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

Arthritis Rheum. 2012 Jul;64(7):2169-78. doi: 10.1002/art.34406.

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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / therapy*
  • Autoantibodies / immunology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / pathology
  • Cell Differentiation
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
  • Lymphocyte Depletion / methods*
  • Mice
  • Mice, Transgenic
  • Secondary Prevention
  • Tryptophan / analogs & derivatives*
  • Tryptophan / therapeutic use

Substances

  • Autoantibodies
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Tryptophan
  • 1-methyltryptophan