title: Addition of an indoleamine 2,3,-dioxygenase inhibitor to B cell-depletion therapy blocks autoreactive B cell activation and recurrence of arthritis in K/BxN mice.
abstract: OBJECTIVE
  To define the role of indoleamine 2,3-dioxygenase (IDO) in driving pathogenic B cell responses that lead to arthritis and to determine if inhibitors of the IDO pathway can be used in conjunction with therapeutic B cell depletion to prevent the reemergence of autoantibodies and arthritis following reconstitution of the B cell repertoire.
  
  
  METHODS
  Immunoglobulin-transgenic mice were treated with the IDO inhibitor 1-methyltryptophan (1-MT) and monitored for the extent of autoreactive B cell activation. Arthritic K/BxN mice were treated with B cell depletion alone or in combination with 1-MT. Mice were monitored for the presence of autoantibody-secreting cells, inflammatory cytokines, and joint inflammation.
  
  
  RESULTS
  Treatment with 1-MT did not affect the initial activation or survival of autoreactive B cells, but it did inhibit their ability to differentiate into autoantibody-secreting cells. Treatment with anti-CD20 depleted the B cell repertoire and attenuated arthritis symptoms; however, the arthritis symptoms rapidly returned as B cells repopulated the repertoire. Administration of 1-MT prior to B cell repopulation prevented the production of autoantibodies and inflammatory cytokines and flare of arthritis symptoms.
  
  
  CONCLUSIONS
  IDO activity is essential for the differentiation of autoreactive B cells into antibody-secreting cells, but it is not necessary for their initial stages of activation. Addition of 1-MT to therapeutic B cell depletion prevents the differentiation of autoantibody-secreting cells and the recurrence of autoimmune arthritis following reconstitution of the B cell repertoire. These data suggest that IDO inhibitors could be used in conjunction with B cell depletion as an effective cotherapeutic strategy in the treatment of rheumatoid arthritis.
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pigott
authors.forename: Laura
authors.initials: L
authors.lastname: Mandik-Nayak
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D001323:Autoantibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D008212:Lymphocyte Depletion / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D055502:Secondary Prevention; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D001323:Autoantibodies; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan; C525396:1-methyltryptophan