title: Development of a Functional Biomarker for Use in Cell-Based Therapy Studies in Seropositive Rheumatoid Arthritis.
abstract: Cell-based therapy has potential therapeutic value in autoimmune diseases such as rheumatoid arthritis (RA). In RA, reduction of disease activity has been associated with improvement in the function of regulatory T cells (Treg) and attenuated responses of proinflammatory effector T cells (Teff). Mesenchymal stem cells (MSCs) and related multipotent adult progenitor cells (MAPC) have strong anti-inflammatory and immunomodulatory properties and may be able to "reset" the immune system to a pre-RA state. MAPC are MSC-like cells that are slightly earlier in lineage, have greater expansion capacity, and can be used as "off-the-shelf" therapy. Assessment of cell-based therapy to treat arthritis and related diseases is limited by the lack of available biological correlates that can be measured early on and indicate treatment response. We set out to develop a functional measure that could be used ex vivo as a biomarker of response. We were able to demonstrate that MAPC products could inhibit Teff responses from patients with active RA and that Treg from RA patients suppressed Teff. This assay used ex vivo can be used with MAPC or Treg alone or in combination and reflects the overall level of Teff suppression. Use of a novel functional biomarker as an exploratory endpoint in trials of cell-based therapy should be of value to detect biological outcomes at a point prior to the time that clinical response might be observed.
  
  
  CONCLUSIONS
  Therapy with mesenchymal stem cells and related multipotent adult progenitor cells is immune modifying in a variety of diseases. There is interest in using cell-based therapy in rheumatoid arthritis (RA) to induce tolerance and "reset" the immune system to its pre-RA state. In a clinical trial, it should be known as soon as possible if there is a chance of response. A biomarker has been developed that permits measurement of the effects of cell-based therapy on effector T cell function.
authors.affiliation: Division of Rheumatology, MetroHealth Medical Center, Cleveland, Ohio, USA.
authors.forename: Gali
authors.initials: G
authors.lastname: Shalev-Malul
authors.affiliation: Department of Dermatology, University Hospitals Case Medical Center, Cleveland, Ohio, USA The Murdough Family Center for Psoriasis, Cleveland, Ohio, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Soler
authors.affiliation: Athersys, Inc., Cleveland, Ohio, USA.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Ting
authors.affiliation: Athersys, Inc., Cleveland, Ohio, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Lehman
authors.affiliation: Division of Rheumatology, MetroHealth Medical Center, Cleveland, Ohio, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Barnboym
authors.affiliation: Department of Dermatology, University Hospitals Case Medical Center, Cleveland, Ohio, USA The Murdough Family Center for Psoriasis, Cleveland, Ohio, USA Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: McCormick
authors.affiliation: Case Western Reserve University School of Medicine, Cleveland, Ohio, USA Divisions of Rheumatology, University Hospitals Case Medical Center, Cleveland, Ohio, USA Division of Infectious Disease, University Hospitals Case Medical Center, Cleveland, Ohio, USA Cleveland VA Medical Center, Cleveland, Ohio, USA.
authors.forename: Donald D
authors.initials: DD
authors.lastname: Anthony
authors.affiliation: Case Western Reserve University School of Medicine, Cleveland, Ohio, USA Divison of Hematology Oncology, University Hospitals Case Medical Center, Cleveland, Ohio, USA Case Comprehensive Cancer Center, Cleveland, Ohio, USA.
authors.forename: Hillard M
authors.initials: HM
authors.lastname: Lazarus
authors.affiliation: Case Western Reserve University School of Medicine, Cleveland, Ohio, USA Department of Biology, Skeletal Research Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Arnold I
authors.initials: AI
authors.lastname: Caplan
authors.affiliation: Division of Rheumatology, MetroHealth Medical Center, Cleveland, Ohio, USA Case Western Reserve University School of Medicine, Cleveland, Ohio, USA mbreitman@metrohealth.org.
authors.forename: Maya
authors.initials: M
authors.lastname: Breitman
authors.affiliation: Division of Rheumatology, MetroHealth Medical Center, Cleveland, Ohio, USA Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Nora G
authors.initials: NG
authors.lastname: Singer
mesh_terms: D053687:Adult Stem Cells / Q000276:immunology / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000175:diagnosis / Q000276:immunology / Q000628:therapy*; D001681:Biological Assay / Q000379:methods*; D015415:Biomarkers / Q000097:blood; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D039902:Multipotent Stem Cells / Q000276:immunology / Q000378:metabolism*; D010641:Phenotype; D011237:Predictive Value of Tests; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D017077:Culture Media, Conditioned
keywords: Arthritis; Autoimmune diseases; Biological markers; Mesenchymal stromal cells; Rheumatoid; T lymphocytes