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

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2012-07, Vol.64 (7), p.2169-2178
• Main Authors: Pigott, Elizabeth, Mandik-Nayak, Laura
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Arthritis; Arthritis, Experimental - drug therapy; Arthritis, Experimental - immunology; Arthritis, Experimental - therapy; Autoantibodies - immunology; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Biological and medical sciences; Cell Differentiation; Diseases of the osteoarticular system; Immune system; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors; Lymphocyte Depletion - methods; Medical sciences; Mice; Mice, Transgenic; Miscellaneous. Osteoarticular involvement in other diseases; Rodents; Secondary Prevention; T cell receptors; Tryptophan - analogs & derivatives; Tryptophan - therapeutic use
• ISSN: 0004-3591; 2326-5191; 1529-0131; 2326-5205
• DOI: 10.1002/art.34406

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.