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
Article first published online: 26 JUN 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 7, pages 2169–2178, July 2012
How to Cite
Pigott, E. and Mandik-Nayak, L. (2012), 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 & Rheumatism, 64: 2169–2178. doi: 10.1002/art.34406
- Issue published online: 26 JUN 2012
- Article first published online: 26 JUN 2012
- Accepted manuscript online: 31 JAN 2012 10:38AM EST
- Manuscript Accepted: 24 JAN 2012
- Manuscript Received: 3 AUG 2011
- NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases). Grant Number: 5-R01-AR-057847-01
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.
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.
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.
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.