Background/Purpose:

The clinical benefit of B-cell depletion therapy in rheumatoid arthritis(RA) is a well-known fact, but problems such as relapse of tuberculosis and reactivation of hepatitis B are reported.We thought that these problems were resolved by focusing on depletion of pathogenic antigen-specific B cells using a B cell epitope tetramer conjugated with immunotoxin. We treated collagen-induced arthritis (CIA) mice by the peptide-tetramer method.

Methods:

Arthritis was induced by immunizing DBA/1J mice with Bovine Type II collagen. Toxin-conjugated peptide tetramers, which had the ability to deplete peptide-specific B cells, were intravenously administered to CIA mice. After first immunization (day0), tetramers were administrated in day10 and day20 and boost immunization was carried out in day 21.We used three kinds of peptides for preparing tetramers. One (CIA1), which has citrullinated arginine residue of C1 domain, is a major epitope of type II collagen. The second (CIAC) has non-citrullinated arginine residue of C1 domain. The third has the lysine residue-rich peptide (LKP) as a control. We conjugated immunotoxin to these peptide tetramers in order to deplete peptide-specific B cells. We chose saporin which was class I ribosome-inactivating proteins as a immunotoxin. Non-cytotoxic tetramer using CIA1, anti-CD20 antibody, the anti-CD79β antibody and PBS were also injected mice as a comparison. The incidence, arthritis score and antibodies to peptide were evaluated.

Results:

In mice administered CIA1 tetramer, anti-CIA antibody completely dissapeared as compared with PBS group (P = 0.01) and the onset of arthritis was delayed. Because the antibody titers for U1 epitope of the type II collagen did not have the significant difference between CIA1 and PBS group, it was shown that we depleted the B cells which were an antigen-specific. In mice administered tetramers using CIAC or LKP, anti-CD20 antibody, antiCD79 antibody and non-cytotoxic tetramer using CIA1, the antibody titers for CIA1 have increased and the onset of the arthritis was delayed.

Conclusion:

By the depletion of citrullinated antigen-specific B cells using a B cell-epitope tetramer, the onset of the arthritis was delayed. It was necessary for the tetramer to have the cytotoxicity and the citrullinated peptide in order to improve clinical and pathological score. Targeting of citrullinated antigen-specific B cells might be a new strategy of RA treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeting-therapy-of-citrullinated-antigen-specific-b-cells-ameliorates-collagen-induced-arthritis/