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Departments of
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Pathology and
Microbiology, University of Virginia, Charlottesville, VA 22908
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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80% of mice OX at 3 or 4 wk had maximal AOD, thus Ag stimulus for
2.5 wk following d3tx is sufficient. AOD progression requires
additional endogenous Ag stimulation from the ovarian graft. In mice OX
at 3 wk, ovaries engrafted at 5 wk had more severe oophoritis than
ovaries engrafted at 6 or 12 wk; moreover, only mice engrafted at 5 wk
developed ovarian atrophy and oocyte autoantibodies. Similar results
were obtained in mice OX at 4 wk. Thus endogenous tissue Ag are
critical in autoimmune disease induction and progression that occur
spontaneously upon regulatory T cell depletion. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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An imbalance of effector and regulatory T cells has been proposed
as the basis of the d3tx autoimmune diseases for several reasons. A
regulatory T cell population has been found in normal adult mice that
expresses the IL-2 receptor 
-chain (CD25) (11, 12, 13). The
infusion of CD4+ CD25+
spleen T cells or
CD4+CD8-CD25+
thymocytes from normal syngeneic adults completely blocks d3tx diseases
(11, 14). In addition, the thymus derived
CD25+ CD4 T cells are detected in the periphery
after day 3 of life, thus this T cell population would be depleted or
reduced by d3tx (12). Finally,
CD25- T cells that emigrate from the thymus
before day 3 have pathogenic potentials in the absence of
CD25+ T cells (12). For example,
CD4+ T cells from 3-day-old, but not adult,
euthymic BALB/c donors were found to transfer autoimmune diseases into
syngeneic nu/nu recipients (12, 15).
In addition to elucidating the regulatory T cells and their mode of action, it is important to define the parameters surrounding the development of autoimmune diseases that follow regulatory T cell depletion. One parameter is the source of antigenic stimulus responsible for the spontaneous autoimmune response. Because d3tx disease induction does not follow deliberate Ag injection, a critical question is whether the response is initiated by exogenous Ag through molecular mimicry, or alternatively, represents the response of a dysregulated immune system driven by endogenous Ag? One might also ask whether endogenous Ag are required for the maintenance of the ongoing autoimmune response, and, would the response regress upon removal of the endogenous Ag? These questions are pertinent to the understanding of neonatal immune responses, the capacity of Ag from normal organs to initiate pathogenic autoimmune responses, self tolerance mechanism, and eventually the regulatory T cell action.
For this study, we have taken advantage of autoimmune ovarian disease (AOD) that occurs at high frequency in the d3tx (C57BL/6xA/J)F1 (B6AF1) mice. Ovarian Ag is gender specific and its expression can be manipulated experimentally. As an example, ovarian Ag can be depleted surgically at any time of life. In mice without endogenous ovaries, viable syngeneic ovarian grafts provide a potential source of ovarian Ag stimulus and can be the target for AOD. Based on this model, we investigated the requirement and the duration of endogenous ovarian Ag stimulation necessary for the initiation and progression of AOD in d3tx mice. As an integral part of this investigation, we defined the nature and ontogeny of ovarian Ag relevant to AOD in the d3tx mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A breeding colony B6AF1 mice was established by mating C57BL/6 female and A/J male mice purchased from National Cancer Institute (Frederick, MD). Mice were kept and handled in accordance of approved National Institutes of Health guidelines. Thymectomy was performed on 3-day-old B6AF1 pups using the suction technique (16). Completeness of thymectomy was verified histologically, and mice with incomplete thymectomy were excluded from analysis. Ovariectomy (OX) was performed by removing both ovaries through a posterior incision, under dissection microscopy. To implant ovaries, the ovary from a 6-wk-old B6AF1 mouse was inserted under the kidney capsule through a posterior incision. Neonatal mice were anesthetized by hypothermia or metofane and adult mice with tribromoethanol.
Histologic evaluation of ovarian and lacrimal gland inflammation
The ovaries and lacrimal glands were fixed in Bouin’s solution and embedded in paraffin, and 5-µm sections were stained with hematoxylin and eosin. The extent of ovarian pathology was determined as unknown samples. Ovarian inflammation and ovarian atrophy were graded separately, each from 1 to 4, as described previously (16). Grade 1 inflammation consisted of 1–2 foci of inflammatory cells, consisting of monocytes, lymphocytes, and a few granulocytes, usually at the ovarian hilum. Grade 4 represented diffuse inflammation throughout the ovary involving both follicles and interstitial space. Grades 2 and 3 represented intermediate inflammation of incremental severity. Atrophy was evidenced as loss of growing or mature ovarian follicles, hypertrophy, leuteinization of interstitial cells, and eventually, loss of primordial oocytes. Lacrimal gland inflammation was graded from 1 to 4. Grade 1 lacrimalitis contained 1–2 foci of periductal mononuclear inflammatory cells. Grade 4 disease exhibited atrophy of lacrimal acini and severe lymphoid infiltration with destruction of lacrimal ducts. Grades 2 and 3 lacrimalitis represented incremental intermediate degrees of inflammation between grades 1 and 4.
Detection of ovarian Ags and Abs by immunofluorescence and immunoblot
Frozen sections of ovaries from naive B6AF1 or BALB/c scid mice were fixed in acetone, and processed for indirect immunofluorescence. All mouse sera were tested at a 1:50 dilution, and FITC labeled goat Ab to mouse IgG was used as the second Ab. The slides were viewed and photographed with an Olympus fluorescence microscope (New Hyde Park, NY). Absence of endogenous IgG in young BALB/c scid mice eliminated background staining and permitted detection of Ag in small ovarian oocytes in the neonatal ovaries.
Ovulated oocytes were used as Ag for immunoblot detection of Ab.
Four-week-old B6AF1 female mice were injected i.p. with 7.5 IU/mouse of
pregnant mare serum (Sigma, St. Louis, MO) and 48 h later with 7.5
IU/mouse of human chorionic gonadotrophin (Sigma). Oocytes collected
12–13 h later from the ovarian bursa were treated with 0.1 mg/ml
hyaluronidase to disperse granulose cells, and rinsed in medium 199
(Life Technologies, Rockville, MD). The zona pellucida-intact
oocytes were added to the loading buffer that consists of 50 mM
Tris-HCl (pH 6.8), 1% 
mercaptoethanol, 2% SDS, 0.1% bromophenol
blue, and 10% glycerol, and boiled for 5 min. Proteins from 10 oocytes
per lane were electrophoresed in 8% polyacrylamide gel, transferred to
a nitrocellulose membrane, and blocked with 5% skim milk. The membrane
was subsequently incubated for 1.5 h at room temperature with the
antiserum, diluted 1:100, from d3tx mice known to have positive
fluorescent oocyte Ab. The antigenic protein band was visualized by
further reaction with HRP conjugated goat Ab to mouse IgG, followed by
a chemiluminescent substrate (SuperSignal; Pierce, Rockford, IL), and
exposed on x-ray film.
Detection of the 110-kDa oocyte Ag messenger RNA by RT-PCR
Total RNA was isolated from the ovaries and testes of B6AF1 mice
at days 0, 1, 3, 7, and 21 after birth using RNAqueous-4PCR kit
(Ambion, Austin, TX). RNA concentration was quantified by absorbance at
260 nm. To perform RT-PCR, 2 µg of total RNA was
reverse-transcribed into cDNAs with 1 µg of
oligo(dT)12–18 using SuperScript Preamplication
System (Life Technologies, Rockville, MD). To compare the expression of
the mRNA of the oocyte 110-kDa Ag between samples, each sample was
coamplified with hypoxanthine guanine phosphoribosyl transferase (HPRT)
using PCR. To ensure the linearity of both the oocyte 110-kDa Ag and
HPRT, 10-µl aliquots of PCR product at 22, 24, 26, 28, 30, 32, or 34
cycles were resolved onto 2% agarose gel using 1x Tris-acetic
acid-EDTA (TAE) as a running buffer to ensure linearity in
estimating the concentrations of primers and reverse
transcription products for PCR. PCR was performed by combining 1
µl of the reverse transcription product with 8 pmol specific primers
of the oocyte 110-kDa Ag, known as OP1 or mater (17)
(sense primer, 5'-AGG ACT GTC TGC ATC AAG GAG AT-3' and antisense
primer, 5'-AGT GTC GTC AGT TCT CTT CA-3'), and 40 pmol each of the
HPRT-specific primers (sense primer, 5'-GTT GGA TAC AGG CCA GAC TTT GTT
G-3' and antisense primer, 5'-GAG GGT AGG CTG GCC TAT AGG CT-3')
(18). The PCR mixture in a final volume of 50 µl
contained 5 µl of 10x PCR buffer, 1.5 µl of 50 mM
MgCl2, 1 µl of 10 mM dNTPs, 2 U Taq
DNA polymerase (Life Technologies), and double-distilled water. The
cycling parameters for PCR were as follows: denaturation at 95°C for
1 min, annealing at 57°C for 1 min and extension at 72°C for 1 min
for a total of 28 cycles, which was followed by a 10-min extension at
72°C in PTC-200 DNA Engine (MJ Research, Watertown, MA). The identity
of the PCR products was confirmed by the nucleotide sequences of the
110-kDa oocyte Ag (18) and of HPRT (18).
Adoptive transfer of disease to young recipient
Spleen cells were dissociated and filtered through nylon mesh, and erythrocytes were lysed in hypotonic 0.1% ammonium chloride. After washing in RPMI 1640, the cells were suspended in PBS. Each recipient (<7 days old) was injected i.p. with 35 x 106 viable cells in a 100-µl volume, and their ovaries were studied histologically 10 days later.
Isolation and transfer of CD25+ CD4+ T cells to prevent AOD in d3tx mice
Lymphoid cells were obtained from axillary, inguinal, brachial, and cervical lymph nodes, and from the spleen of 8-wk-old normal B6AF1 female mice. They were enriched for CD4+ cells using the CD4 enrichment column (R&D Systems, Minneapolis, MN). CD4+ T cells were then labeled with biotinylated anti-CD25 Ab (PharMingen, San Diego, CA), incubated with streptavidin-iron beads (Miltenyi Biotec, Auburn, CA), and isolated on a magnetic column. Seventy percent of the cell preparation were CD25+ T cells (data not shown). A total of 2 x 106 cells in 100 µl PBS were injected i.p. into 7-day-old d3tx mice.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first established the prevalence and the time of onset of the
different components of AOD in female B6AF1 mice thymectomized at the
University of Virginia facility (Charlottesville, VA). Ovarian
inflammation (oophoritis), detected in occasional mice at 2 wk, reached
70% by 3 wk (Table I
). At this time,
<10% of the ovaries were atrophic. In parallel, the spleen cells from
3-wk-old but not 2-wk-old d3tx donors transferred oophoritis to young
recipients. The severity of AOD then escalated in the ensuing week.
Although oocyte autoantibodies were not detected at 3 wk, most d3tx
mice had oocyte autoantibodies in their sera by 4 wk. At the same time,
the ovaries of 40% of the animals became atrophic, some with residual
oophoritis. This sequence of events occurred in d3tx mice from
different B6AF1 colonies although the exact time of onset could differ
by 1–2 wk (8, 19, 20).
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To determine the requirement of endogenous ovaries as a source of
antigenic stimulus for ovarian autoimmune response, the responses of
female and male mice were compared (Table II). They were thymectomized on day 3,
engrafted with a 6-wk-old B6AF1 ovary at 6 wk, and studied at 8 wk.
Female mice developed AOD in the ovarian graft and serum autoantibodies
to oocytes (Fig. 1A). In
contrast, the ovarian grafts of male mice that lack endogenous
ovaries were normal and their sera were free of detectable oocyte
autoantibodies when they were studied at 2 wk (Fig. 1B), or
at 6 wk after ovarian engraftment (one of nine had focal AOD). The
requirement of endogenous ovaries for AOD induction was confirmed by
the absence of AOD in d3tx females that were OX at day 3 of age (Table II). In contrast to AOD, autoimmune lacrimalitis occurred in d3tx mice
regardless of whether they had endogenous ovaries or not (Table II).
Thus, loss of the endogenous ovaries does not impact on pathogenic
autoimmune responses in general.
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). In addition, autoimmunity was absent in sham
thymectomized mice. The findings indicate that endogenous ovarian Ag is
required for AOD development in the d3tx female mice. In the next
study, we analyze the nature of the ovarian autoantigens and the
ontogeny of their expression. The nature and ontogeny of endogenous ovarian Ag
The majority of serum autoantibodies in the d3tx B6AF1 mice
reacted with the intracellular Ags of growing and mature oocytes
detected by immunofluorescence on ovarian sections (Fig. 2). By immunoblot, the autoantibodies
were found to react with three distinct oocyte Ag with the apparent
molecular mass of 110, 90, and 75 kDa (Fig. 2B).
Among 38 sera from B6AF1 mice with oocyte Ab detected by
immunofluorescence, 26 (69%) were also detected by immunoblot, and
among them, 50% reacted with the 110-kDa oocyte Ag, 37% reacted with
the 75-kDa oocyte Ag, and 18% reacted with the 90-kDa oocyte
Ag.
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We next determined the ontogeny of oocyte Ag to establish the earliest
age when endogenous antigenic stimulus could occur. As shown in Fig. 2, D and E, oocyte Ag was detected in normal BALB/c
scid mice at 1 day (6 of 8 sera) or 5 days (11 of 12 sera)
of age by immunofluorescence. This finding parallels the detection of
mRNA for the major 110-kDa Ag by RT-PCR on the day of birth (Fig. 2C). Thus ovarian autoAg that react with Abs, produced by
d3tx mice, are detectable close to the day of birth in female
pups.
To determine whether ovarian autoAg is recognized by pathogenic T cells
from the d3tx mice, spleen cells from 6-wk-old d3tx mice were injected
i.p. into neonatal recipients on the day of birth. Ovarian inflammation
was detected 3 days later, whereas spleen cells from sham thymectomized
mice did not transfer disease (Fig. 2, F and G).
Inflammation was not detected in organs outside the ovaries. Thus,
within the first 3 days of life, ovarian oocyte Ag was processed and
presented by ovarian APCs that can be recognized by pathogenic
oocyte-specific T cells. The expression of the oocyte Ag early in life
indicates that immunogenic ovarian Ag are available to trigger an
autoimmune response in neonatal mice.
Endogenous ovarian antigenic stimulus for 3 wk is required for induction of oophoritis
We next determined the duration of endogenous antigenic stimulation required for the induction of AOD and autoantibody response. By removing the ovaries from the d3tx female mice at 2, 3, or 4 wk, and assuming that Ag stimulation occurs from the day of thymectomy (day 3), we allowed endogenous ovarian antigenic stimulation to persist for 1.5, 2.5, or 3.5 wk. Each mouse was then engrafted with an adult ovary 2 wk after OX, and the ovarian graft was studied 2 wk later at 6, 7, or 8 wk of age, respectively.
Of the d3tx mice OX at 2 wk, none developed AOD or autoantibody
response although most animals in this group developed autoimmune
lacrimalitis (Table III). Therefore,
consistent with the time of onset of AOD in the d3tx mice, ovarian Ag
stimulation for <1.5 wk is not sufficient to elicit AOD in the
d3tx mice.
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). Because
these responses were indistinguishable from the responses of mice that
were OX at 4 wk (and studied at 6 wk; Table III), we concluded that Ag
stimulation from endogenous ovaries for 2.5 wk from d3tx was sufficient
to elicit maximum autoimmune response and AOD.
Regardless of the age when the OX was performed, all d3tx mice
developed high incidences of lacrimalitis (Table III). Thus ovarian
ablation impacted specifically on the ovarian immune response.
Ovarian antigenic stimulus is required for progression from oophoritis to ovarian atrophy and autoantibody response
Although d3tx mice OX at 3 wk and engrafted at 5 wk developed
severe AOD that progressed to atrophy and oocyte Ab production (Table III), it was surprising that the ovarian disease of d3tx mice studied
at 3 wk had oophoritis without atrophy or autoantibodies response
(Table II). In addition, mice that were OX at 3 wk and engrafted at 12
wk had significantly reduced incidences and severity of AOD, including
oophoritis (p < 0.05) and oocyte
autoantibodies (p < 0.01; Table IV). Both observations suggest that
endogenous ovarian Ag derived from ovarian grafts are required for the
maintenance and progression of the autoimmune response associated with
severe AOD. In the following experiments, we test the hypothesis that
endogenous ovarian Ag is also required for disease progression.
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). Indeed, the ovarian
inflammation was much more severe in ovaries engrafted at 5 wk (Fig. 1C) than those engrafted at 6 wk (Fig. 1D)
(p = 0.02). Moreover, the progression from
oophoritis to atrophy and induction of autoantibodies response were
largely halted in mice that were devoid of ovaries for 3 wk rather than
2 wk (p < 0.01). A similar finding was noted in d3tx mice OX at 4 wk, with a higher incidence of atrophy in the ovaries engrafted at 6 wk rather than 7 wk (p < 0.05). The difference was less prominent in mice OX at 5 wk. Although there was a significant reduction in autoantibodies response in mice engrafted at 8 wk instead of 7 wk (p < 0.001), the incidence of oophoritis and atrophy in ovaries engrafted at 7 or 8 wk were comparable. These data, together, indicate that ovarian Ag from endogenous ovaries or ovarian graft is required to stimulate full progression of AOD induced by d3tx.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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cells of NOD mice, and their T cells did not
transfer diabetes to irradiated male NOD recipients. A more recent
study with a transgenic diabetogenic peptide-specific TCR indicated
that T cell activation in the regional lymph node was the first
observable pathogenic event in NOD mice (23). However,
these studies did not investigate the duration of Ag stimulation
required for disease induction, nor did they address the impact of
endogenous Ag on autoimmune disease progression.
The present study demonstrated clearly that Ag provided by an ovarian
graft is required for progression of AOD. As shown in Tables III and IV, although Ag exposure for the first 2.5 wk in the d3tx mice is
sufficient for AOD development, including oocyte Ab and atrophy, this
maximum response was observed only when the ovaries were engrafted 2 wk
after removal of the endogenous ovaries. When ovarian engraftment was
delayed by an extra week (i.e., ovarian engraftment at 3 instead of 2
wk after OX), oophoritis was no longer accompanied by ovarian
atrophy or autoantibodies response. Thus disease progression to atrophy
and autoantibody response was halted when persistent Ag stimulation was
interrupted by 3 instead of 2 wk. This trend was also observed in mice
OX at 4 wk; and in this case, more severe disease was observed in mice
engrafted at 6 rather than 7 wk. Indeed, the disease may regress upon
further withdrawal of Ag stimulus. For example, in d3tx mice that were
OX at 3 wk and studied at 12 wk, the incidence of oophoritis was
significantly reduced (p < 0.05; Table IV). In
mice OX at 5 wk, reduction in subsequent Ag exposure from the ovarian
graft also reduced autoantibodies response but had little effect on
progression from oophoritis to atrophy. It is known that the number of
oocyte progenitors is finite, and when they are lost upon ovarian
atrophy, recovery from AOD might not be possible. We have recently
obtained direct evidence for the capacity of an ovarian graft to confer
antigenic stimulation. Male mice injected with a T cell epitope of the
ovarian zona pellucida Ag ZP3 (24) did not produce Ab to
distant B cell epitopes of ZP3 unless they were engrafted with an ovary
(P. Pramoonjago, C. Sharp, and K. S. K. Tung, unpublished
observation). Therefore, we conclude that endogenous or engrafted
ovarian Ag is required for AOD induction as well as for AOD
progression.
The presence of the ovarian Ag for 3 wk from birth was required for
maximum disease induction, whereas Ag exposure for 2 wk didnot induce
autoimmune disease (Table III). Assuming that endogenous Ag stimulation
occurs on day 3 when the mice were thymectomized, the finding suggests
that Ag stimulation for the first 2.5 wk after thymectomy is sufficient
to initiate a maximum T cell response. This is consistent with AOD
transfer by spleen cells from d3tx mice at 3 wk but not at 2 wk of age
(Table I). This duration is comparable to the time required for
induction of autoimmune diseases by immunization with tissue peptides
in complete adjuvant. The rapid induction of autoimmune response by
endogenous Ag in the neonatal mice without the use of adjuvant is quite
surprising and has several interesting and important implications. It
suggests that endogenous ovarian Ag are available and are presentable
in immunogenic form by APC capable of activating neonatal T cells that
are presumably naive. It also suggests that neonatal T cells in the
d3tx mice have full capacity to mount a pathogenic autoimmune response.
Thus tight regulation must normally guard against spontaneous
autoimmune disease in the neonatal mice, and this begs the question as
to how the regulation is abrogated by CD25+
regulatory T cell depletion.
The lack of autoimmune response in the d3tx mice studied at 2 wk, or in the d3tx mice OX at 2 wk and engrafted at 4 wk, is not due to a late ontogeny of oocyte Ag. In this study, we have documented the multiple oocyte Ag to which the autoimmune responses of d3tx B6AF1 mice are directed. The 110-kDa oocyte Ag, which may elicit the earliest autoimmune response, has been characterized by Tong and Nelson (17) as a prefertilization oocyte protein required for blastocyst formation after fertilization (25). In this study, we have shown clearly that the transcript for this oocyte autoantigen is detectable in B6AF1 ovaries on the day of birth, and that oocyte Ag are recognized by autoantibodies 1 day later, and by CD4 T cells as early as 3 days later. In the neonatal week, a large fraction of oocytes are normally eliminated by apoptosis from normal ovaries. For example, an C57BL/6 ovary contains 60,000 oocytes on day 0, and the number is reduced to 20,000 by day 3 (26) (J.L. Tilly, unpublished observation). This rate of oocyte loss is further accelerated by d3tx, before detectable oophoritis (27). Although the fraction of the apoptotic oocytes that contains relevant autoAg is currently unknown, 100% of Ag positive and Ag negative oocytes in the prepubertal ovaries are eliminated by apoptosis (26) and, therefore, are available to invoke the autoimmune responses observed in the d3tx mice.
With regard to the availability of autoreactive effector T cells, it has been shown that neonatal T cells are immunocompetent (28, 29). Moreover, when transferred to nude recipients, the spleen cells from normal 3-day-old BALB/c mice induce ovarian and gastric autoimmune diseases spontaneously (12, 15). Therefore, the accessibility of endogenous Ag and the competence of pathogenic T cells are not limiting for induction of spontaneous autoimmune disease in the neonatal mice. A more likely limiting factor is the immaturity of the neonatal APC.
Macrophages from neonatal mice have minimal MHC II expression
(30). A recent study indicated that B cells and plastic
adherent cells from normal neonatal spleens presented Ag to memory T
cells at 30% of the adult level in the first week
(31). However, it has also been shown that the immature
neonatal APC function might be modified, for example, after adjuvant or
CD40 agonist Ab treatment. Thus autoimmune responses and autoimmune
diseases were elicited in the neonatal mice by injection of self
peptides in complete or incomplete adjuvant (32, 33, 34); and
CD40 Ab was found to abrogate induction of neonatal tolerance to
alloantigen (35). In the d3tx mice, because the self
Ag-driven autoimmune disease is inhibitable by
CD25+ T cells, it is possible that deletion of
the regulatory T cell population by d3tx somehow capacitates neonatal
APC to present ovarian self Ag to naive autoreactive T cells. Recent
literature supports this contention. For example,
CD4+ CD25+ T cells
(36) and anergic regulatory T cells (37) have
been reported to down-regulate expression of costimulatory molecules on
APC and to reduce APC function. In addition, cytokines produced by T
cells, including IL-10 (38, 39) and TGF
(40), also inhibit APC function. Powrie and colleagues
(41, 42) have provided in vivo evidence that these two
cytokines are involved in the control of T cell-mediated colitis by
regulatory T cells that express CD45RBhigh and
CD25. Therefore, CD25+ T cells may normally
regulate APC function directly, or via the secretion of IL-10 and/or
TGF.
In summary, although there is considerable evidence that autoimmune disease can be elicited by exogenous Ag through molecular mimicry at the level of T or B cell response (43, 44), research based on the AOD and other spontaneous autoimmune models emphasize a more critical role for endogenous Ag in the prevention, induction, and maintenance of pathogenic autoimmune responses. In a recent study, we documented the requirement of endogenous Ag for the maintenance of physiological tolerance to ovarian self Ag (45). Now, in the d3tx context, we have demonstrated that ovarian endogenous Ag can also trigger and sustain AOD progression. To accommodate this apparent paradox, we propose that endogenous Ag stimulation occurs normally, and that the outcome is dependent on the integrity and the continuous operation of the immune regulatory mechanisms.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Microbiology and Immunology, University of Louisville Health Science Center, Louisville, KY 40292.
3 Address correspondence and reprint requests to Dr. Kenneth Tung, Department of Pathology, University of Virginia, Box 214, Charlottesville, VA 22908.
4 Abbreviations used in this paper: d3tx, thymectomy on day 3 after birth; AOD, autoimmune ovarian disease; OX, ovariectomy/ovariectomized; B6AF1, (C57BL/6 x A/J)F1; HPRT, hypoxanthine guanine phosphoribosyl transferase; NOD, nonobese diabetic.
Received for publication November 27, 2000. Accepted for publication January 24, 2001.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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  E. T. Samy, K. M. Wheeler, R. J. Roper, C. Teuscher, and K. S. K. Tung Cutting Edge: Autoimmune Disease in Day 3 Thymectomized Mice Is Actively Controlled by Endogenous Disease-Specific Regulatory T Cells J. Immunol., April 1, 2008; 180(7): 4366 - 4370. [Abstract] [Full Text] [PDF]
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 P. Alard, J. N. Manirarora, S. A. Parnell, J. L. Hudkins, S. L. Clark, and M. M. Kosiewicz Deficiency in NOD Antigen-Presenting Cell Function May Be Responsible for Suboptimal CD4+CD25+ T-Cell-Mediated Regulation and Type 1 Diabetes Development in NOD Mice. Diabetes, July 1, 2006; 55(7): 2098 - 2105. [Abstract] [Full Text] [PDF]
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 S. Yu, P. K. Maiti, M. Dyson, R. Jain, and H. Braley-Mullen B cell-deficient NOD.H-2h4 mice have CD4+CD25+ T regulatory cells that inhibit the development of spontaneous autoimmune thyroiditis J. Exp. Med., February 21, 2006; 203(2): 349 - 358. [Abstract] [Full Text] [PDF]
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 Y. Y. Setiady, K. Ohno, E. T. Samy, H. Bagavant, H. Qiao, C. Sharp, J. X. She, and K. S. K. Tung Physiologic self antigens rapidly capacitate autoimmune disease-specific polyclonal CD4+CD25+ regulatory T cells Blood, February 1, 2006; 107(3): 1056 - 1062. [Abstract] [Full Text] [PDF]
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 D. Wolf, A. M. Wolf, H. Rumpold, H. Fiegl, A. G. Zeimet, E. Muller-Holzner, M. Deibl, G. Gastl, E. Gunsilius, and C. Marth The Expression of the Regulatory T Cell-Specific Forkhead Box Transcription Factor FoxP3 Is Associated with Poor Prognosis in Ovarian Cancer Clin. Cancer Res., December 1, 2005; 11(23): 8326 - 8331. [Abstract] [Full Text] [PDF]
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E. T. Samy, L. A. Parker, C. P. Sharp, and K. S.K. Tung Continuous control of autoimmune disease by antigen-dependent polyclonal CD4+CD25+ regulatory T cells in the regional lymph node J. Exp. Med., September 19, 2005; 202(6): 771 - 781. [Abstract] [Full Text] [PDF]
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F. F. Shih, L. Mandik-Nayak, B. T. Wipke, and P. M. Allen Massive Thymic Deletion Results in Systemic Autoimmunity through Elimination of CD4+ CD25+ T Regulatory Cells J. Exp. Med., February 2, 2004; 199(3): 323 - 335. [Abstract] [Full Text] [PDF]
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Y. Y. Setiady, E. T. Samy, and K. S. K. Tung Maternal Autoantibody Triggers De Novo T Cell-Mediated Neonatal Autoimmune Disease J. Immunol., May 1, 2003; 170(9): 4656 - 4664. [Abstract] [Full Text] [PDF]
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C. Sharp, C. Thompson, E. T. Samy, R. Noelle, and K. S. K. Tung CD40 Ligand in Pathogenesis of Autoimmune Ovarian Disease of Day 3-Thymectomized Mice: Implication for CD40 Ligand Antibody Therapy J. Immunol., February 15, 2003; 170(4): 1667 - 1674. [Abstract] [Full Text] [PDF]
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 H. Bagavant, C. Thompson, K. Ohno, Y. Setiady, and K. S. K. Tung Differential effect of neonatal thymectomy on systemic and organ-specific autoimmune disease Int. Immunol., December 1, 2002; 14(12): 1397 - 1406. [Abstract] [Full Text] [PDF]
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R. J. Roper, R. Z. Ma, J. E. Biggins, R. J. Butterfield, S. D. Michael, K. S. K. Tung, R. W. Doerge, and C. Teuscher Interacting Quantitative Trait Loci Control Loss of Peripheral Tolerance and Susceptibility to Autoimmune Ovarian Dysgenesis After Day 3 Thymectomy in Mice J. Immunol., August 1, 2002; 169(3): 1640 - 1646. [Abstract] [Full Text] [PDF]
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 S. Hori, M. Haury, A. Coutinho, and J. Demengeot Specificity requirements for selection and effector functions of CD25+4+ regulatory T cells in anti-myelin basic protein T cell receptor transgenic mice PNAS, June 11, 2002; 99(12): 8213 - 8218. [Abstract] [Full Text] [PDF]
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 Z.-B. Tong, C. A. Bondy, J. Zhou, and L. M. Nelson A human homologue of mouse Mater, a maternal effect gene essential for early embryonic development Hum. Reprod., April 1, 2002; 17(4): 903 - 911. [Abstract] [Full Text] [PDF]
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 H. Bagavant, C. Sharp, B. Kurth, and K. S. K. Tung Induction and Immunohistology of Autoimmune Ovarian Disease in Cynomolgus Macaques (Macaca fascicularis) Am. J. Pathol., January 1, 2002; 160(1): 141 - 149. [Abstract] [Full Text] [PDF]
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