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James A. Hutchinson - One of the best experts on this subject based on the ideXlab platform.
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Novel molecules mediate specialized functions of human Regulatory Macrophages.
Current Opinion in Organ Transplantation, 2018Co-Authors: Paloma Riquelme, James A. HutchinsonAbstract:PURPOSE OF REVIEW Now that adoptive transfer of Regulatory Macrophages (Mregs) is clinically practicable, we ask whether this approach could be used to achieve self-sustaining peripheral regulation and what mechanisms may be involved. RECENT FINDINGS Dehydrogenase/reductase 9 (DHRS9)-expressing Mregs are a specialized subset of monocyte-derived Macrophages that are currently being investigated as a tolerogenic cell-based therapy. Human Mregs are defined by their capacity to convert naive CD4 T cells to IL-10-secreting FoxP3 Regulatory T cells (Tregs) through an activation-dependent process involving signals mediated by TGF-β, retinoic acid, indoleamine 2,3-dioxygenase activity, notch and progestagen associated endometrial protein (PAEP). Mreg-induced iTregs (miTregs) are a phenotypically distinct type of in-vitro-derived human iTreg that expresses butyrophilin-like protein 8 (BTNL8) and T cell immunoreceptor with Ig and ITIM domains (TIGIT). miTregs are nonspecifically suppressive of mitogen-stimulated bystander T cell proliferation and inhibit TNFα-induced maturation of monocyte-derived dendritic cells. Preclinical and clinical studies find that intravenous infusion of allogeneic Mregs leads to enrichment of circulating TIGIT Tregs. SUMMARY These results suggest a feed-forward mechanism by which Mreg treatment could promote solid organ transplant acceptance through rapid induction of direct pathway Tregs.
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MITAP-compliant characterization of human Regulatory Macrophages.
Transplant International, 2017Co-Authors: James A. Hutchinson, Nobert Ahrens, Edward K. GeisslerAbstract:This article provides a transparent description of Mreg_UKR cell products, including manufacture and quality-control processes, using the structure and vocabulary of the ‘Minimum Information about Tolerogenic Antigen-presenting Cells’ reporting guidelines. This information is intended as a resource for those in the field, as well as a stimulus to develop a new wave of immunoRegulatory and tissue-reparative monocyte-derived cell therapies. This article is protected by copyright. All rights reserved.
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Clinical management of patients receiving cell-based immunoRegulatory therapy.
Transfusion, 2014Co-Authors: James A. Hutchinson, Paloma Riquelme, Lisa Walter, Norbert Ahrens, Christiane Broichhausen, Michael Gruber, Carsten A. Böger, Stefan Farkas, Marcus N. Scherer, Thomas BeinAbstract:Administering immunoRegulatory cells as medicinal agents is a revolutionary approach to the treatment of immunologically mediated diseases. Isolating, propagating, and modifying cells before applying them to patients allows complementation of specific cellular functions, which opens astonishing new possibilities for gain-of-function antigen-specific treatments in autoimmunity, chronic inflammatory disorders, and transplantation. This critical review presents a systematic assessment of the potential clinical risks posed by cell-based immunotherapy, focusing on treatment of renal transplant recipients with Regulatory Macrophages as a concrete example.
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IFN-γ-induced iNOS Expression in Mouse Regulatory Macrophages Prolongs Allograft Survival in Fully Immunocompetent Recipients
Molecular Therapy, 2013Co-Authors: Paloma Riquelme, Fred Fändrich, Anja Kammler, Stefan Tomiuk, Hans J Schlitt, E. K. Geissler, James A. HutchinsonAbstract:Mouse monocytes exposed to macrophage colony-stimulating factor (M-CSF) and interferon-γ (IFN-γ) were driven to a novel suppressor phenotype. These Regulatory Macrophages (M regs) expressed markers distinguishing them from M0-, M1-, and M2-polarized Macrophages and monocyte-derived dendritic cells (DCs). M regs completely suppressed polyclonal T cell proliferation through an inducible nitric oxide synthase (iNOS)-dependent mechanism. Additionally, M regs eliminated cocultured T cells in an allospecific fashion. In a heterotopic heart transplant model, a single intravenous administration of 5 × 106 donor-strain M regs before transplantation significantly prolonged allograft survival in fully immunocompetent recipients using both the stringent C3H-to-BALB/c (32.6 ± 4.5 versus 8.7 ± 0.2 days) and B6-to-BALB/c (31.1 ± 12 versus 9.7 ± 0.4 days) strain combinations. Nos2-deficient M regs did not prolong allograft survival, proving that M reg function in vivo is iNOS-dependent and mediated by living cells. M regs were detectable for at least 2 weeks postinfusion in allogeneic recipients. In their origin, development, phenotypic relationship with other in vitro-derived Macrophages and functions, there are solid grounds to assert a near-equivalence of mouse and human M regs. It is concluded that mouse M regs represent a novel, phenotypically distinct subset of suppressor Macrophages. Clinical applications of M reg therapy as an adjunct immunosuppressive therapy are currently being investigated within The ONE Study.
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Alternative approaches to myeloid suppressor cell therapy in transplantation: comparing Regulatory Macrophages to tolerogenic DCs and MDSCs
Transplantation Research, 2012Co-Authors: Paloma Riquelme, Edward K. Geissler, James A. HutchinsonAbstract:Several types of myeloid suppressor cell are currently being developed as cell-based immunosuppressive agents. Despite detailed knowledge about the molecular and cellular functions of these cell types, expert opinions differ on how to best implement such therapies in solid organ transplantation. Efforts in our laboratory to develop a cell-based medicinal product for promoting tolerance in renal transplant patients have focused on a type of suppressor macrophage, which we call the Regulatory macrophage (M reg). Our favoured clinical strategy is to administer donor-derived M regs to recipients one week prior to transplantation. In contrast, many groups working with tolerogenic dendritic cells (DCs) advocate post-transplant administration of recipient-derived cells. A third alternative, using myeloid-derived suppressor cells, presumably demands that cells are given around the time of transplantation, so that they can infiltrate the graft to create a suppressive environment. On present evidence, it is not possible to say which cell type and treatment strategy might be clinically superior. This review seeks to position our basic scientific and early-stage clinical studies of human Regulatory Macrophages within the broader context of myeloid suppressor cell therapy in transplantation.
Paloma Riquelme - One of the best experts on this subject based on the ideXlab platform.
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TIGIT+ iTregs elicited by human Regulatory Macrophages control T cell immunity.
Nature Communications, 2018Co-Authors: Paloma Riquelme, Jan Haarer, Anja Kammler, Lisa Walter, Stefan Tomiuk, Norbert Ahrens, Anja K. Wege, Ivan Goecze, Daniel Zecher, Bernhard BanasAbstract:Human Regulatory Macrophages (Mreg) have shown early clinical promise as a cell-based adjunct immunosuppressive therapy in solid organ transplantation. It is hypothesised that recipient CD4+ T cell responses are actively regulated through direct allorecognition of donor-derived Mregs. Here we show that human Mregs convert allogeneic CD4+ T cells to IL-10-producing, TIGIT+ FoxP3+-induced Regulatory T cells that non-specifically suppress bystander T cells and inhibit dendritic cell maturation. Differentiation of Mreg-induced Tregs relies on multiple non-redundant mechanisms that are not exclusive to interaction of Mregs and T cells, including signals mediated by indoleamine 2,3-dioxygenase, TGF-β, retinoic acid, Notch and progestagen-associated endometrial protein. Preoperative administration of donor-derived Mregs to living-donor kidney transplant recipients results in an acute increase in circulating TIGIT+ Tregs. These results suggest a feed-forward mechanism by which Mreg treatment promotes allograft acceptance through rapid induction of direct-pathway Tregs.
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Novel molecules mediate specialized functions of human Regulatory Macrophages.
Current Opinion in Organ Transplantation, 2018Co-Authors: Paloma Riquelme, James A. HutchinsonAbstract:PURPOSE OF REVIEW Now that adoptive transfer of Regulatory Macrophages (Mregs) is clinically practicable, we ask whether this approach could be used to achieve self-sustaining peripheral regulation and what mechanisms may be involved. RECENT FINDINGS Dehydrogenase/reductase 9 (DHRS9)-expressing Mregs are a specialized subset of monocyte-derived Macrophages that are currently being investigated as a tolerogenic cell-based therapy. Human Mregs are defined by their capacity to convert naive CD4 T cells to IL-10-secreting FoxP3 Regulatory T cells (Tregs) through an activation-dependent process involving signals mediated by TGF-β, retinoic acid, indoleamine 2,3-dioxygenase activity, notch and progestagen associated endometrial protein (PAEP). Mreg-induced iTregs (miTregs) are a phenotypically distinct type of in-vitro-derived human iTreg that expresses butyrophilin-like protein 8 (BTNL8) and T cell immunoreceptor with Ig and ITIM domains (TIGIT). miTregs are nonspecifically suppressive of mitogen-stimulated bystander T cell proliferation and inhibit TNFα-induced maturation of monocyte-derived dendritic cells. Preclinical and clinical studies find that intravenous infusion of allogeneic Mregs leads to enrichment of circulating TIGIT Tregs. SUMMARY These results suggest a feed-forward mechanism by which Mreg treatment could promote solid organ transplant acceptance through rapid induction of direct pathway Tregs.
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DHRS9 Is a Stable Marker of Human Regulatory Macrophages.
Transplantation, 2017Co-Authors: Paloma Riquelme, Fred Fändrich, Norbert Ahrens, Tuija Kekarainen, Giada Amodio, Camila Macedo, Aurélie Moreau, Nataša Obermajer, Christoph Brochhausen, Cristina CuturiAbstract:BackgroundThe human Regulatory macrophage (Mreg) has emerged as a promising cell type for use as a cell-based adjunct immunosuppressive therapy in solid organ transplant recipients. In this brief report, dehydrogenase/reductase 9 (DHRS9) is identified as a robust marker of human Mregs.MethodsThe cog
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Clinical management of patients receiving cell-based immunoRegulatory therapy.
Transfusion, 2014Co-Authors: James A. Hutchinson, Paloma Riquelme, Lisa Walter, Norbert Ahrens, Christiane Broichhausen, Michael Gruber, Carsten A. Böger, Stefan Farkas, Marcus N. Scherer, Thomas BeinAbstract:Administering immunoRegulatory cells as medicinal agents is a revolutionary approach to the treatment of immunologically mediated diseases. Isolating, propagating, and modifying cells before applying them to patients allows complementation of specific cellular functions, which opens astonishing new possibilities for gain-of-function antigen-specific treatments in autoimmunity, chronic inflammatory disorders, and transplantation. This critical review presents a systematic assessment of the potential clinical risks posed by cell-based immunotherapy, focusing on treatment of renal transplant recipients with Regulatory Macrophages as a concrete example.
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in question the scientific value of preclinical safety pharmacology and toxicology studies with cell based therapies
Molecular therapy. Methods & clinical development, 2014Co-Authors: Christiane Oichhause, Paloma Riquelme, Fred Fändrich, Anja K. Wege, Norbe Ahrens, Gudru E Koehl, Hans J Schli, Ernhard Anas, Edward K Geissle, James A HutchinsoAbstract:A new cell-based medicinal product containing human Regulatory Macrophages, known as Mreg_UKR, has been developed and conforms to expectations of a therapeutic drug. Here, Mreg_UKR was subjected to pharmacokinetic, safety pharmacology, and toxicological testing, which identified no adverse reactions. These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion. This leads us to question whether there is adequate scientific justification for preclinical safety testing of similar novel cell-based medicinal products using animal models. In earlier work, two patients were treated with Regulatory Macrophages prior to kidney transplantation. In our opinion, the absence of acute or chronic adverse effects in these cases is the most convincing available evidence of the likely safety of Mreg_UKR in future recipients. On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products. By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances.
Manon E. Wildenberg - One of the best experts on this subject based on the ideXlab platform.
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Anatomical Variation in Mesenteric Macrophage Phenotypes in Crohn's Disease.
Clinical and Translational Gastroenterology, 2020Co-Authors: Jonathan H.m. Van Der Meer, Manon E. Wildenberg, Karin A. T. G. M. Wasmann, Jarmila D. W. Van Der Bilt, M Becker, Marja A. Boermeester, Willem A. Bemelman, Christianne J. BuskensAbstract:INTRODUCTION: Clinical trials are currently investigating whether an extended mesenteric resection for ileocecal resections could reduce postoperative recurrence in Crohn's disease. Resection of the mesorectum, which contains proinflammatory Macrophages, during proct(ocol)ectomy, is associated with reduced recurrent inflammation and improved wound healing. We aimed to characterize the Macrophages in the ileocecal mesentery, which were compared with those in the mesorectum, to provide a biological rationale for the ongoing trials. METHODS: In 13 patients with Crohn's disease and 4 control patients undergoing a proctectomy, tissue specimens were sampled at 3 locations from the mesorectum: distal (rectum), middle, and proximal (sigmoid). In 38 patients with Crohn's disease and 7 control patients undergoing ileocecal resections, tissue specimens also obtained from 3 locations: adjacent to the inflamed terminal ileum, adjacent to the noninflamed ileal resection margin, and centrally along the ileocolic artery. Immune cells from these tissue specimens were analyzed by flow cytometry for expression of CD206 to determine their inflammatory status. RESULTS: In the mesorectum, a gradient from proinflammatory to Regulatory Macrophages from distal to proximal was observed, corresponding to the adjacent inflammation of the intestine. By contrast, the ileocecal mesentery did not contain high amounts of proinflammatory Macrophages adjacent to the inflamed tissue, and a gradient toward a more proinflammatory phenotype was seen in the central mesenteric area. DISCUSSION: Although the mesentery is a continuous structure, the mesorectum and the ileocecal mesentery show different immunological characteristics. Therefore, currently, there is no basis to perform an extended ileocecal resection in patients with Crohn's disease.
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Benzimidazoles Promote Anti-TNF Mediated Induction of Regulatory Macrophages and Enhance Therapeutic Efficacy in a Murine Model.
Journal of Crohn's and Colitis, 2017Co-Authors: Manon E. Wildenberg, A. Levin, Alessandro Ceroni, Zhen Guo, Pim J. Koelink, Theodorus B. M. Hakvoort, Liset Westera, Felicia M. Bloemendaal, Johannan F. Brandse, Alison SimmonsAbstract:Background and Aims: Regulatory Macrophages play a critical role in tissue repair, and we have previously shown that anti-tumour necrosis factor [TNF] antibodies induce these Macrophages in vitro and in vivo in IBD patients. The induction of Regulatory Macrophages can be potentiated using the combination of anti-TNF and thiopurines, consistent with the enhanced efficacy of this combination therapy described in clinical trials. As thiopurines are unfortunately associated with significant side effects, we here aimed to identify alternatives for combination therapy with anti-TNF, using the macrophage induction model as a screening tool. Methods: Mixed lymphocyte reactions were treated with anti-TNF and a library of 1600 drug compounds. Induction of CD14+ CD206+ Macrophages was analysed by flow cytometry. Positive hits were validated in vitro and in the T cell transfer model of colitis. Results: Among the 98 compounds potentiating the induction of Regulatory Macrophages by anti-TNF were six benzimidazoles, including albendazole. Albendazole treatment in the presence of anti-TNF resulted in alterations in the tubulin skeleton and signalling though AMPK, which was required for the enhanced induction. Combination therapy also increased expression levels of the immunoRegulatory cytokine IL-10. In vivo, albendazole plus anti-TNF combination therapy was superior to monotherapy in a model of colitis, in terms of both induction of Regulatory Macrophages and improvement of clinical symptoms. Conclusions: Albendazole enhances the induction of Regulatory Macrophages by anti-TNF and potentiates clinical efficacy in murine colitis. Given its favourable safety profile, these data indicate that the repurposing of albendazole may be a novel option for anti-TNF combination therapy in IBD
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Regulatory Macrophages induced by infliximab are involved in healing in vivo and in vitro
Inflammatory Bowel Diseases, 2012Co-Authors: Anne Christine W. Vos, Manon E. Wildenberg, Ingrid Arijs, Marjolijn Duijvestein, Auke P. Verhaar, Gert De Hertogh, Severine Vermeire, Paul Rutgeerts, Gijs R. Van Den Brink, Daniel W. HommesAbstract:Background: Regulatory Macrophages play an important role in wound healing and gut homeostasis and have antiinflammatory properties. Induction of this cell type (Mψind) by the anti-tumor necrosis factor (TNF) antibodies, infliximab and adalimumab, has recently been shown in vitro. Also, the superiority of infliximab/azathioprine combination therapy over infliximab or azathioprine monotherapy has recently been established, but the mechanism behind this remains unclear. The aim of this study was to examine the induction of Regulatory Macrophages in patients with and without mucosal healing in response to infliximab. In addition, we studied the effect of infliximab/azathioprine combination treatment on the differentiation and function of Regulatory Macrophages. Methods: Inflammatory bowel disease (IBD) patients (n = 10) underwent endoscopy before and after first infliximab treatment. Immunohistochemical staining of CD68 and CD206 was performed in all patients. Mixed lymphocyte reactions (MLRs) were treated with infliximab, azathioprine, or both. Macrophage phenotype was evaluated by flow cytometry and inhibition of T-cell proliferation was measured in a secondary MLR containing Macrophages and third-party lymphocytes. Results: A significant induction of Regulatory Macrophages was observed in patients with mucosal healing after treatment with infliximab; this induction was absent in patients without mucosal healing. In addition, Mψind have the ability to induce wound healing in an in vitro model, further suggesting a key role for infliximab-induced Macrophages in mucosal healing. Upon infliximab/azathioprine combination treatment, an increased number of Regulatory Macrophages was observed. These Macrophages also displayed stronger immunosuppressive properties than Macrophages induced by infliximab monotherapy. Conclusions: These data show that Regulatory Macrophages may be involved in mucosal healing and provide a rationale for the superiority of infliximab/azathioprine combination treatment observed in the clinic. (Inflamm Bowel Dis 2012;)
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P061 Anti-TNF-induced Regulatory Macrophages mechanisms of immunosuppression
Journal of Crohn's and Colitis, 2012Co-Authors: A. Levin, Anne Christine W. Vos, Manon E. Wildenberg, Daan W. Hommes, G. Van Den BrinkAbstract:stiffness-mediated induction of aSMA protein expression, FAK phosphorylation, and MLCK and ET-1 gene expression. In addition, CARD-024 partially stimulated members of the COX2/IL-1b inflammatory pathway. Conclusions: In summary, CARD-024 attenuated the pro-fibrotic response of colonic myofibroblasts to either TGFb stimulation or high matrix stiffness, suggesting that vitamin D analogs such as CARD-024 may ameliorate intestinal fibrosis.
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P069 Anti-TNF induced Regulatory Macrophages display high levels of autophagy
Journal of Crohn's and Colitis, 2012Co-Authors: Anne Christine W. Vos, Manon E. Wildenberg, A. Levin, G. Van Den Brink, Daan W. HommesAbstract:primed, but not IL8 stimulated PMN from CD patients was observed. Conclusions: Although initiation of apoptosis in CD PMN is normal as determined by Annexin V staining, an enhanced survival signal provided by GM-CSF-induced PKB activation may lead to a decreased cleaving of caspases, thereby rescuing PMN from the apoptotic pathway. In toto, our results suggest an enhanced GM-CSF-mediated PMN survival, which may play a role in the chronic intestinal inflammation in CD.
Anne Christine W. Vos - One of the best experts on this subject based on the ideXlab platform.
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Regulatory Macrophages induced by infliximab are involved in healing in vivo and in vitro
Inflammatory Bowel Diseases, 2012Co-Authors: Anne Christine W. Vos, Manon E. Wildenberg, Ingrid Arijs, Marjolijn Duijvestein, Auke P. Verhaar, Gert De Hertogh, Severine Vermeire, Paul Rutgeerts, Gijs R. Van Den Brink, Daniel W. HommesAbstract:Background: Regulatory Macrophages play an important role in wound healing and gut homeostasis and have antiinflammatory properties. Induction of this cell type (Mψind) by the anti-tumor necrosis factor (TNF) antibodies, infliximab and adalimumab, has recently been shown in vitro. Also, the superiority of infliximab/azathioprine combination therapy over infliximab or azathioprine monotherapy has recently been established, but the mechanism behind this remains unclear. The aim of this study was to examine the induction of Regulatory Macrophages in patients with and without mucosal healing in response to infliximab. In addition, we studied the effect of infliximab/azathioprine combination treatment on the differentiation and function of Regulatory Macrophages. Methods: Inflammatory bowel disease (IBD) patients (n = 10) underwent endoscopy before and after first infliximab treatment. Immunohistochemical staining of CD68 and CD206 was performed in all patients. Mixed lymphocyte reactions (MLRs) were treated with infliximab, azathioprine, or both. Macrophage phenotype was evaluated by flow cytometry and inhibition of T-cell proliferation was measured in a secondary MLR containing Macrophages and third-party lymphocytes. Results: A significant induction of Regulatory Macrophages was observed in patients with mucosal healing after treatment with infliximab; this induction was absent in patients without mucosal healing. In addition, Mψind have the ability to induce wound healing in an in vitro model, further suggesting a key role for infliximab-induced Macrophages in mucosal healing. Upon infliximab/azathioprine combination treatment, an increased number of Regulatory Macrophages was observed. These Macrophages also displayed stronger immunosuppressive properties than Macrophages induced by infliximab monotherapy. Conclusions: These data show that Regulatory Macrophages may be involved in mucosal healing and provide a rationale for the superiority of infliximab/azathioprine combination treatment observed in the clinic. (Inflamm Bowel Dis 2012;)
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P061 Anti-TNF-induced Regulatory Macrophages mechanisms of immunosuppression
Journal of Crohn's and Colitis, 2012Co-Authors: A. Levin, Anne Christine W. Vos, Manon E. Wildenberg, Daan W. Hommes, G. Van Den BrinkAbstract:stiffness-mediated induction of aSMA protein expression, FAK phosphorylation, and MLCK and ET-1 gene expression. In addition, CARD-024 partially stimulated members of the COX2/IL-1b inflammatory pathway. Conclusions: In summary, CARD-024 attenuated the pro-fibrotic response of colonic myofibroblasts to either TGFb stimulation or high matrix stiffness, suggesting that vitamin D analogs such as CARD-024 may ameliorate intestinal fibrosis.
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P069 Anti-TNF induced Regulatory Macrophages display high levels of autophagy
Journal of Crohn's and Colitis, 2012Co-Authors: Anne Christine W. Vos, Manon E. Wildenberg, A. Levin, G. Van Den Brink, Daan W. HommesAbstract:primed, but not IL8 stimulated PMN from CD patients was observed. Conclusions: Although initiation of apoptosis in CD PMN is normal as determined by Annexin V staining, an enhanced survival signal provided by GM-CSF-induced PKB activation may lead to a decreased cleaving of caspases, thereby rescuing PMN from the apoptotic pathway. In toto, our results suggest an enhanced GM-CSF-mediated PMN survival, which may play a role in the chronic intestinal inflammation in CD.
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Anti-tumor necrosis factor-α antibodies induce Regulatory Macrophages in an Fc region-dependent manner.
Gastroenterology, 2011Co-Authors: Anne Christine W. Vos, Manon E. Wildenberg, Marjolijn Duijvestein, Auke P. Verhaar, Gijs R. Van Den Brink, Daniel W. HommesAbstract:Background & Aims Anti–tumor necrosis factor (TNF)α antibodies are effective in treating patients with Crohn's disease whereas soluble TNFα receptors have not shown clinical efficacy; the mechanism that underlies these different effects is not clear. We examined the immunosuppressive effects of different anti-TNFα reagents on activated T cells. Methods We studied the effects of anti-TNFα antibodies infliximab and adalimumab, the soluble TNFα receptor etanercept, the pegylated F(ab') fragment certolizumab, and certolizumab–immunoglobulin (Ig)G on primary activated T cells. T cells were grown in isolation or in a mixed lymphocyte reaction (MLR). Proliferation was measured by 3 H thymidine incorporation and apoptosis was examined using Annexin V labeling and a colorimetric assay for activated caspase-3. Macrophage phenotypes were assayed by flow cytometry and cytokine secretion. Results Infliximab and adalimumab reduced T-cell proliferation in an MLR whereas etanercept and certolizumab did not; this effect was lost after Fc receptors were blocked. The infliximab F(ab')2 fragment did not inhibit proliferation whereas certolizumab-IgG did inhibit proliferation. In the MLR, the antibodies against TNF induced formation of a new population of Macrophages in an Fc region-dependent manner; these Macrophages had an immunosuppressive phenotype because they inhibit proliferation of activated T cells, produce anti-inflammatory cytokines, and express the Regulatory macrophage marker CD206. Conclusions Regulatory Macrophages have immunosuppressive properties and an important role in wound healing. Antibodies against TNF induce Regulatory Macrophages in an Fc region-dependent manner. These functions of anti-TNFs might contribute to the resolution of inflammation.
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Enhanced Induction of Regulatory Macrophages Upon Azathioprine/Infliximab Combination Treatment In Vitro
Gastroenterology, 2011Co-Authors: Anne Christine W. Vos, Manon E. Wildenberg, Marjolijn Duijvestein, Auke P. Verhaar, Gijs R. Van Den Brink, Daniel W. HommesAbstract:G A A b st ra ct s to determine whether Treg defects resulted from either increased apoptosis or decreased maintenance of Foxp3 expression in Tregs. Methods/Results: WASP-deficient DCs led to decreased In Vitro generation of adaptive Tregs. More importantly, upon transfer of Foxp3cells into recipient mice, there was a marked reduction in the generation of Foxp3+ inducible Tregs in WASP/RAG DKO mice compared to RAG KO controls. The defects in WT Treg function in chimeric mice could not be explained by alterations in the maintenance or apoptosis of Foxp3+ donor cells in WASP/RAG DKO mice compared to RAG KO mice. Employing an In Vitro suppression assay, WT Tregs functioned normally when MLN DCs isolated from either WT or WASP-deficient mice were used as APCs. In contrast, there was aberrant Treg function when DCs were isolated from WASP/RAG DKO mice. Conclusions: WASP deficiency in innate immune cells leads to defective Treg generation and function In Vivo. Similarly, there was reduced generation of WT Tregs In Vitro in the presence of WASPdeficient DCs. However, Treg function was compromised only when DCs were harvested from WASP/RAG DKO mice but not WASP-deficient mice, suggesting an intrinsic aberrancy in WASP-deficient DCs unmasked in a lymphopenic setting. In summary, colitis in chimeric mice may result from DC-driven alterations in Treg number and function.
Daniel W. Hommes - One of the best experts on this subject based on the ideXlab platform.
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Regulatory Macrophages induced by infliximab are involved in healing in vivo and in vitro
Inflammatory Bowel Diseases, 2012Co-Authors: Anne Christine W. Vos, Manon E. Wildenberg, Ingrid Arijs, Marjolijn Duijvestein, Auke P. Verhaar, Gert De Hertogh, Severine Vermeire, Paul Rutgeerts, Gijs R. Van Den Brink, Daniel W. HommesAbstract:Background: Regulatory Macrophages play an important role in wound healing and gut homeostasis and have antiinflammatory properties. Induction of this cell type (Mψind) by the anti-tumor necrosis factor (TNF) antibodies, infliximab and adalimumab, has recently been shown in vitro. Also, the superiority of infliximab/azathioprine combination therapy over infliximab or azathioprine monotherapy has recently been established, but the mechanism behind this remains unclear. The aim of this study was to examine the induction of Regulatory Macrophages in patients with and without mucosal healing in response to infliximab. In addition, we studied the effect of infliximab/azathioprine combination treatment on the differentiation and function of Regulatory Macrophages. Methods: Inflammatory bowel disease (IBD) patients (n = 10) underwent endoscopy before and after first infliximab treatment. Immunohistochemical staining of CD68 and CD206 was performed in all patients. Mixed lymphocyte reactions (MLRs) were treated with infliximab, azathioprine, or both. Macrophage phenotype was evaluated by flow cytometry and inhibition of T-cell proliferation was measured in a secondary MLR containing Macrophages and third-party lymphocytes. Results: A significant induction of Regulatory Macrophages was observed in patients with mucosal healing after treatment with infliximab; this induction was absent in patients without mucosal healing. In addition, Mψind have the ability to induce wound healing in an in vitro model, further suggesting a key role for infliximab-induced Macrophages in mucosal healing. Upon infliximab/azathioprine combination treatment, an increased number of Regulatory Macrophages was observed. These Macrophages also displayed stronger immunosuppressive properties than Macrophages induced by infliximab monotherapy. Conclusions: These data show that Regulatory Macrophages may be involved in mucosal healing and provide a rationale for the superiority of infliximab/azathioprine combination treatment observed in the clinic. (Inflamm Bowel Dis 2012;)
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Anti-tumor necrosis factor-α antibodies induce Regulatory Macrophages in an Fc region-dependent manner.
Gastroenterology, 2011Co-Authors: Anne Christine W. Vos, Manon E. Wildenberg, Marjolijn Duijvestein, Auke P. Verhaar, Gijs R. Van Den Brink, Daniel W. HommesAbstract:Background & Aims Anti–tumor necrosis factor (TNF)α antibodies are effective in treating patients with Crohn's disease whereas soluble TNFα receptors have not shown clinical efficacy; the mechanism that underlies these different effects is not clear. We examined the immunosuppressive effects of different anti-TNFα reagents on activated T cells. Methods We studied the effects of anti-TNFα antibodies infliximab and adalimumab, the soluble TNFα receptor etanercept, the pegylated F(ab') fragment certolizumab, and certolizumab–immunoglobulin (Ig)G on primary activated T cells. T cells were grown in isolation or in a mixed lymphocyte reaction (MLR). Proliferation was measured by 3 H thymidine incorporation and apoptosis was examined using Annexin V labeling and a colorimetric assay for activated caspase-3. Macrophage phenotypes were assayed by flow cytometry and cytokine secretion. Results Infliximab and adalimumab reduced T-cell proliferation in an MLR whereas etanercept and certolizumab did not; this effect was lost after Fc receptors were blocked. The infliximab F(ab')2 fragment did not inhibit proliferation whereas certolizumab-IgG did inhibit proliferation. In the MLR, the antibodies against TNF induced formation of a new population of Macrophages in an Fc region-dependent manner; these Macrophages had an immunosuppressive phenotype because they inhibit proliferation of activated T cells, produce anti-inflammatory cytokines, and express the Regulatory macrophage marker CD206. Conclusions Regulatory Macrophages have immunosuppressive properties and an important role in wound healing. Antibodies against TNF induce Regulatory Macrophages in an Fc region-dependent manner. These functions of anti-TNFs might contribute to the resolution of inflammation.
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Enhanced Induction of Regulatory Macrophages Upon Azathioprine/Infliximab Combination Treatment In Vitro
Gastroenterology, 2011Co-Authors: Anne Christine W. Vos, Manon E. Wildenberg, Marjolijn Duijvestein, Auke P. Verhaar, Gijs R. Van Den Brink, Daniel W. HommesAbstract:G A A b st ra ct s to determine whether Treg defects resulted from either increased apoptosis or decreased maintenance of Foxp3 expression in Tregs. Methods/Results: WASP-deficient DCs led to decreased In Vitro generation of adaptive Tregs. More importantly, upon transfer of Foxp3cells into recipient mice, there was a marked reduction in the generation of Foxp3+ inducible Tregs in WASP/RAG DKO mice compared to RAG KO controls. The defects in WT Treg function in chimeric mice could not be explained by alterations in the maintenance or apoptosis of Foxp3+ donor cells in WASP/RAG DKO mice compared to RAG KO mice. Employing an In Vitro suppression assay, WT Tregs functioned normally when MLN DCs isolated from either WT or WASP-deficient mice were used as APCs. In contrast, there was aberrant Treg function when DCs were isolated from WASP/RAG DKO mice. Conclusions: WASP deficiency in innate immune cells leads to defective Treg generation and function In Vivo. Similarly, there was reduced generation of WT Tregs In Vitro in the presence of WASPdeficient DCs. However, Treg function was compromised only when DCs were harvested from WASP/RAG DKO mice but not WASP-deficient mice, suggesting an intrinsic aberrancy in WASP-deficient DCs unmasked in a lymphopenic setting. In summary, colitis in chimeric mice may result from DC-driven alterations in Treg number and function.