title: Mesenchymal stem cells are conditionally therapeutic in preclinical models of rheumatoid arthritis.
abstract: OBJECTIVE
  The role of mesenchymal stem cells (MSC) in experimental arthritis is undoubtedly conflicting. This study explored the effect of bone marrow-derived MSC in previously untested and pathogenetically different models of rheumatoid arthritis (RA).
  
  
  METHODS
  MSC were tested both in an induced (adjuvant-induced) and a spontaneous (K/BxN) arthritis model. Arthritis was assessed clinically and histologically. The proliferation of splenocytes and fibroblast-like synoviocytes (FLS) in the presence of MSC was measured by radioactivity incorporation. Toll-like receptor (TLR) expression was measured by real-time PCR. T-regulatory cell (Treg) frequency, T-cell apoptosis and cytokine secretion were monitored by flow cytometry.
  
  
  RESULTS
  MSC, in vitro, strongly inhibited critical cell populations; splenocytes and FLS. In contrast, MSC proved ineffective in vivo, unless they were administered before disease onset, an effect implying that the inflammatory arthritic milieu potentially abrogates MSC immunomodulatory properties. In order to alleviate inflammation before MSC infusion, the authors administered, at arthritis onset, a short course with a proteasome inhibitor, bortezomib, whereas MSC were infused when established disease was expected. The bortezomib plus MSC group demonstrated a significantly decreased arthritis score over arthritic, MSC-only, bortezomib-only groups, also confirmed by histology and immunohistochemistry. The bortezomib plus MSC combination restored TLR expression and Treg frequency in blood and normalised FLS and splenocyte proliferation, apoptosis and cytokine secretion.
  
  
  CONCLUSIONS
  MSC lose their immunomodulatory properties when infused in the inflammatory micromilieu of autoimmune arthritis. Conditioning of the recipient with bortezomib alters the disease microenvironment enabling MSC to modulate arthritis. Should milieu limitations also operate in human disease, this approach could serve as a strategy to treat RA by MSC.
authors.affiliation: George Papanicolaou Hospital, Gene and Cell Therapy Center, Hematology Department-BMT Unit, Thessaloniki 57010, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Papadopoulou
authors.forename: Minas
authors.initials: M
authors.lastname: Yiangou
authors.forename: Evangelia
authors.initials: E
authors.lastname: Athanasiou
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Zogas
authors.forename: Panayotis
authors.initials: P
authors.lastname: Kaloyannidis
authors.forename: Ioannis
authors.initials: I
authors.lastname: Batsis
authors.forename: Athanasios
authors.initials: A
authors.lastname: Fassas
authors.forename: Achilles
authors.initials: A
authors.lastname: Anagnostopoulos
authors.forename: Evangelia
authors.initials: E
authors.lastname: Yannaki
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage*; D001169:Arthritis, Experimental / Q000276:immunology / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy*; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D004195:Disease Models, Animal; D005434:Flow Cytometry; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011719:Pyrazines / Q000008:administration & dosage*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018501:Antirheumatic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib