990 - Innate Immune Stimulation Triggers Early-Onset Spondyloarthritis in HLA-B27/Human beta2 Microglobulin Transgenic Rats

Monday, November 7, 2011: 9:00 AM-6:00 PM
Hall F2 - Poster Hall (McCormick Place West)
Leonie M. van Duivenvoorde1, Gleb M. Slobodin2, Nimman Satumtira2, Martha L. Dorris2, Paul P. Tak3, Dominique L. Baeten1 and Joel D. Taurog2, 1Academic Medical Center / University of Amsterdam, Amsterdam, Netherlands, 2UT Southwestern Medical Center, Dallas, TX, 3Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam The Netherlands, Amsterdam, Netherlands
Presentation Number: 990

Background/Purpose: We recently proposed that spondyloarthritis (SpA) is driven by altered innate immune responses rather than by autoantigen-specific T or B cell responses1. The objective of this study aimed to test directly the hypothesis that stimulation of the innate immune system triggers experimental SpA.

Methods: Rats were injected subcutaneously with Mtb in oil or IFA with doses of 30 – 100 µg Mtb, which is lower than doses typically used to trigger arthritis adjuvant arthritis in non-tg LEW rats. In the first experiments, HLA-B27/hb2m rats from several different tg lines2, HLA-B7/hb2m tg&rats 2and non-tg LEW control rats were injected with 30, 60 or 100 mg Mtb in IFA. The second set of experiments, used (21-3x283-2)F1 HLA-B27/hb2m tg and (120-4x283-2)F1 HLA-B7/hb2m control rats, both with high copy hb2m, and non-tg LEW controls. These rats were immunized with 30, 60 or 90 mg Mtb in IFA at 6 wk of age. Arthritis and spondylitis were monitored clinically.

Results: In the first set of experiments, arthritis was induced in both HLA-B27/hb2m and HLA-B7/hb2m tg rats at doses of ≤60 µg of Mycobacterium tuberculosis (Mtb)(B27/hb2m: 10/22; B7/hb2m: 8/17 vs. 1/24 non-tg controls). To test whether this effect was more specifically related to HLA-B27 and to assess the effect on spondylitis, which only occurs spontaneously in (21-3x283-2)F1 males, the second set of experiment was carried out as described in Methods. In the spontaneous SpA of (21-3x283-2)F1 rats, the males develop arthritis and spondylitis beginning at 110 d of age, reaching an incidence of 70% and 40% respectively. The female (21-3x283-2)F1 and both sexes of the (120-4x283-2)F1 B7/hb2m rats remain healthy. Data obtained in these rats are depicted in the table.

In males, 30 mMtb induced arthritis and/or spondylitis in 6/6 HLA-B27/hb2m rats, but not in the HLA-B7/hb2m controls. In females, 60 or 90 mMtb induced both arthritis and spondylitis in 6/6 of the HLA-B27/hb2m tg rats, but in none of the HLA-B7/hb2m controls. Arthritis and spondylitis appeared 2-3 weeks after immunization in both genders, over 40 d before the age of earliest onset of spontaneous arthritis in males.

Conclusions: These data indicate that low dose Mtb, an innate immune stimulus, triggers SpA in HLA-B27/hb2m tg rats. Moreover, it induces SpA in females, increases incidence in males, and accelerates and synchronizes disease onset, all of which will facilitate use of this model for experimental and preclinical research.

References

  1. Lories RJ and Baeten DL., Clin Exp Rheumatol. 2009; 27(4 Suppl 55):S10-4
  2. Taurog JD et al., Immunol Rev 1999; 169,:209-223
  3. Tran TM et al., Arthritis Rheum. 2006; 54(4):1317-27

Keywords: adjuvant arthritis, animal models and spondylarthropathy

Disclosure: L. M. van Duivenvoorde, None; G. M. Slobodin, None; N. Satumtira, None; M. L. Dorris, None; P. P. Tak, None; D. L. Baeten, None; J. D. Taurog, Taconic, Inc., 7 .