Induction of Inflammatory Arthropathy Resembling Rheumatoid Arthritis in Mice Transgenic for HTLV-I

Abstract

Human T cell leukemia virus type-I (HTLV-I) is the etiologic agent of adult T cell leukemia and has also been suggested to be involved in other diseases such as chronic arthritis or myelopathy. To elucidate pathological roles of the virus in disease, transgenic mice were produced that carry the HTLV-I genome. At 2 to 3 months of age, many of the mice developed chronic arthritis resembling rheumatoid arthritis. Synovial and periarticular inflammation with articular erosion caused by invasion of granulation tissues were marked. These observations suggest a possibility that HTLV-I is one of the etiologic agents of chronic arthritis in humans.

Suppression of autoimmune arthritis in interleukin‐1‐deficient mice in which T cell activation is impaired due to low levels of CD40 ligand and OX40 expression on T cells

“…IL-1␣ Ϫ/Ϫ , IL-1␤ Ϫ/Ϫ , and IL-1␣/␤ Ϫ/Ϫ mice were generated as previously described (7). HTLV-I Tg mice, originally produced by injecting the LTR-env-pX-LTR region of the HTLV-I genome into a (C3H/HeN ϫ C57BL/6J)F 1 ovum (18), were backcrossed to BALB/cA mice (Clea, Tokyo, Japan) for 12 generations and then were used for the experiments. These mice start to develop arthritis spontaneously at 4 534 SAIJO ET AL weeks of age, and 60% and 80% of the mice are affected at 3 months and 6 months of age, respectively.…”

“…Development of arthritis was then compared between homozygous-deficient mice and wild-type littermates. The pX transgene was detected by dot-blot hybridization of the tail DNA (18).…”

“…The human T cell leukemia virus type I transgenic (HTLV-I Tg) mouse model is another RA model (18). These mice carry the env-pX region of HTLV-I, the etiologic agent of adult T cell leukemia (for review, see refs.…”

Induction of apoptosis in the rheumatoid synovium by Fas ligand gene transfer

“…[10][11][12] We previously established mice carrying human T cell leukemia virus type 1 (HTLV-1) representing one of the most suitable animal models of human RA. 13 Using this model, we have recently demonstrated that intra-articular administration of anti-Fas MAb improved the paw swelling and histological features of arthritis by induction of apoptosis of both synoviocytes and mononuclear cells in the inflamed synovium. 14 These findings clearly suggest that apoptosis via the Fas/FasL system may be an important factor for regression of proliferative rheumatoid synovium and administration of anti-Fas MAb could be a novel therapeutic strategy for RA.…”

The C-terminus of the HTLV-1 Tax oncoprotein mediates interaction with the PDZ domain of cellular proteins

“…The oncogenic properties of this protein have been established by various assays, including transformation of primary T lymphocytes (Grassmann et al, 1989), cooperation with Ras in transformation of ®broblasts (Pozzatti et al, 1990) and induction of tumours in transgenic mice (Nerenberg et al, 1987;Benvenisty et al, 1992;Grossman et al, 1995). Tax transgenic mice are also known to develop several pathologies including thymus atrophy (Furuta et al, 1989), muscle degeneracy (Nerenberg and Wiley, 1989), arthritis (Iwakura et al, 1991) and a proliferation of ductal cells of the salivary gland resembling the SjoÈ gren syndrome (Green et al, 1989). These disorders correlate with observations made in HTLV-1-infected patients (Ozden et al, 1996).…”