| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and
TNF-
uniquely allows the induction of Fas-mediated apoptosis. To
investigate the role of this cytokine combination in vivo, CBA/J mice
were immunized with thyroglobulin and then injected with IFN- and
TNF-. Compared with control animals, mice treated with IFN- and
TNF- showed significantly sustained lymphocytic infiltration in the
thyroid, which was associated with the destruction of portions of the
follicular architecture at wk 6 after initial immunization.
Furthermore, the number of apoptotic thyroid follicular cells was
increased only in the thyroids from mice treated with the IFN- and
TNF-. We also analyzed the function of the Fas pathway in vivo in
cytokine-treated mice by using an agonist anti-Fas Ab injected
directly into the thyroid. Minimal apoptosis of thyroid epithelial
cells was observed unless the mice were pretreated with IFN- and
TNF-. These data demonstrate that this unique combination of
inflammatory cytokines facilitates the apoptotic destruction of thyroid
follicular cells in experimental autoimmune thyroiditis, in a manner
similar to what is observed in Hashimoto’s thyroiditis in
humans. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Apoptosis is a mechanism of physiological cell elimination that induces cells to self-destruct when stimulated by an appropriate trigger, and improper regulation of apoptosis can lead to disease (4, 5). It can be initiated in cells through endogenous molecules such as TNF and Fas ligand (FasL). Apoptosis appears to play a role in the pathogenesis of autoimmune thyroiditis in humans (6, 7). Normal thyroids show a low level of apoptosis, a possible result of basal thyroid cell turnover (6, 7). In contrast, thyroid cells from patients with autoimmune thyroiditis display an increased frequency of apoptotic cells (6, 7, 8, 9). Many of the apoptotic cells in these glands are found in the areas of disrupted follicles, in proximity to infiltrating lymphoid cells (9, 10). This suggests that the increase in thyroid follicular cell apoptosis in thyroiditis may occur through a mechanism related to immune responses and inflammation, and may underlie thyroid destruction.
It has been shown that inflammatory cytokines are involved in the
regulation of apoptosis (11). Cytokines can regulate the
expression of apoptotic signaling components and inhibitors in target
cells, as well as control the expression of apoptotic initiators in
effector cells (12). Many inflammatory cytokines are
present in the thyroid gland in autoimmune thyroid disease, and there
is evidence that these cytokines play an important role in the
development of this process (13, 14, 15, 16). It has been shown
that T cell clones isolated from intrathyroidal lymphocytic infiltrates
of HT produce high levels of IFN- and TNF- (17, 18),
and cytokine-producing lymphocytes also are observed adjacent to
thyrocytes (19). Furthermore, IFN- in combination with
TNF- impairs the growth of thyrocytes (20), and
previous studies from our laboratory have shown that the pretreatment
of primary normal human thyroid cells with the combination of IFN-
and TNF- allowed the induction of Fas-mediated apoptosis in vitro
(12). Several publications have suggested a crucial role
for cytokines in pathogenesis of EAT (13, 14, 15, 16), but the
exact function of these molecules is not clear. There has also been no
information on the effect of the administration of both IFN- and
TNF- on the thyroid in vivo. We used the EAT model to test the
influence of the in vivo administration of IFN- and TNF- and show
data suggesting that these cytokines can facilitate thyroid destruction
in thyroiditis.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Eight-week-old female CBA/J mice, a strain susceptible to EAT,
were obtained from The Jackson Laboratory (Bar Harbor, ME). Mice were
maintained under specific pathogen-free conditions with free access to
food and water. They were allowed to adapt to their environment for 1
wk before initiating the experiment. Mice were s.c. challenged at the
base of the tail with 100 µg of porcine Tg (pTg; Sigma-Aldrich, St.
Louis, MO) emulsified in CFA (Difco, Detroit, MI). Two weeks later, the
mice were boosted with the same dose of pTg in incomplete Freund’s
adjuvant. Control animals were injected with OVA (Sigma-Aldrich) in
adjuvant at the same time intervals as pTg-injected animals. One week
after the booster immunization, mice were i.p. injected with 5 µg of
mouse rIFN- (R&D Systems, Minneapolis, MN), 0.5 µg of mouse
rTNF- (R&D Systems), or 5 µg of IFN- and 0.5 µg of TNF- in
PBS for 3 consecutive days. Control animals were injected with BSA
in PBS.
Serum anti-Tg Ab quantitation
Anti-Tg Ab was assayed by solid-phase ELISA. Serial dilutions of sera collected before immunization, 2 wk after initial immunization, and before sacrifice were used to determine endpoint titers. Briefly, round-bottom microtiter plates were coated with pTg, and the plates were then blocked by adding BSA. After washing the wells, sera from individual mice, diluted 1/200,000, were added and incubated overnight at 4°C. Alkaline phosphatase-conjugated sheep anti-mouse IgG (Jackson ImmunoResearch Laboratories, West Grove, PA) was added as second Ab, and the colorimetric reaction was revealed by the addition of p-nitrophenyl phosphate substrate (Sigma-Aldrich). The plate was quantitated with an ELISA reader at 405 nm. Murine Tg was isolated from CBA/J mice by M-per mammalian protein extraction reagent (Pierce, Rockford, IL), then run on SDS-polyacrylamide gel, and immunoblot analysis was performed with mouse serum (diluted 1/4,000) prepared from pTg-immunized mice treated with or without cytokines. A commercial rabbit anti-Tg (DAKO, Carpenteria, CA) was used as a positive control.
Thyroid histopathology
Thyroid glands were fixed in 10% formalin, embedded in paraffin, or directly frozen in Tissue-Tek OCT (Sakura Finetechnical, Nihombashi, Chuo-ku, Tokyo) and sectioned by standard method. Infiltration was evaluated on 5-µm-thick sections stained with H&E. The severity of thyroiditis was graded on a scale of 0–4, as follows (21): grade 0, normal histology; grade 1, interstitial accumulation of inflammatory cells distributed around one or two follicles; grade 2, one or more foci of inflammatory cells reaching at least the size of one follicle; grade 3, 10–40% of thyroid replaced by inflammatory cells; and grade 4, >40% of the thyroid replaced by inflammatory cells. Scoring was performed blind to the animal treatment groups.
TUNEL staining and immunohistochemistry
Apoptosis in thyroid sections was detected by TUNEL staining of fragmented DNA. Specific staining for in situ apoptosis was performed using the ApopTag peroxidase kit (Intergen, Purchase, NY), according to the manufacturer’s protocol. The infiltrating immune cells in mouse thyroid were evaluated for CD45, CD4, and CD8 expression by immunohistochemical staining. The paraffin-embedded sections were used to stain for CD45, whereas the frozen sections were used to stain for CD4 and CD8. Briefly, after the endogenous peroxidase was neutralized by 3% H2O2, slides were blocked for nonspecific binding by histomouse blocking solution (Zymed Laboratories, San Francisco, CA) and incubated with biotin-conjugated rat monoclonal anti-mouse CD45 (Ly-5), CD4 (L3T4), or CD8 (Ly-2) Abs or isotype-matched rat IgG2b or IgG2a (BD PharMingen, San Diego, CA). Then, the sections were incubated with streptavidin-peroxidase conjugate and were developed by incubation with diaminobenzidine substrate. The slides were counterstained with hematoxylin or methyl green and mounted with GVA MOUNT (Zymed Laboratories).
Thyroid injection with anti-Fas Ab
For direct injection of Ab into the thyroid, mice were
anesthetized with ketamin (0.5 mg/g) and xylazine (0.05 mg/g) i.p. Mice
were pretreated with 5 µg of IFN- and 0.5 µg of TNF- or BSA
in PBS for 3 consecutive days before Ab application. Using sterile
procedures, a lateral neck dissection was performed to visualize the
thyroid gland and dissect it free of surrounding fascia, connective
tissue, or muscle while maintaining its intact capsule and blood
supply. Either anti-murine Fas (Jo2) or control IgG (BD PharMingen)
was injected directly into the thyroid gland using a Hamilton 50-µl
syringe (Reno, NV). The wound was closed in layers using
conventional surgical procedures and, after 8 h, mice were
sacrificed and thyroid tissues were harvested for analysis of apoptosis
by TUNEL staining.
Statistical analysis
All values were expressed as mean ± SE. The relationships among variables were analyzed with the Wilcoxon matched pairs test using Stat View software (Abacus Concepts, Berkeley, CA). A p value of <0.05 was taken as statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and TNF- enhances lymphocytic
infiltration induced by pTg
CBA/J mice were immunized with heterologous Tg in CFA to evaluate
the effect of IFN- and TNF- in murine EAT. IFN- and TNF-,
either singly or together, were injected into mice on wk 3 after Tg
immunization. On wk 4 and 6 after initial immunization, thyroid glands
were collected for histopathological studies. As expected for this
model, animals immunized with Tg showed mononuclear cell infiltration
by 4 wk postimmunization, but no infiltration was present in thyroids
of mice injected with OVA. There also was no significant difference in
infiltration between Tg-injected mice with or without cytokine
treatment at this time point (Fig. 1
a). In contrast, 6 wk
post-pTg immunization, thyroids from mice treated with pTg and
IFN-/TNF- showed markedly sustained mononuclear cell infiltration
compared with thyroids from mice without cytokine treatment
(p < 0.01; Fig. 1b). Thyroids from
mice treated with pTg and TNF- showed increased mononuclear cell
infiltration compared with thyroids from pTg alone mice, but less than
that observed with the combination of two cytokines. The destruction of
portions of the follicular architecture was observed in
IFN-/TNF--treated mice (Fig. 2),
but not in the animals immunized with either Tg alone or each cytokine
singly.
|
|
To identify the phenotype of cellular inflammation in the thyroid,
we stained mice thyroid sections with CD45 Ab, which identifies
leukocytes. Fig. 3 (upper
right) identified the infiltrating mononuclear cells in the
thyroid as primarily leukocytes. Further staining with CD4 and CD8 Abs
showed that both CD4+ and
CD8+ T cells were present in thyroids from mice
treated with pTg and IFN- and TNF-, and these findings were
similar to those observed in animals immunized with Tg alone (data not
shown).
|
and
TNF-
Tg-induced autoimmunity in this model has not previously resulted
in a destructive thyroiditis, although recent reports (22, 23) have demonstrated that cytokine treatments can alter the
pathology of EAT from a lymphocytic to a granulomatous form. To
determine whether IFN- and TNF- treatment specifically promotes
thyrocyte destruction, thyroids from EAT mice were evaluated for cell
death by in situ TUNEL staining. On wk 6 after initial immunization,
the number of apoptotic cells was markedly increased in the thyroids of
EAT mice treated with the combination of IFN- and TNF-, compared
with mice without cytokine treatment. This was demonstrated by the
number of TUNEL-positive cells shown in the lower panel of
Fig. 4. Our prior work suggested that
alterations of the Fas pathway were involved in the ability of TNF-
and IFN- to facilitate apoptosis in thyroid cells (12).
Fas was expressed on the thyroid cell surface in our EAT mice, and the
level of expression was not altered by cytokine treatment (data not
shown). Therefore, we analyzed the function of the Fas pathway in vivo
in only cytokine-treated mice by injecting an agonist anti-Fas Ab
directly into the thyroid. The number of apoptotic thyroid epithelial
cells was markedly increased in the thyroids of mice pretreated with
IFN-/TNF- compared with mice treated with Fas agonist alone (Fig. 5).
|
|
To ascertain whether the cytokine treatment and associated
lymphocyte infiltration and thyrocyte apoptosis altered the humoral
immune response, we determined the titer of Abs to the immunogen pTg.
Titers of anti-Tg Abs were determined in sera from pTg- and
OVA-immunized mice with or without cytokine treatment, and this was
compared with preimmune serum. As expected, the titers of anti-Tg
Ab were significantly increased in all pTg-immunized mice, while
control mice injected with OVA had no evidence of anti-Tg Ab
regardless of cytokine treatment. However, the titers of anti-pTg
Ab from sera of pTg-immunized mice treated with or without cytokines
did not differ significantly (data not shown). IFN- has a
demonstrated role in modulating isotype switching (24),
and to examine this effect in the EAT model, subclasses of Ab to pTg
were determined in sera from immunized mice treated with or without
cytokine. The titers of IgG1 and IgG2a anti-Tg Abs were similar in
sera from Tg-immunized mice regardless of cytokine treatment (data not
shown). We also examined the mouse serum Abs for the ability to bind to
purified mouse Tg using immunoblot analysis. Serum from pTg-immunized
mice treated with or without cytokines produced staining of similar
intensity to the mouse Tg band, which was identified using a commercial
rabbit anti-Tg Ab (data not shown).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
EAT is a well-defined murine model of thyroiditis induced by the
injection of a homologous or heterologous thyroid Ag into genetically
susceptible mice. EAT is characterized by the accumulation of
lymphocytes in the thyroid gland of immunized animals and the presence
of high titers of anti-Tg autoantibodies (13). In
contrast to spontaneous thyroiditis in humans and animals, EAT is
self-limited, resolving over several weeks, and does not result in
follicular disruption (13). Our studies were able to
reproduce traditional EAT by the injection of thyroid Ag, and this
resulted in thyroid-infiltrating T lymphocytes. As expected, there was
no significant evidence of increased apoptosis or follicular disruption
in the thyroids from these animals. In contrast, the thyroids of mice
immunized with thyroid Ag, but also systemically treated with two Th1
cytokines, IFN- and TNF-, showed markedly sustained lymphocytic
infiltration compared with control mice. These data indicated that the
duration of thyroid infiltration was extended by cytokine treatment. It
also coincided with enhanced apoptosis in the mouse thyroid with
follicular disruption. In contrast, treatment with any single
inflammatory cytokine did not result in enhanced lymphocytic
infiltration or follicular disruption. Also, cytokine treatments that
enhanced follicular disruption did not increase titers of Abs to
homologous or heterologous Tg. Together, this suggests that thyroid
disruption is enhanced in the presence of these cytokines without
altering the overall immune response to immunized Tg. These data also
suggest that the Ab response alone is not adequate to mediate apoptotic
disruption of the thyroid.
The role that IFN- and TNF- play in modifying EAT and
facilitating thyroid disruption is not definitive, but our studies
suggest that target cell susceptibility to immune attack is altered by
these molecules. Previous studies from our laboratory demonstrate that
the unique combination of IFN- and TNF- facilitates Fas-mediated
apoptosis in primary human thyrocytes in vitro (12), while
a double dose of IFN- or TNF- alone is not effective in mediating
these effects (data not shown). A recent independent study also showed
that Fas-induced apoptosis in HT was tightly regulated by Th1 cytokines
(25). In the current studies, injection of anti-Fas Ab
into the thyroids of mice yielded apoptosis only in animals pretreated
with IFN- and TNF-. This suggests that these cytokines may also
facilitate Fas-mediated thyroid cell apoptosis in destructive
thyroiditis in humans. In contrast, no study has shown that a single,
inflammatory cytokine could induce destructive thyroiditis in EAT. The
effects of IFN- administered alone on the pathogenesis of autoimmune
thyroiditis are still not clear. Experiments by Remy et al.
(26) induced EAT-like infiltrates, but not cytolysis
through intrathyroidal injection of IFN-, and the application of
IFN--neutralizing Ab appears to retard the development of EAT
(27). However, others have reported that the
neutralization of endogenous IFN- exacerbates granulomatous EAT
(28). IFN- is also not required for the experimental
induction of autoimmune thyroiditis, as traditional pathologic changes
of EAT can occur in mice with disrupted IFN- or
IFN-rR genes (13). In contrast, synergy
between IFN- and TNF- has only been reported in the regulation of
the Fas pathway (29, 30) and can reduce Fas pathway
inhibitors that are normally present in the thyroid (31).
Thus, the induction of destructive thyroiditis in EAT is not simply the
result of independent inflammatory actions of either IFN- or
TNF-, but relates to a unique interaction between these cytokines
that facilitates apoptosis.
It is interesting that the addition of these two cytokines is necessary to mediate destructive thyroiditis in EAT, especially since the immune cells infiltrating the thyroid in this model are Th1 and should produce both of these cytokines. CFA generates a Th1 response (32), so one might expect the presence of these cytokines in immunized animals. However, it is possible that the Th1 environment in the mouse thyroid did not produce adequate amounts of both cytokines to reach a threshold to efficiently activate the Fas apoptotic pathway(s). This could be because the primary inflammatory response in EAT is at the site of immunization and not in the thyroid as it is in spontaneous thyroiditis. However, it may be that immunogenetic factors that control the production of Th1 cytokines are not adequate to produce these cytokines in the thyroids of some mice and potentially humans.
The mechanism of cytotoxicity in thyroiditis may also be important in
generating cytotoxicity. CTL kill their target cells predominantly
through granule exocytosis with perforin/granzyme and/or the Fas-FasL
system (33, 34), with the Fas-FasL pathway operative in
both CD4+ and CD8+ T cells
(25, 35, 36, 37). Although granule exocytosis-mediated CTL
against thyroid follicular cells might play a role in the destruction
of HT thyrocytes (38), increasing evidence suggests that
the Fas-FasL pathway is central to this process (31).
Because FasL is present on activated T lymphocytes (39, 40)
and the lymphocytic infiltration of the thyroid of IFN-- and
TNF--treated EAT includes both CD4+ and
CD8+ T effector cells (25), Fas on
the surface of thyrocytes should mediate thyroid apoptosis. However,
prior studies we have conducted indicate that this pathway is normally
blocked in thyroid cell (12, 31), and this was confirmed in
our animals by the inability of an agonist anti-Fas Ab to induce
apoptosis when injected into the thyroid gland. This is reversed by
treatment with IFN- and TNF-, but it is unclear what mechanism is
used by the two cytokines to influence the Fas pathway. Our previous
study demonstrated that susceptibility to Fas-induced death by the
combination of IFN- and TNF- in thyroid cell correlated with an
increase in expression of a tunicamycin-inhibitable high m.w. form of
Fas (12). This strongly suggested that the Fas
glycosylation might play an important role in regulating Fas signaling.
Thus, it appears that altering the environment in the thyroid to
activate the Fas pathway is adequate to allow for the induction of
apoptosis and thyroid disruption in EAT.
In summary, the combination of IFN- and TNF- enhanced thyrocyte
apoptosis through the Fas pathway and induced follicular disruption in
EAT. This may help to explain the differences between EAT and HT,
because the thyroid in patients with HT has a chronic inflammatory
environment enriched in Th1 cytokines such as IFN- and TNF- and
increased thyrocyte apoptosis (25). These results also
suggest that other disorders with Th1 immune response may result in
cellular apoptosis through the Fas-FasL pathway due to the cytokine
environment. Genetic differences in the cytokine regulation of this
pathway involving Fas-associated death domain protein-like interleukin
1
-coverting enzyme-inhibitory protein or other Fas regulatory
proteins may predispose individuals to these disorders.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. James R. Baker, Jr., Department of Medicine, University of Michigan Medical Center, 9220 Medical Science Research Building III, Ann Arbor, MI 48109-0648. E-mail address: jbakerjr{at}umich.edu
3 Abbreviations used in this paper: Tg, thyroglobulin; EAT, experimental autoimmune thyroiditis; FasL, Fas ligand; HT, Hashimoto’s thyroiditis; pTg, porcine Tg.
Received for publication August 14, 2001. Accepted for publication December 18, 2001.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
receptor gene. Eur. J. Immunol. 28:201.[Medline]
. J. Immunol. 146:2227.[Abstract]
administration. Acta Endocrinol. 122:41.
(TNF-) production of thyroid infiltrating T lymphocytes in Hashimoto’s thyroiditis: a peculiar feature of destructive thyroid autoimmunity. Autoimmunity 4:267.[Medline]
-containing lymphocytes in human thyroid autoimmune disease. Clin. Exp. Immunol. 83:64.[Medline]
on rat thyroid cell growth and Ia antigen expression. Immunology 63:285.[Medline]
. Immunol. Today 8:73.
on experimental autoimmune thyroiditis (EAT): prevention of disease and decrease of EAT-specific T cells. Eur. J. Immunol. 23:275.[Medline]
antibody. J. Immunol. 149:2219.[Abstract]
This article has been cited by other articles:
|
|
 |
|
  S. Fountoulakis, G. Vartholomatos, N. Kolaitis, S. Frillingos, G. Philippou, and A. Tsatsoulis Differential expression of Fas system apoptotic molecules in peripheral lymphocytes from patients with Graves' disease and Hashimoto's thyroiditis. Eur. J. Endocrinol., June 1, 2008; 158(6): 853 - 859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Fang, G. C. Sharp, and H. Braley-Mullen Interleukin-10 Promotes Resolution of Granulomatous Experimental Autoimmune Thyroiditis Am. J. Pathol., June 1, 2008; 172(6): 1591 - 1602. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Fang, V. G. DeMarco, G. C. Sharp, and H. Braley-Mullen Expression of Transgenic FLIP on Thyroid Epithelial Cells Inhibits Induction and Promotes Resolution of Granulomatous Experimental Autoimmune Thyroiditis in CBA/J Mice Endocrinology, December 1, 2007; 148(12): 5734 - 5745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Wang, M. Van Antwerp, R. Kuick, P. G. Gauger, G. M. Doherty, Y. Y. Fan, and J. R. Baker Jr. Microarray Analysis of Cytokine Activation of Apoptosis Pathways in the Thyroid Endocrinology, October 1, 2007; 148(10): 4844 - 4852. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rotondi, L. Chiovato, S. Romagnani, M. Serio, and P. Romagnani Role of Chemokines in Endocrine Autoimmune Diseases Endocr. Rev., August 1, 2007; 28(5): 492 - 520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Fang, Y. Wei, V. DeMarco, K. Chen, G. C. Sharp, and H. Braley-Mullen Murine FLIP Transgene Expressed on Thyroid Epithelial Cells Promotes Resolution of Granulomatous Experimental Autoimmune Thyroiditis in DBA/1 Mice Am. J. Pathol., March 1, 2007; 170(3): 875 - 887. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Chen, Y. Wei, G. C. Sharp, and H. Braley-Mullen Decreasing TNF-{alpha} results in less fibrosis and earlier resolution of granulomatous experimental autoimmune thyroiditis J. Leukoc. Biol., January 1, 2007; 81(1): 306 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Vojdani and J. Erde Regulatory T Cells, a Potent Immunoregulatory Target for CAM Researchers: Modulating Tumor Immunity, Autoimmunity and Alloreactive Immunity (III) Evid. Based Complement. Altern. Med., September 1, 2006; 3(3): 309 - 316. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Antonelli, P. Fallahi, M. Rotondi, S. M. Ferrari, P. Romagnani, M. Grosso, E. Ferrannini, and M. Serio Increased serum CXCL10 in Graves' disease or autoimmune thyroiditis is not associated with hyper- or hypothyroidism per se, but is specifically sustained by the autoimmune, inflammatory process. Eur. J. Endocrinol., May 1, 2006; 154(5): 651 - 658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Wang, Z. Cao, J. M. Wolf, M. Van Antwerp, and J. R. Baker Jr. Death Ligand Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Inhibits Experimental Autoimmune Thyroiditis Endocrinology, November 1, 2005; 146(11): 4721 - 4726. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Gangi, C. Vasu, D. Cheatem, and B. S. Prabhakar IL-10-Producing CD4+CD25+ Regulatory T Cells Play a Critical Role in Granulocyte-Macrophage Colony-Stimulating Factor-Induced Suppression of Experimental Autoimmune Thyroiditis J. Immunol., June 1, 2005; 174(11): 7006 - 7013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Mezosi, S. H. Wang, S. Utsugi, L. Bajnok, J. D. Bretz, P. G. Gauger, N. W. Thompson, and J. R. Baker Jr. Induction and Regulation of Fas-Mediated Apoptosis in Human Thyroid Epithelial Cells Mol. Endocrinol., March 1, 2005; 19(3): 804 - 811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Antonelli, M. Rotondi, P. Fallahi, P. Romagnani, S. M. Ferrari, A. Paolicchi, E. Ferrannini, and M. Serio Increase of interferon-{gamma} inducible {alpha} chemokine CXCL10 but not {beta} chemokine CCL2 serum levels in chronic autoimmune thyroiditis Eur. J. Endocrinol., February 1, 2005; 152(2): 171 - 177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Antonelli, M. Rotondi, P. Fallahi, P. Romagnani, S. M. Ferrari, A. Buonamano, E. Ferrannini, and M. Serio High Levels of Circulating CXC Chemokine Ligand 10 Are Associated with Chronic Autoimmune Thyroiditis and Hypothyroidism J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5496 - 5499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Carella, G. Mazziotti, G. Amato, L. E. Braverman, and E. Roti Interferon-{alpha}-Related Thyroid Disease: Pathophysiological, Epidemiological, and Clinical Aspects J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3656 - 3661. [Full Text] [PDF]
|
|
|
|
|
|
K. Chen, Y. Wei, G. C. Sharp, and H. Braley-Mullen Mechanisms of Spontaneous Resolution versus Fibrosis in Granulomatous Experimental Autoimmune Thyroiditis J. Immunol., December 1, 2003; 171(11): 6236 - 6243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Amato, M. Conte, G. Mazziotti, E. Lalli, G. Vitolo, A. T. Tucker, A. Bellastella, C. Carella, and A. Izzo Serum and Follicular Fluid Cytokines in Polycystic Ovary Syndrome During Stimulated Cycles Obstet. Gynecol., June 1, 2003; 101(6): 1177 - 1182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Vasu, R.-N. E. Dogan, M. J. Holterman, and B. S. Prabhakar Selective Induction of Dendritic Cells Using Granulocyte Macrophage-Colony Stimulating Factor, But Not fms-Like Tyrosine Kinase Receptor 3-Ligand, Activates Thyroglobulin-Specific CD4+/CD25+ T Cells and Suppresses Experimental Autoimmune Thyroiditis J. Immunol., June 1, 2003; 170(11): 5511 - 5522. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Vasu, S. R. Gorla, B. S. Prabhakar, and M. J. Holterman Targeted engagement of CTLA-4 prevents autoimmune thyroiditis Int. Immunol., May 1, 2003; 15(5): 641 - 654. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
