue 2, Page(s) 261–265

Abstract: Several guidelines recommended routine use of Disease Activity Score-28 (DAS28) to monitor disease and the response to treatment for rheumatoid arthritis (RA). In practice, it may be appropriate to use historical erythrocyte sedimentation rate (ESR) ... ...

Abstract	Several guidelines recommended routine use of Disease Activity Score-28 (DAS28) to monitor disease and the response to treatment for rheumatoid arthritis (RA). In practice, it may be appropriate to use historical erythrocyte sedimentation rate (ESR) values in place of same-day ESR, thereby preventing unnecessary delay in adjusting intervention. We asked whether ESR blood samples taken up to 3 months prior to the clinic appointment were adequate to accurately assess RA disease activity using the DAS28. RA patients (N = 66) who met the inclusion criteria were assessed at baseline and ESR obtained on the day of review to calculate the DAS28 and compared with the DAS28 derived from the latest previous ESR (mean interval, 38.6 days; range, 6-99 days). Limits of agreement (LoA) were used to assess the agreement between the DAS28 pairs. The mean age of the participants was 61.5 years (range, 20-83 years), with mean disease duration of 11.0 years (range, 0.1-40 years). Comparing the DAS28 using same-day ESR versus pre-recorded historical ESR showed a small statistical difference (mean, -0.09; 95 %CI, -0.1602 to -0.017) in the DAS28 score. The calculated LoA (-0.66 and 0.48) demonstrated acceptable agreement between DAS28 pairs, with 7.6 % of patients residing outside the LoA, all of whom had a significant treatment change. Disease misclassification occurred in 9.1 % of patients who were close to disease activity boundaries. Our results indicate that differences in the DAS28 due to a previous or same-day ESR are unlikely to be clinically significant for RA patients with established disease. A decision to adjust treatment therefore may be confidently made for most patients using the most recent ESR for calculating the DAS28, provided there was no major change in treatment since the last ESR measurement.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antiemetics/therapeutic use ; Arthritis, Rheumatoid/blood ; Arthritis, Rheumatoid/diagnosis ; Arthritis, Rheumatoid/drug therapy ; Blood Sedimentation ; Drug Therapy, Combination ; Female ; Hematologic Tests/methods ; Hematologic Tests/standards ; Humans ; Male ; Middle Aged ; Reproducibility of Results ; Severity of Illness Index ; Time Factors ; Unnecessary Procedures ; Young Adult
Chemical Substances	Antiemetics
Language	English
Publishing date	2012-11-24
Publishing country	Germany
Document type	Journal Article ; Validation Study
ZDB-ID	604755-5
ISSN	1434-9949 ; 0770-3198
ISSN (online)	1434-9949
ISSN	0770-3198
DOI	10.1007/s10067-012-2121-2
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Article: Cross-presentation: dendritic cells and macrophages bite off more than they can chew!

Brode, Sven / Macary, Paul A

Immunology

2004 Volume 112, Issue 3, Page(s) 345–351

Abstract: As immunologists, our knowledge of the molecular mechanisms which underlie the presentation of antigens derived from extracellular or 'exogenous' sources to CD8 cytotoxic lymphocytes (CTL) has been limited. This process, termed 'cross-presentation', has ... ...

Abstract	As immunologists, our knowledge of the molecular mechanisms which underlie the presentation of antigens derived from extracellular or 'exogenous' sources to CD8 cytotoxic lymphocytes (CTL) has been limited. This process, termed 'cross-presentation', has been linked to the elicitation of protective CTL responses against tumours and may be extremely important in generating immune responses against clinically relevant pathogens that do not infect tissues of haemopoietic origin. It is now known that cross-presentation of exogenous antigens on major histocompatibility complex (MHC) class I occurs through several distinct cellular pathways. In this review we outline and discuss some recent advances in our understanding of these pathways.
MeSH term(s)	Antigen Presentation/physiology ; Dendritic Cells/immunology ; Endoplasmic Reticulum/physiology ; Histocompatibility Antigens Class I/immunology ; Humans ; Lymphocyte Activation ; Macrophages/immunology ; Phagocytosis/physiology ; T-Lymphocytes, Cytotoxic/immunology
Chemical Substances	Histocompatibility Antigens Class I
Language	English
Publishing date	2004-07
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/j.1365-2567.2004.01920.x
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Article ; Online: Interleukin-5 inhibits glucocorticoid-mediated apoptosis in human eosinophils.

Brode, Sven / Farahi, Neda / Cowburn, Andrew S / Juss, Jatinder K / Condliffe, Alison M / Chilvers, Edwin R

Thorax

2010 Volume 65, Issue 12, Page(s) 1116–1117

MeSH term(s)	Apoptosis/drug effects ; Cells, Cultured ; Eosinophils/drug effects ; Glucocorticoids/antagonists & inhibitors ; Humans ; Interleukin-5/pharmacology
Chemical Substances	Glucocorticoids ; Interleukin-5
Language	English
Publishing date	2010-12
Publishing country	England
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	204353-1
ISSN	1468-3296 ; 0040-6376
ISSN (online)	1468-3296
ISSN	0040-6376
DOI	10.1136/thx.2009.124909
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Article ; Online: Detection of a microbial metabolite by STING regulates inflammasome activation in response to Chlamydia trachomatis infection.

Webster, Steve J / Brode, Sven / Ellis, Lou / Fitzmaurice, Timothy J / Elder, Matthew J / Gekara, Nelson O / Tourlomousis, Panagiotis / Bryant, Clare / Clare, Simon / Chee, Ronnie / Gaston, Hill J S / Goodall, Jane C

PLoS pathogens

2017 Volume 13, Issue 6, Page(s) e1006383

Abstract: The innate immune system is a critical component of host defence against microbial pathogens, but effective responses require an ability to distinguish between infectious and non-infectious insult to prevent inappropriate inflammation. Using the ... ...

Abstract	The innate immune system is a critical component of host defence against microbial pathogens, but effective responses require an ability to distinguish between infectious and non-infectious insult to prevent inappropriate inflammation. Using the important obligate intracellular human pathogen Chlamydia trachomatis; an organism that causes significant immunopathology, we sought to determine critical host and pathogen factors that contribute to the induction of inflammasome activation. We assayed inflammasome activation by immunoblotting and ELISA to detect IL-1β processing and LDH release to determine pyroptosis. Using primary murine bone marrow derived macrophages or human monocyte derived dendritic cells, infected with live or attenuated Chlamydia trachomatis we report that the live organism activates both canonical and non-canonical inflammasomes, but only canonical inflammasomes controlled IL-1β processing which preceded pyroptosis. NADPH oxidase deficient macrophages were permissive to Chlamydia trachomatis replication and displayed elevated type-1 interferon and inflammasome activation. Conversely, attenuated, non-replicating Chlamydia trachomatis, primed but did not activate inflammasomes and stimulated reduced type-1 interferon responses. This suggested bacterial replication or metabolism as important factors that determine interferon responses and inflammasome activation. We identified STING but not cGAS as a central mediator of interferon regulated inflammasome activation. Interestingly, exogenous delivery of a Chlamydia trachomatis metabolite and STING ligand-cyclic di-AMP, recovered inflammasome activation to attenuated bacteria in a STING dependent manner thus indicating that a bacterial metabolite is a key factor initiating inflammasome activation through STING, independent of cGAS. These data suggest a potential mechanism of how the innate immune system can distinguish between infectious and non-infectious insult and instigate appropriate immune responses that could be therapeutically targeted.
MeSH term(s)	Animals ; Chlamydia Infections/immunology ; Chlamydia Infections/microbiology ; Chlamydia trachomatis/genetics ; Chlamydia trachomatis/immunology ; Chlamydia trachomatis/physiology ; Cyclic AMP/immunology ; Dendritic Cells/immunology ; Dendritic Cells/microbiology ; Female ; Humans ; Inflammasomes/immunology ; Interferon Type I/genetics ; Interferon Type I/immunology ; Interleukin-1beta/genetics ; Interleukin-1beta/immunology ; Macrophages/immunology ; Macrophages/microbiology ; Male ; Membrane Proteins/genetics ; Membrane Proteins/immunology ; Mice ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/immunology
Chemical Substances	Inflammasomes ; Interferon Type I ; Interleukin-1beta ; Membrane Proteins ; Sting1 protein, mouse ; Cyclic AMP (E0399OZS9N) ; Nucleotidyltransferases (EC 2.7.7.-) ; cGAS protein, mouse (EC 2.7.7.-)
Language	English
Publishing date	2017-06-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1006383
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Article: Cyclophosphamide-induced type-1 diabetes in the NOD mouse is associated with a reduction of CD4+CD25+Foxp3+ regulatory T cells.

Brode, Sven / Raine, Tim / Zaccone, Paola / Cooke, Anne

Journal of immunology (Baltimore, Md. : 1950)

2005 Volume 177, Issue 10, Page(s) 6603–6612

Abstract: Regulatory T cells (Tregs) have been implicated as key players in immune tolerance as well as suppression of antitumor responses. The chemotherapeutic alkylating agent cyclophosphamide (CY) is widely used in the treatment of tumors and some autoimmune ... ...

Abstract	Regulatory T cells (Tregs) have been implicated as key players in immune tolerance as well as suppression of antitumor responses. The chemotherapeutic alkylating agent cyclophosphamide (CY) is widely used in the treatment of tumors and some autoimmune conditions. Although previous data has demonstrated that Tregs may be preferentially affected by CY, its relevance in promoting autoimmune conditions has not been addressed. The nonobese diabetic mouse spontaneously develops type-1 diabetes (T1D). We demonstrate in this study that CY targets CD4+CD25+Foxp3+ Tregs in vivo. CD4+CD25+ T cells isolated from CY-treated mice display reduced suppressive activity in vitro and increased expression of apoptotic markers. Although Treg numbers rapidly recovered to pretreatment levels in the peripheral lymphoid tissues, Tregs failed to recover proportionally within pancreatic infiltrates. T1D progression was effectively prevented by adoptive transfer of a small number of islet Ag-specific CD4+CD25+ Tregs to CY-treated recipients. Prevention of T1D was associated with reduced T cell activation and higher Treg proportions in the pancreas. We conclude that acceleration of T1D by CY is associated with a reduction in CD4+CD25+Foxp3+ Tregs and can be prevented by transfer of CD4+CD25+ Tregs.
MeSH term(s)	Adoptive Transfer ; Animals ; Apoptosis/genetics ; Apoptosis/immunology ; Autoantigens/immunology ; Cyclophosphamide/administration & dosage ; Cyclophosphamide/toxicity ; Diabetes Mellitus, Type 1/chemically induced ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/immunology ; Diabetes Mellitus, Type 1/prevention & control ; Down-Regulation/genetics ; Down-Regulation/immunology ; Epitopes/immunology ; Forkhead Transcription Factors/biosynthesis ; Genetic Predisposition to Disease ; Interleukin-2 Receptor alpha Subunit/biosynthesis ; Islets of Langerhans/immunology ; Lymphocyte Subsets/drug effects ; Lymphocyte Subsets/pathology ; Lymphocyte Subsets/transplantation ; Lymphopenia/genetics ; Lymphopenia/immunology ; Lymphopenia/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Mice, Transgenic ; T-Lymphocytes, Regulatory/drug effects ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/pathology ; T-Lymphocytes, Regulatory/transplantation ; Up-Regulation/genetics ; Up-Regulation/immunology
Chemical Substances	Autoantigens ; Epitopes ; Forkhead Transcription Factors ; Foxp3 protein, mouse ; Interleukin-2 Receptor alpha Subunit ; Cyclophosphamide (8N3DW7272P)
Language	English
Publishing date	2005-01-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.177.10.6603
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Article ; Online: Detection of a microbial metabolite by STING regulates inflammasome activation in response to Chlamydia trachomatis infection.

Steve J Webster / Sven Brode / Lou Ellis / Timothy J Fitzmaurice / Matthew J Elder / Nelson O Gekara / Panagiotis Tourlomousis / Clare Bryant / Simon Clare / Ronnie Chee / Hill J S Gaston / Jane C Goodall

PLoS Pathogens, Vol 13, Iss 6, p e

2017 Volume 1006383

Abstract	The innate immune system is a critical component of host defence against microbial pathogens, but effective responses require an ability to distinguish between infectious and non-infectious insult to prevent inappropriate inflammation. Using the important obligate intracellular human pathogen Chlamydia trachomatis; an organism that causes significant immunopathology, we sought to determine critical host and pathogen factors that contribute to the induction of inflammasome activation. We assayed inflammasome activation by immunoblotting and ELISA to detect IL-1β processing and LDH release to determine pyroptosis. Using primary murine bone marrow derived macrophages or human monocyte derived dendritic cells, infected with live or attenuated Chlamydia trachomatis we report that the live organism activates both canonical and non-canonical inflammasomes, but only canonical inflammasomes controlled IL-1β processing which preceded pyroptosis. NADPH oxidase deficient macrophages were permissive to Chlamydia trachomatis replication and displayed elevated type-1 interferon and inflammasome activation. Conversely, attenuated, non-replicating Chlamydia trachomatis, primed but did not activate inflammasomes and stimulated reduced type-1 interferon responses. This suggested bacterial replication or metabolism as important factors that determine interferon responses and inflammasome activation. We identified STING but not cGAS as a central mediator of interferon regulated inflammasome activation. Interestingly, exogenous delivery of a Chlamydia trachomatis metabolite and STING ligand-cyclic di-AMP, recovered inflammasome activation to attenuated bacteria in a STING dependent manner thus indicating that a bacterial metabolite is a key factor initiating inflammasome activation through STING, independent of cGAS. These data suggest a potential mechanism of how the innate immune system can distinguish between infectious and non-infectious insult and instigate appropriate immune responses that could be therapeutically targeted.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2017-06-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Slc11a1, formerly Nramp1, is expressed in dendritic cells and influences major histocompatibility complex class II expression and antigen-presenting cell function.

Stober, Carmel B / Brode, Sven / White, Jacqueline K / Popoff, Jean-François / Blackwell, Jenefer M

Infection and immunity

2007 Volume 75, Issue 10, Page(s) 5059–5067

Abstract: Solute carrier family 11 member a1 (Slc11a1; formerly Nramp1) encodes a late endosomal/lysosomal protein/divalent cation transporter that regulates iron homeostasis in macrophages. During macrophage activation, Slc11a1 has multiple pleiotropic effects on ...

Abstract	Solute carrier family 11 member a1 (Slc11a1; formerly Nramp1) encodes a late endosomal/lysosomal protein/divalent cation transporter that regulates iron homeostasis in macrophages. During macrophage activation, Slc11a1 has multiple pleiotropic effects on gene regulation and function, including gamma interferon-induced class II expression and antigen-presenting cell function. The wild-type allele at Slc11a1 has been associated with a bias in Th1 cell function in vivo, which is beneficial in resistance to infection against intracellular macrophage pathogens but detrimental in contributing to development of type 1 diabetes. The extent to which this depends on macrophage versus dendritic cell (DC) function is not known. Here we show that Slc11a1 is expressed in late endosomes and/or lysosomes of CD11c(+) DCs. DCs from mutant and congenic wild-type mice upregulate interleukin-12 (IL-12) and IL-10 mRNA in response to lipopolysaccharide (LPS) stimulation, but the ratio of IL-10 to IL-12 is higher in unstimulated DCs and DCs stimulated for 15 h with LPS from mutant mice than from wild-type mice. DCs from wild-type mice upregulate major histocompatibility complex class II in response to LPS more efficiently than DCs from mutant mice. Unstimulated DCs from wild-type and mutant mice present ovalbumin (OVA) peptide with an efficiency equivalent to that of an OVA-specific CD4 T-cell line, but DCs from wild-type mice are more efficient at processing and presenting OVA or Leishmania activator of cell kinase (LACK) protein to OVA- and LACK-specific T cells. These data indicate that wild-type Slc11a1 expressed in DCs may play a role both in determining resistance to infectious disease and in susceptibility to autoimmune disease such as type 1 diabetes.
MeSH term(s)	Animals ; Antigen Presentation/immunology ; Antigens, Protozoan/immunology ; Bias ; Cation Transport Proteins/biosynthesis ; Cation Transport Proteins/immunology ; Cells, Cultured ; Dendritic Cells/chemistry ; Dendritic Cells/immunology ; Endosomes/chemistry ; Flow Cytometry ; Gene Expression Regulation ; Histocompatibility Antigens Class II/biosynthesis ; Histocompatibility Antigens Class II/immunology ; Interleukin-10/biosynthesis ; Interleukin-10/genetics ; Interleukin-12/biosynthesis ; Interleukin-12/genetics ; Leishmania ; Lipopolysaccharides/immunology ; Lysosomes/chemistry ; Major Histocompatibility Complex ; Mice ; Mice, Mutant Strains ; Microscopy, Confocal ; Ovalbumin/immunology ; Protozoan Proteins/immunology ; RNA, Messenger/biosynthesis ; RNA, Messenger/genetics ; Reverse Transcriptase Polymerase Chain Reaction
Chemical Substances	Antigens, Protozoan ; Cation Transport Proteins ; Histocompatibility Antigens Class II ; Lipopolysaccharides ; Protozoan Proteins ; RNA, Messenger ; natural resistance-associated macrophage protein 1 ; Interleukin-10 (130068-27-8) ; LACK antigen, Leishmania (163832-69-7) ; Interleukin-12 (187348-17-0) ; Ovalbumin (9006-59-1)
Language	English
Publishing date	2007-07-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
DOI	10.1128/IAI.00153-07
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Article: Slc11a1, Formerly Nramp1, Is Expressed in Dendritic Cells and Influences Major Histocompatibility Complex Class II Expression and Antigen-Presenting Cell Function

Stober, Carmel B / Brode, Sven / White, Jacqueline K / Popoff, Jean-François / Blackwell, Jenefer M

Infection and immunity. 2007 Oct., v. 75, no. 10

2007

Abstract	Solute carrier family 11 member a1 (Slc11a1; formerly Nramp1) encodes a late endosomal/lysosomal protein/divalent cation transporter that regulates iron homeostasis in macrophages. During macrophage activation, Slc11a1 has multiple pleiotropic effects on gene regulation and function, including gamma interferon-induced class II expression and antigen-presenting cell function. The wild-type allele at Slc11a1 has been associated with a bias in Th1 cell function in vivo, which is beneficial in resistance to infection against intracellular macrophage pathogens but detrimental in contributing to development of type 1 diabetes. The extent to which this depends on macrophage versus dendritic cell (DC) function is not known. Here we show that Slc11a1 is expressed in late endosomes and/or lysosomes of CD11c⁺ DCs. DCs from mutant and congenic wild-type mice upregulate interleukin-12 (IL-12) and IL-10 mRNA in response to lipopolysaccharide (LPS) stimulation, but the ratio of IL-10 to IL-12 is higher in unstimulated DCs and DCs stimulated for 15 h with LPS from mutant mice than from wild-type mice. DCs from wild-type mice upregulate major histocompatibility complex class II in response to LPS more efficiently than DCs from mutant mice. Unstimulated DCs from wild-type and mutant mice present ovalbumin (OVA) peptide with an efficiency equivalent to that of an OVA-specific CD4 T-cell line, but DCs from wild-type mice are more efficient at processing and presenting OVA or Leishmania activator of cell kinase (LACK) protein to OVA- and LACK-specific T cells. These data indicate that wild-type Slc11a1 expressed in DCs may play a role both in determining resistance to infectious disease and in susceptibility to autoimmune disease such as type 1 diabetes.
Keywords	Leishmania ; T-lymphocytes ; alleles ; dendritic cells ; disease resistance ; endosomes ; homeostasis ; infectious diseases ; insulin-dependent diabetes mellitus ; interleukin-10 ; interleukin-12 ; lipopolysaccharides ; lysosomes ; macrophage activation ; macrophages ; major histocompatibility complex ; messenger RNA ; mice ; mutants ; ovalbumin ; pathogens ; solutes
Language	English
Size	p. 5059-5067.
Publishing place	American Society for Microbiology
Document type	Article
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
Database	NAL-Catalogue (AGRICOLA)

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