Apoptotic cell infusion treats ongoing collagen-induced arthritis, even in the presence of methotrexate, and is synergic with anti-TNF therapy

BackgroundApoptotic cell-based therapies have been proposed to treat chronic inflammatory diseases. The aim of this study was to investigate the effect of intravenous (i.v.) apoptotic cell infusion in ongoing collagen-induced arthritis (CIA) and the interaction of this therapy with other treatments used in rheumatoid arthritis (RA), including methotrexate (MTX) or anti-TNF therapy.MethodsThe effects of i.v. apoptotic cell infusion were evaluated in a CIA mouse model in DBA/1 mice immunized with bovine type II collagen. The number and functions of antigen-presenting cells (APC), regulatory CD4+ T cells (Treg), and circulating anti-collagen auto-antibodies were analyzed in CIA mice.ResultsTreatment of arthritic mice with i.v. apoptotic cell infusion significantly reduced the arthritis clinical score. This therapeutic approach modified T cell responses against the collagen auto-antigen with selective induction of collagen-specific Treg. In addition, we observed that APC from apoptotic-cell-treated animals were resistant to toll-like receptor ligand activation and favored ex vivo Treg induction, indicating APC reprogramming. Apoptotic cell injection-induced arthritis modulation was dependent on transforming growth factor (TGF)-β, as neutralizing anti-TGF-β antibody prevented the effects of apoptotic cells. Methotrexate did not interfere, while anti-TNF therapy was synergic with apoptotic-cell-based therapy.ConclusionOverall, our data demonstrate that apoptotic-cell-based therapy is efficient in treating ongoing CIA, compatible with current RA treatments, and needs to be evaluated in humans in the treatment of RA.

• Publication year

  2016

• Venue

  Arthritis Research & Therapy

• Publication date

  2016-08-11

• Fields of study

  Medicine

• Identifiers
  DOI 10.1186/s13075-016-1084-0PMID 27516061PMCID 4982016
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Reply to Suppressive activity of human regulatory T cells is maintained in the presence of TNF

  2016cited by this paper
• Suppressive activity of human regulatory T cells is maintained in the presence of TNF

  2016cited by this paper
• Concise Review: Apoptotic Cell‐Based Therapies–Rationale, Preclinical Results and Future Clinical Developments

  2016cited by this paper
• Alterations in immune function with biologic therapies for autoimmune disease.

  2016cited by this paper
• Engulfment of Activated Apoptotic Cells Abolishes TGF-β–Mediated Immunoregulation via the Induction of IL-6

  2015cited by this paper
• Arthritogenic T cells in autoimmune arthritis.

  2015cited by this paper
• Emerging cell and cytokine targets in rheumatoid arthritis

  2014cited by this paper
• Apoptotic cell clearance: basic biology and therapeutic potential

  2014cited by this paper
• In Vivo–Generated Antigen-Specific Regulatory T Cells Treat Autoimmunity Without Compromising Antibacterial Immune Response

  2014cited by this paper
• Single infusion of donor mononuclear early apoptotic cells as prophylaxis for graft-versus-host disease in myeloablative HLA-matched allogeneic bone marrow transplantation: a phase I/IIa clinical trial.

  2014influential reference
• Prospects of apoptotic cell-based therapies for transplantation and inflammatory diseases.

  2013cited by this paper
• Drug levels, anti-drug antibodies, and clinical efficacy of the anti-TNFα biologics in rheumatic diseases

  2013cited by this paper
• Natural IgM Is Required for Suppression of Inflammatory Arthritis by Apoptotic Cells

  2011cited by this paper
• The pathogenesis of rheumatoid arthritis.

  2011cited by this paper
• Plasmacytoid Dendritic Cells Play a Major Role in Apoptotic Leukocyte-Induced Immune Modulation

  2011cited by this paper
• Regulatory T Cells

  2011cited by this paper
• TGF-β–Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

  2011cited by this paper
• Methotrexate—how does it really work?

  2010influential reference
• Apoptotic cell-mediated suppression of streptococcal cell wall-induced arthritis is associated with alteration of macrophage function and local regulatory T-cell increase: a potential cell-based therapy?

  2009cited by this paper
• Methotrexate: long‐term safety and efficacy in an Australian consultant rheumatology practice

  2009cited by this paper
• CD3-specific antibody–induced immune tolerance involves transforming growth factor-β from phagocytes digesting apoptotic T cells

  2008cited by this paper
• Apoptotic Cells Protect Mice against Lipopolysaccharide-Induced Shock1

  2008cited by this paper
• How regulatory T cells work

  2008cited by this paper
• Sirolimus enhances the effect of apoptotic cell infusion on hematopoietic engraftment and tolerance induction

  2008cited by this paper
• Utility of animal models for identification of potential therapeutics for rheumatoid arthritis

  2007cited by this paper
• Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs—from bench to bedside

  2007cited by this paper
• Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells

  2007cited by this paper
• The pathogenesis of rheumatoid arthritis.

  2007cited by this paper
• Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

  2006cited by this paper
• Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis

  2005cited by this paper
• Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells.

  2005cited by this paper
• Intravenous Infusion of Apoptotic Cells Simultaneously with Allogeneic Hematopoietic Grafts Alters Anti‐Donor Humoral Immune Responses

  2004cited by this paper
• Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis.

  2003cited by this paper
• Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation.

  2002cited by this paper
• Inhibitory Effects of Apoptotic Cell Ingestion upon Endotoxin-Driven Myeloid Dendritic Cell Maturation1

  2002cited by this paper
• Adenovirus-mediated gene transfer of urokinase plasminogen inhibitor inhibits angiogenesis in experimental arthritis

  2002cited by this paper
• Intravenous injection of apoptotic leukocytes enhances bone marrow engraftment across major histocompatibility barriers.

  2001cited by this paper
• TGF-β Released by Apoptotic T Cells Contributes to an Immunosuppressive Milieu

  2001cited by this paper
• TGF-beta released by apoptotic T cells contributes to an immunosuppressive milieu.

  2001cited by this paper
• Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.

  1998cited by this paper

• DHA sustains frozen-cell-induced efferocytosis by mitigating endoplasmic reticulum stress to promote inflammation resolution and bone repair

  2025cites this paper
• Metabolic Implications of Efferocytosis During Inflammation.

  2025cites this paper
• Efferocytosis in inflammatory bone disorders.

  2025cites this paper
• Extracellular vesicle as a next-generation drug delivery platform for rheumatoid arthritis therapy.

  2025cites this paper
• Augmenting regulatory T cells: new therapeutic strategy for rheumatoid arthritis

  2024cites this paper
• Mechanism of Efferocytosis in Determining Ischaemic Stroke Resolution—Diving into Microglia/Macrophage Functions and Therapeutic Modality

  2024cites this paper
• Efferocytosis: Unveiling its potential in autoimmune disease and treatment strategies.

  2024cites this paper
• Efferocytosis and Bone Dynamics

  2024cites this paper
• Efferocytosis: Current status and future prospects in the treatment of autoimmune diseases

  2024cites this paper
• The regulation of TRPA1 expression and function by Th1 and Th2-type inflammation in human A549 lung epithelial cells

  2023cites this paper
• The gut-joint axis mediates the TNF-induced RA process and PBMT therapeutic effects through the metabolites of gut microbiota

  2023cites this paper
• L-arginine metabolism inhibits arthritis and inflammatory bone loss

  2023cites this paper
• Apoptotic cell clearance components in inflammatory arthritis

  2023cites this paper
• LED irradiation at 630 nm alleviates collagen-induced arthritis in mice by inhibition of NF-κB-mediated MMPs production

  2023cites this paper
• The role of efferocytosis‐fueled macrophage metabolism in the resolution of inflammation

  2023cites this paper
• Methylprednisolone pulse therapy promotes the differentiation of regulatory T cells by inducing the apoptosis of CD4+ T cells in patients with systemic lupus erythematosus.

  2022cites this paper
• Overload of the Temporomandibular Joints Accumulates γδ T Cells in a Mouse Model of Rheumatoid Arthritis: A Morphological and Histological Evaluation

  2022cites this paper
• A2M inhibits inflammatory mediators of chondrocytes by blocking IL‐1β/NF‐κB pathway

  2022cites this paper
• Secondary Lymphoid Organs in Mesenchymal Stromal Cell Therapy: More Than Just a Filter

  2022cites this paper
• Resolution therapy: Harnessing efferocytic macrophages to trigger the resolution of inflammation

  2022cites this paper
• EC-18 prevents autoimmune arthritis by suppressing inflammatory cytokines and osteoclastogenesis

  2022cites this paper
• Immunomodulatory nano-preparations for rheumatoid arthritis

  2022cites this paper
• Gingival mesenchymal stem cell‐derived exosomes are immunosuppressive in preventing collagen‐induced arthritis

  2021cites this paper
• Apoptotic Donor Cells in Transplantation

  2021cites this paper
• Mini-Review: The Administration of Apoptotic Cells for Treating Rheumatoid Arthritis: Current Knowledge and Clinical Perspectives

  2021cites this paper
• Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly

  2020cites this paper
• Efficacy of Granulocyte and Monocyte Adsorptive Apheresis in Patients with Inflammatory Bowel Disease Showing Lost Response to Infliximab.

  2020cites this paper
• Early supplemental α2‐macroglobulin attenuates cartilage and bone damage by inhibiting inflammation in collagen II‐induced arthritis model

  2019cites this paper
• Treatment of Borrelia burgdorferi–Infected Mice with Apoptotic Cells Attenuates Lyme Arthritis via PPAR-γ

  2019cites this paper
• Regulation of macrophage activation by proteins expressed on apoptotic neutrophils: Subversion towards autoimmunity by proteinase 3

  2018cites this paper
• Factors Produced by Macrophages Eliminating Apoptotic Cells Demonstrate Pro-Resolutive Properties and Terminate Ongoing Inflammation

  2018cites this paper
• Harnessing Apoptotic Cell Clearance to Treat Autoimmune Arthritis

  2017cites this paper
• Recognizing and managing on toxicities in cancer immunotherapy

  2017cites this paper
• Etude des mécanismes d'action de la photochimiothérapie extracorporelle

  2017cites this paper
• Evaluation des facteurs issus de l'efferocytose comme médicament innovant dans le traitement des maladies inflammatoires chroniques de l'intestin

  2017cites this paper
• The many ways tissue phagocytes respond to dying cells

  2017cites this paper
• Targeting the Monocyte–Macrophage Lineage in Solid Organ Transplantation

  2017cites this paper
• Plasmacytoid Dendritic Cells Respond Directly to Apoptotic Cells by Secreting Immune Regulatory IL-10 or IFN-α

  2016influential citation