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*
Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan;
Kohno Clinical Medicine Research Institute, Kitashinagawa, Shinagawa-ku, Tokyo, Japan; and
Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit 3 , IL-2 4, 5 , c-Fos
6, 7 , c-Jun 8 , nerve growth factor 9 , granulocyte-macrophage CSF
10 , TGF-ß 11 , and Lyn 12 . It has been postulated that the
transactivation activity of Tax may be responsible for the development
of diseases caused by this virus 2 . In a previous paper, we produced the long terminal repeat (LTR)-pX-Tg mice that carry the HTLV-I env-pX region under its own LTR promoter and showed that these mice develop chronic inflammatory polyarthropathy 13 . The arthritis developed as early as 4 wk of age and increased in incidence gradually after that. By 3 mo of age about 20% of the mice and by 6 mo 40% of the mice (C3H/HeN background) were affected. The affected mice were easily detected by swelling and redness of the joints with lesions most frequently seen in the hind leg ankles. The histopathology of the lesions showed marked synovial and periarticular inflammation with articular erosion caused by the invasion of granulation tissues 14 .
Immunologically, these mice produced autoantibodies against IgG, type
II collagen (IIC), and heat shock proteins, and had accompanying IgG
hypergammaglobulinemia 15 . Cellular immune response to IIC as well as
to heat shock proteins was also activated. In addition, the N-linked
sugar chains of the transgenic IgG had more agalactosylated forms than
those from nontransgenic IgG, as is seen in patients with rheumatoid
arthritis (RA) 16 . We also found that genes for inflammatory
cytokines including IL-1, IL-1ß, IL-6, TNF-, TGF-ß, IFN-
,
and IL-2 as well as MHC genes were activated in the transgenic joints
15 . Because these pathological observations were very similar to
those of RA, we suggested that HTLV-I may be involved in the
development of RA in humans 13 . However, it remains to be elucidated
which gene in the pX region is involved in the development
of the disease, as the transgene of LTR-pX-Tg mice consisted
of the env, tax, rex, and p21 genes.
In the current study, to elucidate the pathogenesis of the disease, we tested the involvement of the tax gene in disease pathogenesis by producing transgenic mice that expressed only the tax gene under two different enhancer/promoters. The results showed that tax expression by itself induced arthropathy resembling RA. Interestingly, two founder mice developed ankylotic arthropathy with bone hyperplasia but without inflammation, which is a considerably different pathology from that seen in RA.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rabbit IgG was purified from serum by ammonium sulfate precipitation followed by protein A column chromatography and heat denatured at 62°C for 20 min. Bovine IIC (K42) was obtained from Collagen Gijyutsu-kenshukai (Tokyo, Japan).
Plasmids
pLTR-tax was constructed by ligating a 4.0-kb
HindIII fragment containing the HTLV-I 5' LTR region of
pHLX-1 13 to a 2.5-kb HindIII fragment of pKCR40 M 17
containing the HTLV-I pX and 3' LTR regions (see Fig. 1
A). The pX region of pKCR40 M was constructed so
as to produce only Tax protein as described previously 17 . In brief,
the rex gene was disrupted by deleting its initiation codon,
and the p21 gene was also disrupted by changing the
initiation codon at nucleotide 7477 from ATG to ACG, whereas
tax mRNA is intact because its initiation codon was supplied
by a synthetic oligonucleotide (see Fig. 1B). To construct
pCD4-tax, a 0.85-kb HindIII-XhoI
fragment from the mouse CD4 enhancer/promoter (pBLCD4/0.35 wt) 18 and
a 0.64-kb HindIII-BamHI fragment from the rabbit
ß-globin gene (p1757) 19 were ligated, then a 1.59-kb
HindIII-BamHI fragment from this construct, and a
2.3-kb BamHI-BglII fragment from pKCR40 M,
containing the tax gene, were inserted into
HindIII-BglII site of p1017 20 , which provides
an extra poly(A) additional signal of the human growth hormone gene
(see Fig. 1C).
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LTR-tax-Tg mice were produced by injecting a 3.2-kb EcoRI fragment from pLTR-tax into fertilized C3H/HeN mouse ova. The founder mouse was crossed with C3H/HeN, and the homozygotes were produced by intercrossing the F1 mice. The line was maintained by sister-brother mating. In the case of CD4-tax-Tg mice, a 4.6-kb SphI fragment was injected into fertilized C3H/HeN ova. The LTR-pX-Tg mice (line T647) were those previously described by our group 13 . These mice were produced by introducing an EcoRI fragment from pHLX-I containing the env-pX region of the HTLV-I genome with its own promoter into fertilized mouse ova ((C3H/HeN x C57BL/6J)F1), backcrossing each of the mice with a C3H/HeN mouse. Mice from backcross generation 10–12 were used for the experiments.
Female mice at the age of 2–3 mo were used in this study, except for certain experiments described in the figure legends, and the littermates were used as controls. The transgenes were detected through dot-blot hybridization using DNA prepared from mouse tails and 32P-labeled transgene as the probes 15 . These mice were kept in specific pathogen-free conditions in environmentally controlled clean rooms of the Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo (Tokyo, Japan). The experiments were conducted according to the institutional ethical guidelines for animal experiments and safety guidelines for gene manipulation experiments in Japan.
Southern blot hybridization
Genomic DNA (15 µg) prepared from the liver was digested with
MboI and DraI, and after electrophoresis on a
0.8% agarose gel, it was transferred to nylon membranes
(GeneScreenplus, DuPont/NEN, Boston, MA). Hybridization was
conducted using 32P-labeled 0.76-kb
AccI-ScaI fragment (probe
A in Fig. 1
A) from pLTR-tax as the
probe (1 x 108 dpm/µg) at 42°C for overnight,
then membranes were washed twice with 2x SSC plus 1.0% SDS at room
temperature and three times with 0.1x SSC plus 1.0% SDS at 65°C.
The intensity of the bands on the autoradiogram was estimated by BAS
2000 system (Fuji Photo Film, Kanagawa, Japan).
Detection of mRNA
Cytokine mRNAs were analyzed by Northern blot hybridization as
previously described 15 . Briefly, total RNA was prepared from various
tissues using acid guanidinium thiocyanate-phenol-chloroform method
21 and poly(A)+ RNA was purified from the total RNA with
an oligo(dT)-cellulose column (QuickPrep; Pharmacia Biotech,
Piscataway, NJ). For thighbone RNA preparation, bone marrow cells and
muscles and skin were removed from the bone. For Northern blot
hybridization, 5 µg poly(A)+ RNA was electrophoresed on a
denatured agarose gel. Then, RNA was transfered onto a nylon membrane
filter and hybridized at 42°C for overnight with a
32P-labeled DNA probe (109 dpm/µg) labeled
with [-32P]dCTP (3000 Ci/mmol; DuPont/NEN) by a
multiprime DNA labeling system (Amersham, Arlington Heights, IL).
tax mRNA was detected by RNase protection assay 13 . Total
RNA purified from pooled tissues from two mice (40 µg) or from MT-2
cells 13 (0.1 µg) was hybridized at 50°C overnight with an
antisense RNA probe (837-base) made with T7 RNA polymerase using
the AccI-ScaI fragment (probe
B in Fig. 1A) from pLTR-tax that had been
subcloned into the EcoRV site of pBluescript KS(+)
(Stratagene, La Jolla, CA) as a template. After RNase A (40 µg/ml)
and T1 (2 µg/ml) treatment at 37°C for 1 h, the RNA samples
were electrophoresed on a 4% polyacrylamide gel containing 7.8 M urea.
Tax mRNA was detected as a 758-base band in the RNase
protection assay. The intensity of the bands on the autoradiogram was
estimated by the BAS 2000 system (Fuji Photo Film).
Probes
The probes used in this study were described previously 15 .
Briefly, the XhoI fragments from CDMmIL-1 (2.0 kb) 22
and CDMmIL-1ß (1.3 kb) 23 were used to detect IL-1 and IL-1ß.
IL-6 was probed with the BamHI (1.2 kb) fragment from
moIL-6 24 , and TNF- was detected with the BglII
fragment (711 bp) from moTNF- 25 . The
EcoRI-XbaI rat TGF-ß1 cDNA clone (pBluescript
TGF-ß1) was used for a probe 11 . ß-Actin was detected using the
PstI fragment (1.0 kb) from pAL41 26 and used as a
control.
Histological examination
Tissues were fixed with 10% formalin in PBS and decalcified by treatment with Plank-Rycole solution (50% formic acid, 3% HCl, 0.3 M NH4Cl). Four-micrometer sections were prepared after embedding in paraffin and were stained with hematoxylin and eosin.
Ab titration
Serum IgG and IgM levels were determined as previously described 27 . Serum Ab levels were measured by ELISA 15, 28 . Briefly, polyvinyl microtiter plates (Falcon MicroTest III; Becton Dickinson, Tokyo, Japan) were coated with either heat-denatured rabbit IgG (10 µg/ml) or bovine IIC (20 µg/ml). Then, the plates were blocked with 1% skim milk (Sigma, St. Louis, MO) and 5 mM EDTA, and diluted mouse serum was added to each well and incubated for 1 h at room temperature. After washing, alkaline phosphatase-conjugated goat anti-mouse IgG Ab (Zymed, San Francisco, CA) or anti-mouse IgM Ab (Zymed) was added and incubated at 37°C for 1 h, followed by staining with p-nitrophenylphosphate (Sigma). The absorbancy at 415 nm was measured after incubation at 37°C for 1 h.
Protein concentration was measured with a Bradford Protein Determination kit (Bio-Rad, Hercules, CA) and BSA was used as a standard.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We previously reported on LTR-pX-Tg mice that develop
inflammatory arthropathy resembling RA. Because four genes are expected
to be expressed in these transgenic mice, we produced transgenic mice
that only express the tax gene to examine its role in the
development of arthritis. For this, we constructed two types of
transgenes; in one construct, pLTR-tax, the tax
gene was placed under the control of its own LTR promoter, and in the
other construct, pCD4-tax, the tax gene was
ligated downstream to the CD4 enhancer/promoter (Fig. 1).
Seven LTR-tax-Tg mice were produced by injecting the LTR-tax DNA into the pronuclei of 3891 fertilized mouse ova. Three of these mice developed abnormalities of the joints. One of them, T3376 (male), showed remarkable swelling of the digital and ankle joints both of the forelegs and hind legs. This mouse died without producing an offspring. Another, T5571 (male), developed deformities of the left hind leg digital joints and the right ankle joint at 9 mo of age. This mouse showed ankylotic change of the ankle and knee joints later. This mouse also died at 12 mo of age without reproducing. T4055 (male) showed ankylotic changes in the joints without swelling, which was in contrast to those symptoms seen in T3376. None of the other mice showed any obvious joint changes. Thus, T3376 and T5571 founder mice and descendants of T4055 were analyzed further.
In case of CD4-tax-Tg mice, nine transgenic founder mice
were produced by injecting the CD4-tax DNA into 1483
fertilized ova. Among them, five mice showed joint abnormalities with
swelling of the ankle joints and redness of the foot pads before 3 mo
of age. We established three lines, T1887, T5368, and T5562, from those
mice with joint abnormality (Fig. 2B). Transgenic mice from
these lines looked unhealthy, had smaller body size compared with the
normal littermates, and did not breed very well. Because all of these
lines showed similar pathology, we analyzed T5368 line mice in detail.
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, a 1.3-kb band of expected length was
detected in both T5368 line CD4-tax-, T4055 line
LTR-tax-, and LTR-pX-Tg mouse indicating
integration of the transgene into the host chromosome. The copy numbers
were estimated to be 
7, 1, and 50 copies per genome in T5368
line CD4-tax-, T4055 line LTR-tax-, and
LTR-pX-Tg mice, respectively.
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Joint swelling of T3376 LTR-tax-Tg mouse started at the age of 1 mo and continued throughout life. His growth was markedly retarded, and his body weight was 7.3 g at 2 mo old, about one-third the weight of normal mice. This mouse died at 2 mo of age.
On autopsy immediately after death, the spleen was found to be atrophied with a weight of 10 mg, probably reflecting severe wasting, whereas the thymus looked normal with a weight of 29 mg. Calcium deposits were detected in cardiac muscle. No other abnormalities were found on histologic examination in any tissue except for the bones and joints.
Marked proliferation of the synovial tissues was observed as shown in
Fig. 2D. Synovial tissues, consisting of the synovial lining
cells and fibroblastic cells, extended into the joint space forming
villi and covered the surface of the articular cartilage (Fig. 2, D and E). Erosive destruction occurred over the
surface of the cartilage due to the invasion of pannus-like granulation
tissues that extended even into the bone marrow space (Fig. 2F). The granulation tissues consisted of massive
infiltration of inflammatory cells, mostly neutrophils and lymphocytes.
Polymorphonuclear leukocytes were also found in the joint space (Fig. 2E). These histopathological findings contrasted
markedly with those of the non-Tg healthy joint (Fig. 2C).
CD4-tax-Tg mice, line T5368, also showed similar joint
abnormality. Both female and male mice were affected similarly in this
line. These mice showed growth retardation, and the spleen was one and
one-half to three times heavier than a normal spleen. The joint
abnormality became detectable at 6 wk of age, and at 12 wk 50% of
the mice were affected. The histopathology of the joints was similar to
that seen in T3376 LTR-tax-Tg mouse. As shown in Fig. 2, G and H, synovial cell overgrowth, bone erosion
with granulation tissues, and inflammatory cell infiltration into the
granulation tissues were observed in these lesions, although the
infiltration of inflammatory cells did not appear as intensive as that
seen in T3376 (Fig. 2, D–F). Mice from T5562 and
T1887 CD4-tax-Tg line also showed similar histology (data
not shown).
These histopathological changes were similar to those found in LTR-pX-Tg mice 13, 14 and in RA in humans. These findings indicate that Tax by itself can cause inflammatory arthropathy resembling RA. In T3376, mild erosive damage could also be found in other joints including the vertebra and tail (data not shown).
Development of ankylotic polyarthropathy in T4055 line LTR-tax-Tg mice and T5571 LTR-tax-Tg founder mouse
Descendants from the T4055 LTR-tax-Tg founder mouse
showed ankylotic changes of the joints (Table I). Neither swelling nor redness of the
joints was observed in this line, although some joint deformities were
seen. Extension of the knee joints gradually became difficult with age,
starting at 4–6 wk old, and eventually fixed after several months.
Incidence of ankylotic joint changes reached to nearly 100% at 10 mo
old in C3H/HeN background (Table I). Ankylotic changes could be
observed in multiple joints including the vertebral and tail joints in
older mice. The histology of 13 mice (5 females and 8 males) was
examined microscopically, and hyperplasia of bony and cartilaginous
tissues of the joints was found to be the most characteristic feature
of this transgenic line.
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A, the
articular cartilage surface of this line of mice was irregular with
evidence of fissuring and damage, and erosion of the cartilage and
periosteal bone was marked in the joint margins. Secondary ankylosis
occurred due to hyperplasia of bony and cartilaginous tissues and
fusion of opposing bones (Fig. 4B). Thinning of trabeculae
with marked osteoclastic activity and woven bone production were
observed in the epiphyseal area (Fig. 4C). In this lesion,
the bone and marrow cavity were displaced by excessive proliferation of
fibrous tissues. Finally, the joint cavity as well as the bone marrow
space was completely occupied by newly formed bone (Fig. 4D). Proliferation of the synovial tissues was not
obvious. Infiltration of inflammatory cells into synovial tissues was
not observed and infiltration into the bone marrow space was found in
one case in which there were necrotic changes of the fibula.
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, E and
F, hyperplasia of cartilaginous tissues and bone were
observed both in the ankle joints and in the toe joints. No
inflammatory cell infiltration was detected in these joints. Thus, ankylotic joint changes were mainly due to abnormal bone synthesis in the joints. These changes were noticeable only in the joints of the hind legs and forelegs at the beginning, but eventually, most joints including the vertebral and tail joints were affected. These pathological findings were considerably different from those seen in T3376 LTR-tax-, T5368 CD4-tax-, or LTR-pX-Tg mice, in which proliferation of the synovial tissues and infiltration of inflammatory cells were marked.
Tax expression in bones of tax-Tg mice
To know the reason why these tax-Tg mice developed different types of arthropathy, we compared transgene activity in these mice with different phenotypes. Because pups from T3376 and T5571 were not obtained, descendants of T4055 LTR-tax-, T5368 CD4-tax-, and LTR-pX-Tg mice were compared.
As shown in Fig. 5A,
tax mRNA was expressed markedly in the thymus of a T5368
line CD4-tax-Tg mice in which inflammatory arthropathy
developed. Strong expression was also observed in the joints, and weak
expression was seen in the spleen. The expression level in the joint
was 1/200 of that observed in MT-2 cells, as estimated from the
intensity of the tax bands. On the other hand, tax mRNA
expression in T4055 LTR-tax-Tg mice, in which only ankylotic
changes developed, was observed in various tissues including the
joints, spleen, thymus, and kidney (Fig. 5B). Interestingly,
tax mRNA expression in the joints and bones of T4055
LTR-tax-Tg mice was 2–4 times lower than that in
LTR-pX-Tg mice (Fig. 5C), and 20 times lower
than that in T5368 CD4-tax-Tg mice (Fig. 5, A and
B; Table II),
although new bone synthesis was only observed in T4055 line mice. Low
levels of tax expression in T4055 LTR-tax-Tg
mice, compared with those in mice that developed inflammatory
arthropathy, were confirmed using different strains of mice (Fig. 5D and Table II). Thus, these results suggest that high
levels of tax expression in the joints induce inflammatory
arthropathy and that osteogenesis is not proportionally correlated with
the tax expression level.
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Previously, we showed that various cytokines including IL-1, IL-6,
and TNF- are induced in the joints of LTR-pX-Tg mice
15 . Because these cytokines may be involved in inflammation and bone
metabolism, cytokine production in the joints was compared among T4055
line LTR-tax-Tg mice, CD4-tax-Tg mice, and
LTR-pX-Tg mice. Fig. 6 and
Table III show the results. mRNA production of IL-1, IL-1ß, IL-6,
and TNF- was markedly enhanced in the joints of both
CD4-tax-Tg mice (5.1- to 38.7-fold) and LTR-pX-Tg
mice (3.2- to 21.8-fold) compared with non-Tg control mice, although
the augmentation in LTR-pX-Tg mice appeared less intensive.
In contrast, the augmentation of mRNA expression in T4055 line
LTR-tax-Tg mice was much less (1.4- to 3.8-fold) than those
observed in those CD4-tax- or LTR-pX-Tg mice with
inflammation. In contrast, TGF-ß1 11 expression was strongly
induced even in T4055 line LTR-tax-Tg mice, and mRNA levels
for TGF-ß1 were similar among joints of LTR-pX-,
CD4-tax-, or T4055 line LTR-tax-Tg mice. This
observation suggests that the Tax levels required for the induction is
different among genes and that a low level of tax expression
in T4055 line mice is enough to induce TGF-ß1 expression but is not
sufficient to fully activate inflammatory cytokine genes. Cytokine mRNA
levels in the joints of T5562 line CD4-tax-Tg mice were
similar to those found in line T5368 CD4-tax-Tg mice (data
not shown).
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). Both IgG and IgM levels as well
as autoantibody levels were elevated significantly in
LTR-pX-Tg mice and T5368 line CD4-tax-Tg mice.
Although these Ab levels seemed to be slightly elevated in T4055 line
LTR-tax-Tg mice, this elevation was not significant, in
clear contrast with the elevation seen in mice with inflammatory
arthropathy. Thus, augmented production of inflammatory cytokines and
autoantibodies correlates with the development of inflammatory
arthropathy, whereas only low levels of cytokines and autoantibodies
were detected in mice with ankylotic joints.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Interestingly, we found that noninflammatory ankylotic arthropathy also developed in two LTR-tax-Tg mice. Joint deformity caused by hyperosteogenesis was the major change seen in these mice, and neither synovial tissue hyperplasia nor inflammatory cell infiltration was observed in the affected joints. These observations were markedly different from those seen in LTR-pX-Tg, T3376 LTR-tax-Tg and T5368 CD4-tax-Tg mice. Involvement of insertional mutations at the integration site in the ankylotic changes seems unlikely, since two independent founder mice were affected. Thus, the results suggest that Tax can cause at least two different types of arthropathy in mice.
To elucidate mechanisms by which two different types of disease develop
in tax transgenic mice, we examined the expression of
inflammatory cytokines and autoantibody levels in the serum. We found
that both cytokine and autoantibody levels, except for the TGF-ß1
level, were much lower in T4055 line LTR-tax-Tg mice with
joint ankylosis than in LTR-pX-Tg or T5368 line
CD4-tax-Tg mice that develop inflammatory arthropathy. In
this connection, we demonstrated that the tax mRNA
expression level in joints and in bone from T4055 line mice was lower
than that in LTR-pX-Tg mice. Thus, these observations
suggested that a high level of tax expression in the joints
causes inflammatory cytokine production resulting in the induction of
inflammatory arthropathy 15 , whereas a low level of tax
expression only induces osteogenesis in the joints. In this context, it
is worth noticing that TGF-ß1 expression was markedly elevated in the
joints of T4055 line mice in contrast to the moderate activation of
IL-1, IL-6, and TNF- expression in the same joints. Because TGF-ß1
is a potent inducer of osteogenesis 30 , the activation of this gene
could be involved in the enhanced osteogenesis in T4055 line mice.
In a previous paper, Ruddle et al. 31 reported that transgenic mice carrying the tax gene exhibit skeletal alterations resembling Paget’s disease. High bone turnover caused by the increase of both osteoblast and osteoclast is characteristic of their transgenic mice, although they did not describe the development of arthropathy in these mice. In contrast, the number of osteoclasts was within the normal range in T3376, T5368, and LTR-pX-Tg mice that developed RA-like arthritis, and no obvious remodeling of the bone could be observed. Although some activation of osteoclast was observed in T4055 line mice, the activation was not strong and mainly hyperosteogenesis was observed in these mice. Therefore, the histopathological appearance of these mice differs considerably from those reported previously 31 . These observations indicate that Tax can cause a broad spectrum of abnormalities in the joints.
It was suggested that the autoimmunity is involved in the development
of inflammatory arthropathy in those mice 15, 29 . In support of this
notion, it was shown that bone marrow cells from LTR-pX-Tg
mice could induce arthritis in irradiated non-Tg mice. Furthermore,
athymic nu/nu LTR-pX-Tg mice could not develop
arthritis (S.S. and Y.I., unpublished data). Thus, it is
conceivable that the observed pathological difference could be caused
by the difference of tax gene expression in lymphoid
tissues. In regard to this, the tax expression level in the
thymus of T5368 line CD4-tax-Tg mice, in which autoimmunity
developed (our unpublished data), was much higher than that in
T4055 LTR-tax-Tg line mice (Fig. 5). However, Tax
expression levels in the spleen and thymus of LTR-pX-Tg mice
were similar or only 1.2- to 1.5-fold higher than those in T4055 line
mice (Fig. 5 in this study, and Figure 1 in 13 . Therefore,
expression levels of the tax gene in lymphoid tissues may
not be the only factor that controls autoimmune development. Further
study is in progress to elucidate the pathogenesis of inflammatory
arthropathy and ankylosis using tax transgenic mice with
different promoters.
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Acknowledgments |
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and IL-6 cDNAs, ß-actin cDNA, TGF-ß1 cDNA,
IL-1, and IL-1ß cDNAs, respectively. We also thank Drs. Yoh-ichi
Tagawa, Hidenori Ozaki, Motoko Kotani, Kaoru Imura, Noriko Uetani, Jun
Tanaka, Chie Nakajima, Shigeru Kakuta, and Glen N. Barber for
excellent animal care. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Yoichiro Iwakura, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. E-mail address:
3 Abbreviations used in this paper: HTLV-I, human T cell leukemia virus type I; LTR, long terminal repeat; LTR-pX-Tg mouse, transgenic mouse carrying the HTLV-I env-pX region under its own LTR promoter; LTR-tax-Tg mouse, transgenic mouse carrying the HTLV-I tax gene under its own LTR promoter; CD4-tax-Tg mouse, transgenic mouse carrying the HTLV-I tax gene under the murine CD4 promoter/enhancer; RA, rheumatoid arthritis; IIC, type II collagen; m, murine.
Received for publication May 5, 1998. Accepted for publication November 18, 1998.
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