title: Brief report: Autologous stem cell transplantation restores immune tolerance in experimental arthritis by renewal and modulation of the Teff cell compartment.
abstract: OBJECTIVE
  Autologous stem cell transplantation (ASCT) induces long-term drug-free disease remission in patients with juvenile idiopathic arthritis. This study was undertaken to further unravel the immunologic mechanisms underlying ASCT by using a mouse model of proteoglycan-induced arthritis (PGIA).
  
  
  METHODS
  For initiation of PGIA, BALB/c mice received 2 intraperitoneal injections of human PG in a synthetic adjuvant on days 0 and 21. Five weeks after the first immunization, the mice were exposed to total body irradiation (7.5 Gy) and received (un)manipulated bone marrow (BM) grafts from mice with PGIA. Clinical scores, T cell reconstitution, (antigen-specific) T cell cytokine production, and intracellular cytokine expression were determined following autologous BM transplantation (ABMT).
  
  
  RESULTS
  ABMT resulted in amelioration and stabilization of arthritis scores. BM grafts containing T cells and T cell-depleted grafts provided the same clinical benefit, with similar reductions in PG-induced T cell proliferation and the number of PG-specific autoantibodies. In vivo reexposure to PG did not exacerbate disease. Following ABMT, basal levels of disease-associated proinflammatory cytokines (interferon-γ [IFNγ], interleukin-17 [IL-17], and tumor necrosis factor α [TNFα]) were reduced. In addition, restimulation of T cells with PG induced a strong reduction in disease-associated proinflammatory cytokine production. Finally, although the remaining host T cells displayed a proinflammatory phenotype following ABMT, IFNγ, IL-17, and TNFα production by the newly reconstituted donor-derived T cells was significantly lower.
  
  
  CONCLUSIONS
  Taken together, our data suggest that ABMT restores immune tolerance by renewal and modulation of the Teff cell compartment, leading to a strong reduction in proinflammatory (self antigen-specific) T cell cytokine production.
authors: University Medical Center Utrecht and Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors: Eveline M
authors: EM
authors: Delemarre
authors: Sarah T A
authors: ST
authors: Roord
authors: Theo
authors: T
authors: van den Broek
authors: Evelien
authors: E
authors: Zonneveld-Huijssoon
authors: Wilco
authors: W
authors: de Jager
authors: Henk
authors: H
authors: Rozemuller
authors: Anton C
authors: AC
authors: Martens
authors: Femke
authors: F
authors: Broere
authors: Nico M
authors: NM
authors: Wulffraat
authors: Tibor T
authors: TT
authors: Glant
authors: Berent J
authors: BJ
authors: Prakken
authors: Femke
authors: F
authors: van Wijk
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000628:therapy*; D064592:Autografts; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005260:Female; D007108:Immune Tolerance / Q000502:physiology*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011509:Proteoglycans / Q000009:adverse effects; D033581:Stem Cell Transplantation; D016176:T-Lymphocyte Subsets / Q000378:metabolism / Q000473:pathology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D011509:Proteoglycans; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma