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Departments of
*
Medicine,
Immunology, and
Pathology, Duke University Medical Center, Durham, NC 27710; and
§
Department of Medicine, University of Texas Southwestern School of Medicine, Dallas, TX 75235
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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excision
circle (TREC) levels, a molecular marker for active thymopoiesis. LIF,
oncostatin M (OSM), IL-6, M-CSF, and stem cell factor (SCF) mRNA were
elevated in normal and myasthenia gravis-aged thymuses, and correlated
with decreased levels of thymopoiesis, as determined by either
decreased keratin-positive thymic epithelial space or decreased thymic
sjTRECs. IL-7 is a key cytokine required during the early stages of
thymocyte development. Interestingly, IL-7 mRNA expression did not fall
with aging in either normal or myasthenia gravis thymuses. In vivo
administration of LIF, OSM, IL-6, or SCF, but not M-CSF, i.p. to mice
over 3 days induced thymic atrophy with loss of CD4+,
CD8+ cortical thymocytes. Taken together, these data
suggest a role for thymic cytokines in the process of thymic
atrophy. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recent studies have shown that assay for the presence of TCR
(TCRD) signal joint
(sj)3 TCR excision
circles (TRECs) in peripheral blood are markers of either recent thymic
emigrants or of long-lived naive T cells that have not divided since
emigration from the thymus (6, 7, 8, 9). sjTRECs made during
rearrangement of the TCRA locus result in episomal circles
of TCRD DNA in newly produced thymocytes. Measurement of
sjTRECs in thymocytes of adult subjects has demonstrated ongoing
thymopoiesis well into adulthood (10).
The causes of thymic atrophy during aging in humans are not known, but
postulated causes are aging of the stem cell population that gives rise
to T cells (11, 12), loss of thymic epithelium expressing
self-peptides (13), lack of thymocyte rearrangement of
TCRB genes (14), and aging of the thymic
microenvironment with loss of trophic cytokines, such as IL-7
(15, 16, 17, 18, 19). Human thymic epithelial cells grown in vitro
make a wide variety of hematopoietic cytokines, including G-CSF, M-CSF,
GM-CSF, oncostatin M (OSM), LIF, IL-1, IL-6, IL-7, and TGF-
(20, 21, 22, 23, 24) (J. S. Sundy, B. F. Haynes, G. D.
Sempowski, and D. D. Patel, unpublished observations). In this study we
have used TCRD sjTREC analysis to quantitate thymopoiesis in
normal and myasthenia gravis thymus tissue during aging. In addition,
we have utilized RNase protection assays to determine steady-state mRNA
levels of 14 key human thymus cytokines during aging, and then
determined the effect of in vivo administration in mice of the thymic
cytokines that were up-regulated in aged human thymuses. We have found
evidence for an active role of LIF, OSM, stem cell factor (SCF), and
IL-6 in suppression of thymopoiesis during aging.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Normal human thymuses, myasthenia gravis thymuses, and normal adipose tissue were obtained as discarded tissue or after informed consent using a Duke University Institutional Review Board approved protocol. Normal thymus tissues were removed during the course of corrective cardiovascular surgery or other thoracic procedures. Myasthenia gravis thymus tissues were removed during therapeutic thymectomy for treatment of myasthenia gravis. Normal and myasthenia gravis tissue was removed only for clinical or therapeutic reasons, and no tissue was removed solely for research purposes.
Immunohistologic studies
Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded 4-µm sections. Tissue sections were deparaffinized with three changes of xylene substitute (Hemo-De, Fisher Scientific, Bay Shore, NY) for 5 min, rinsed in graded ethanols (100%, 100%, and then 95%), then incubated in 0.6% H2O2 in absolute methanol (15 min) to block endogenous peroxidase activity. Slides were washed in PBS (pH 7.2) and incubated at room temperature (20 min) with goat or horse serum diluted 1:20 in PBS. Slides were then sequentially incubated with anti-cytokeratin (mixture of AE1/AE3, Boehringer Mannheim, Indianapolis, IN; plus CAM5.2, Becton Dickinson, San Jose, CA; diluted in 1% BSA/PBS) for 45 min, biotinylated secondary Ab for 20 min, and avidin-biotin HRP complexes (VectaStainABC; Vector Laboratories, Burlingame, CA) for 20 min, with intervening PBS washes. Bound Ab was detected by reactivity with 3,3'-diaminobenzidine plus H2O2. Slides were dehydrated in graded ethanols and xylene substitute, then mounted.
The percentage of thymus area consisting of thymic epithelial space (TES) was determined by microscopic examination of hematoxylin and eosin-stained and cytokeratin-immunostained sections using a Zeiss video microscope with grid overlay. TES percentages were obtained for at least six representative fields under 10 x magnification (each field was 1.9 mm2), which were averaged to obtain the mean % TES for each tissue. TES percentages were determined independently by B.F.H. and L.P.H. and the mean ± SEM of the two sets of data were combined to yield the final %TES ± SEM.
sjTREC analysis
Quantitative-competitive PCR was used to determine levels of
TCRD locus sjTRECs in whole thymus DNA extracts as
previously described by Douek et al. (9). Genomic DNA was
extracted from homogenized frozen pieces (
1
cm3) of normal and myasthenia gravis human
thymuses using Trizol (Life Technologies, Gaithersburg, MD), per the
manufacturer’s protocol. Thymus pieces were weighed before DNA
extraction, and the total amount of DNA obtained from each piece was
determined by spectrophotometry. The lower limit of detection in the
PCR assay was 100 sjTREC molecules per l µg of genomic DNA.
RNA isolation and RNase protection assays
Total RNA was isolated from normal and myasthenia gravis thymuses using Trizol (Life Technologies), per the manufacturer’s protocol. Approximately 100 mg of tissue was homogenized with an Omni International (Marietta, GA) tissue disrupter in 1 ml of Trizol. Total RNA was extracted according to the manufacturer’s protocol, resuspended in diethylpyrocarbonate-treated water, and quantitated by spectrophotometry.
Specific cytokine mRNAs were determined using the multiprobe RiboQuant RNase Protection System (PharMingen, San Diego, CA). Ten micrograms of RNA from each sample was hybridized overnight with 32P-labeled riboprobe sets (PharMingen) and samples processed as described in the manufacturer’s instructions. Protected RNA transcripts were separated on a 5% denaturing polyacrylamide gel (National Diagnostics, Atlanta, GA). Cytokine mRNA bands were quantified by PhosphorImager (Molecular Dynamics, Sunnyvale, CA) analysis and reported as % of GAPDH signal.
Protein extraction and cytokine ELISA
Protein was extracted from 50 mg of snap-frozen thymus and
adipose tissue by mincing the tissue in 2 volumes of extraction buffer
(1.0% Tween 20, 1 M NaCl, 1x PBS, and 0.1% sodium azide), incubating
at 4°C for 1 h, sonicating for 5 min, and then centrifuging at
10,000 x g for 10 min. The supernatant was collected
and tested for cytokines by a double-determinant ELISA according to the
manufacturers’ protocols. Human IL-7 was detected with Ab pairs from
PharMingen. Human OSM, SCF, LIF, IL-6, and M-CSF were detected with Ab
pairs from R&D Systems (Minneapolis, MN). Cytokine protein
concentrations in the extracts were determined based on a standard
curve of recombinant cytokine provided with the Ab pairs. Whereas OSM,
SCF, IL-6, and M-CSF levels were detectable using these methods, LIF
levels in thymus and adipose tissue extracts were below the detection
range (11 pg/ml) of the ELISA, either due to actual low levels of LIF
in tissue or due to inability to extract LIF from tissue.
In vivo cytokine administration
BALB/c mice (female, 8–10 wk old) (The Jackson Laboratory, Bar Harbor, ME) were used to study the in vivo effects of recombinant murine cytokines on thymic atrophy. Mice (n = 3/treatment) were injected i.p. three times daily for 3 days with saline containing 0.1% BSA, or with 2 µg LIF, 2 µg OSM, 2 µg SCF, 3 µg IL-6, or 1 µg M-CSF (0.1% BSA carrier; R&D Systems) using American Association of Laboratory Animal Care guidelines under protocols approved by the Duke University institutional animal use and care committee. One day after the last injection, animals were euthanized and thymuses excised. Percent and absolute numbers of thymocyte subsets were determined by immunofluorescence and flow cytometry using directly labeled mAbs against mouse CD3, CD4, and CD8 (PharMingen) (single cell suspensions of thymocytes were prepared and analyzed as previously described (25)). For double-positive and single-positive thymocyte subsets, flow cytometric histograms of either live CD3+ thymocytes or total thymocytes were analyzed for CD4 and CD8 expression.
Statistics
Pearson correlation statistical analysis was used to determine
the strength and direction of the linear relationship between data sets
(r = -1 to +1). Significance tests were then performed
to determine whether r was different from 0. Where indicated
Student’s t test was used to compare the means for two data
sets. Differences were considered significantly different with
p 
0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We studied 45 normal human thymuses from individuals 3 days to 78
years old and divided the thymuses into five age groups (Fig. 1
). Hematoxylin and eosin staining and
anti-keratin immunohistochemistry were utilized to distinguish the
TES (keratin-positive) from the keratin-negative thymic perivascular
space. In normal thymuses, the percent of the whole thymus that
contained the TES (cortex and medulla) fell to 5% or less by age 78
(p < 0.0001) (Fig. 1A). Fig. 1B shows representative hematoxylin and eosin plus
anti-keratin-labeled thymus tissue sections from each age group
studied and demonstrates a progressive decrease in TES and concurrent
increase in thymus perivascular space during aging.
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C).
Thymocyte cell suspensions were available for sjTREC analysis from
seven thymuses studied (ages 2–34 years). sjTREC levels per
105 thymocytes did not fall in these samples,
indicating that on a per thymocyte basis TCR rearrangement continued
into adulthood (data not shown). mRNA expression of thymic cytokines during aging
We next studied the mRNA expression profile of 14 cytokines in
normal thymuses from 50 individuals during aging using a multiplex
RNase protection assay (Fig. 2). We
analyzed the cytokines in four groups: LIF, OSM, SCF, and IL-13 (Fig. 2A); IL-2, IL-7, IL-15, and IFN-
(Fig. 2B);
IL-6, G-CSF, and M-CSF (Fig. 2C); and IL-9, IL-10, and IL-14
(Fig. 2D).
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, Table I). The increase in steady-state mRNA
expression of LIF, SCF, IL-6, and M-CSF correlated with age and also
correlated with decreasing thymic sjTRECs (Table I). Increased levels
of mRNA for OSM correlated with increasing age, as well as decreasing
percent TES (p < 0.001), and approached
significance (p < 0.07) with decreasing
sjTRECs (Table I).
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). Expression of IL-2 mRNA
significantly decreased with age and decreasing sjTRECs (Table I).
IL-9, IL-10, IL-13, and IL-14 decreased with age, but not significantly
with decreasing sjTREC levels (Table I). Interestingly, no change in
steady-state mRNA levels was seen for IL-7, IL-15, IFN-, or G-CSF
with respect to age or number of sjTRECs (Table I).
To determine whether the expanded adipose tissue of the thymic
perivascular space (Fig. 1B) could be in part responsible
for elevated cytokine mRNA in normal aged human thymuses, we obtained
adipose tissue from multiple sites (mediastinal perithymic area,
n = 2; perirenal, n = 2; and
subcutaneous, n = 1; total, n = 5).
RNase protection assays were performed on total RNA isolated from
adipose samples and compared with the cytokine mRNA level obtained from
normal thymuses >50 years old (Fig. 3).
Interestingly, we saw that the cytokine mRNA profile for adipose tissue
was similar to that seen in aged normal thymus (Fig. 3). LIF, OSM, SCF,
IL-7, IL-15, IL-6, and M-CSF mRNA were all expressed in adipose tissue
in levels comparable to aged thymus. To confirm that protein could be
measured in tissue that had high expression of cytokine mRNAs by RNase
protection, we assayed for cytokine protein in adipose and >50 years
thymus tissue extracts by ELISA. We found cytokine protein present for
OSM, SCF, IL-6, M-CSF, and IL-7 in both adipose and aged thymus tissue
(data not shown). LIF protein levels in these tissues were either below
detection in our assay, or LIF protein was not extracted optimally with
the methods used.
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Myasthenia gravis is an autoimmune disease characterized by
neuromuscular weakness and is associated with thymoma in 10% of
patients (26, 27). Myasthenia gravis thymuses are
frequently characterized histologically as hyperplastic for age, with
lymphoid areas containing B cell germinal centers (26, 27). It has recently been realized that hyperplastic lymphoid
areas of the myasthenic thymus are entirely in the thymic perivascular
space, whereas actual thymopoiesis is decreased in the TES
(26, 27, 28). To confirm observations of ongoing thymopoiesis
in adults, we compared percent TES and sjTREC levels in a cohort of 34
myasthenia gravis thymuses (age 4–75 years). Our data demonstrated
that as the myasthenic thymus aged, TES also fell to 5% or less by age
75 (Fig. 4A)
(p < 0.0001) and correlated with decreasing
thymus sjTREC levels (p < 0.0001) (Fig. 4B).
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, A–D). We found that
LIF, OSM, SCF, IL-13, IL-7, IFN-, IL-6, and M-CSF steady-state mRNAs
were expressed significantly higher in aged myasthenia gravis thymuses
compared with younger myasthenia gravis thymuses (Table II). Increased levels of mRNA for LIF,
SCF, and M-CSF correlated with decreasing sjTRECs (Table II). All of
the other cytokine mRNAs analyzed remained unchanged with
increasing age in myasthenia gravis thymuses (Table II). A striking
observation in myasthenia gravis thymuses was that the cytokine mRNAs
that were unchanged (IL-7 and IFN-) during aging in normal thymuses
were significantly elevated in aged myasthenia gravis thymuses, and
those cytokine mRNAs that fell during normal aging (IL-2, IL-9, IL-10,
IL-13, and IL-4) did not fall in myasthenia gravis thymuses (Table III). In particular, it is important to
note that in myasthenia gravis thymuses, IL-7 mRNA expression increased
with age despite marked atrophy of TES and fall in thymus sjTREC
levels. Thus, the presence of expression of IL-7 and other trophic
cytokines in myasthenic thymuses in the face of decreased thymopoiesis
suggested the possibility of an active process of suppression of
thymopoiesis during aging.
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TGF-ß is known to be expressed by the thymic microenvironment
and has been demonstrated to be an inhibitor of T cell proliferation
and play a role in murine T cell maturation (29, 30, 31). In
addition, TGF-ß1 has been shown to synergize with epidermal growth
factor for up-regulation of LIF and IL-6 mRNA levels (46).
To explore the potential role of TGF-ß in mediating age-related
atrophy in normal and myasthenia gravis thymus tissue, we determined
the level of TGF-ß mRNA in 10 normal and 10 myasthenia gravis thymus
tissues representative of 0–78 years and 4–65 years of age,
respectively (Fig. 6). Our analysis by
RNase protection assay revealed detectable levels of the TGF-ß1
isoform. In both normal and myasthenia gravis thymus tissue there was a
correlation between increasing TGF-ß1 mRNA levels and increasing age
(p < 0.043 and p < 0.019,
respectively) (Fig. 6). The level of TGF-ß1 mRNA detected in
myasthenia gravis thymus tissue was not significantly higher than that
in normal thymus tissue (p < 0.078). We were
unable to detect TGF-ß2 and TGF-ß3 mRNA transcripts in total RNA
from whole thymus tissue with this technique. However, studies
utilizing RT-PCR have demonstrated detectable levels of TGF-ß2 in
whole thymus tissue (data not shown). Taken together, these data
suggest that TGF-ß1 may also play a role in thymic atrophy directly,
or indirectly by up-regulating thymosuppressive cytokines, such as IL-6
and LIF (46).
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To test the hypothesis that the up-regulated thymic cytokines in
atrophic, aged human thymuses might inhibit thymopoiesis, we
administered LIF, OSM, SCF, IL-6, or M-CSF i.p. into BALB/c mice and
determined whether any of these cytokines could induce acute thymic
atrophy in vivo. We found that injection of LIF, OSM, SCF, and IL-6
three times a day for 3 days, in the dose regimens listed in Table IV, induced thymic atrophy when compared
with a saline control. Total thymus weights and thymocyte numbers were
significantly decreased in LIF-, OSM-, and IL-6-treated mice, whereas
thymocyte numbers were significantly decreased in SCF-treated mice
(Table IV). Phenotypic analysis of thymocytes obtained from each group
of mice demonstrated that LIF-, OSM-, and SCF-treated mice all had
significantly decreased absolute numbers of
CD3-CD4-CD8-
(triple negative),
CD3+CD4+CD8+
(triple positive), as well as CD4+ and
CD8+ single-positive thymocytes (Fig. 7). In one experiment shown in Fig. 7
(n = 3 mice per group) IL-6 induced a decrease in
absolute numbers of
CD3+CD4+CD8+
(5.8 x 106 ± 2.6 x
106 cells vs saline control, 14.6 x
106 cells ± 4.7 x
106) and just missed statistical significance
(p = 0.08). In a second set of experiments
(n = 3 mice per group) the results with LIF, OSM, and
SCF were similar, and IL-6 induced a significant loss
(p = 0.04) of
CD4+CD8+ (double positive)
thymocytes (14.8 x 106 ± 4.8 x
106 cells vs saline control, 40.0 x
106 cells ± 10.5 x
106).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is of interest that M-CSF mRNA levels were significantly elevated in both normal and myasthenia gravis-aged thymus tissue. However, administration of M-CSF alone failed to induce thymic atrophy in BALB/c mice. There are several possibilities for these observations. First, M-CSF may be related to human thymic atrophy but not to murine thymic atrophy, i.e., there may be species differences. Second, M-CSF alone may not be sufficient to cause thymic atrophy but may function in combination with other cytokines such as LIF, OSM, SCF, or IL-6. Studies to determine the effect of combinations of cytokines in murine thymic atrophy will directly address this issue.
Studies of transgenic mice that overexpress LIF, OSM, or SCF have suggested that dysregulated thymic expression of these cytokines may be associated with thymic abnormalities. LIF and OSM transgenic mice had decreased CD4+CD8+ double-positive thymocytes and numerous thymic B cell follicles (32, 33). Injection of mice by others with LIF in the same regimen used in our study also induced thymic atrophy in mice (34). Our study shows similar effects of injected LIF, as well as for the first time shows the effects of OSM, SCF, and IL-6 on thymic atrophy. Although studies in mice are difficult to extrapolate to humans, our results do show an active acute thymopoietic suppressive effect in mice of these cytokines. However, the relevance of our observations in mice to the pathogenesis of human thymic atrophy in aging remains to be shown.
The role of testosterone in active suppression of thymopoiesis and induction of thymic atrophy has been demonstrated by reversal of thymic atrophy by chemical castration by administration of luteinizing hormone releasing hormone or by surgical castration (35). Clearly, corticosteroids also actively suppress thymopoiesis and induce the selective loss of cortical thymocytes (36). One interesting relationship between LIF overproduction and glucocorticoid regulation comes from the observation in LIF deficient animals of decreased adrenocorticotropin (ACTH) secretion (37). It has been demonstrated that LIF is a potent stimulus of pituitary ACTH secretion, modulating the hypothalamic-pituitary-adrenal axis in response to various inflammatory stimuli (38). It will be of great interest to study the levels of glucocorticoids and testosterone in LIF-, OSM-, SCF-, and IL-6-treated mice and in aging humans, both in plasma and in thymus tissue. Thus, it is a plausible notion that LIF may act indirectly through induction of corticosteroids or other factors to suppress thymopoiesis.
Several factors have been reported to be trophic for thymopoiesis,
including IL-1 and GM-CSF (39), IL-7 (18, 19, 40), human growth hormone (41), insulin like growth
factor-1 (41), and IL-11 plus IL-3 (42).
Mutations in IL-7, IL-7R, or in the common chain
(c) of the IL-2, IL-7, and IL-15 receptors
leads to SCID (43, 44, 45). The SCID syndrome of
IL-7-deficient mice can be reversed by bcl-2, demonstrating that IL-7
delivers anti-apoptotic signals to developing thymocytes
(44). Thus, as the thymus ages, up-regulated production of
suppressive cytokines (such as LIF, OSM, SCF, and IL-6) by thymic
epithelial cells, adipocytes, or other stromal cells may directly or
indirectly through other factors such as corticosteroids overcome
anti-apoptotic signals of trophic cytokines such as IL-7, and thus
may play a role in contributing to thymic atrophy. Alternatively, as
the thymus atrophies, IL-7 and other trophic cytokine production may
not be located in the correct thymic compartment for thymopoiesis to
proceed normally (i.e., IL-7 may be in the perivascular space and not
the TES). Studies are underway to directly address these issues.
In general, myasthenia gravis patients in this study received either no medications or various doses of mestinon, prednisone, or rarely azathioprine. Thus, we cannot rule out an effect of medications on the cytokine profiles seen in myasthenia gravis thymus tissue. However, the importance of the myasthenia gravis data set lies in the observation of continued expression of IL-7 during thymic atrophy that occurs in myasthenia gravis.
Finally, our study shows for the first time the rate of decline of sjTREC levels in whole thymus tissue with aging. We show measurable sjTRECs up to age 60, and importantly determined sjTRECs per mg of thymus tissue. Jamieson et al. (10) showed that up to age 50, sjTRECs per 105 thymocytes are high, indicating that thymocyte function during aging is constant on a per thymocyte basis, whereas our data directly demonstrate that the total number of functionally rearranged thymocytes per whole thymus declines with age.
Thus, for patients with HIV infection, and for cancer patients undergoing chemotherapy or bone-marrow transplantation, the critical question is what therapeutic strategies could be employed to promote reconstitution of T cells by enhancing thymopoiesis. Our study demonstrates up-regulated expression of mRNA of cytokines capable of suppressing thymopoiesis (LIF, OSM, IL-6, and SCF) in the atrophic thymus. If a pathophysiologic role in human thymic atrophy for these up-regulated suppressive cytokines can be shown, then these data raise the possibility of treating AIDS and chemotherapy treatment patients with a combination of trophic cytokines and inhibitors of suppressive cytokines to improve postnatal thymic function.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Barton F. Haynes, Box 3703, Duke University Medical Center, Durham, NC 27710. E-mail address:
3 Abbreviations used in this paper: sj, signal joint; TREC, TCR excision circle; OSM, oncostatin M; SCF, stem cell factor; TES, thymic epithelial space.
Received for publication September 20, 1999. Accepted for publication December 3, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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locus V(D)J recombination by-products are abundant in thymocytes and mature T cells. Mol. Cell. Biol. 16:609.[Abstract]
/ locus. EMBO J. 8:3261.[Medline]
-deleting elements in human T cells. J. Immunol. 158:1208.[Abstract]
regulate mRNA levels of interleukin 1 (IL-1), IL-1ß, and IL-6 in human thymic epithelial cells at a post-transcriptional level. J. Exp. Med. 174:1147. chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. Hum. Mol. Genet. 2:1099., and IL-1ß in human thymic epithelial cells. J. Immunol. 158:2704.[Abstract]
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T. J. Fry and C. L. Mackall The Many Faces of IL-7: From Lymphopoiesis to Peripheral T Cell Maintenance J. Immunol., June 1, 2005; 174(11): 6571 - 6576. [Abstract] [Full Text] [PDF]
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 R. G. Smith, L. Betancourt, and Y. Sun Molecular Endocrinology and Physiology of the Aging Central Nervous System Endocr. Rev., April 1, 2005; 26(2): 203 - 250. [Abstract] [Full Text] [PDF]
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J. A. Phillips, T. I. Brondstetter, C. A. English, H. E. Lee, E. L. Virts, and M. L. Thoman IL-7 Gene Therapy in Aging Restores Early Thymopoiesis without Reversing Involution J. Immunol., October 15, 2004; 173(8): 4867 - 4874. [Abstract] [Full Text] [PDF]
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 A. Pazirandeh, M. Jondal, and S. Okret Glucocorticoids Delay Age-Associated Thymic Involution through Directly Affecting the Thymocytes Endocrinology, May 1, 2004; 145(5): 2392 - 2401. [Abstract] [Full Text] [PDF]
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G. D. Sempowski, S. J. Cross, C. S. Heinly, R. M. Scearce, and B. F. Haynes CD7 and CD28 Are Required for Murine CD4+CD25+ Regulatory T Cell Homeostasis and Prevention of Thyroiditis J. Immunol., January 15, 2004; 172(2): 787 - 794. [Abstract] [Full Text] [PDF]
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L. P. Hale and M. L. Markert Corticosteroids Regulate Epithelial Cell Differentiation and Hassall Body Formation in the Human Thymus J. Immunol., January 1, 2004; 172(1): 617 - 624. [Abstract] [Full Text] [PDF]
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F. Ponchel, A. W. Morgan, S. J. Bingham, M. Quinn, M. Buch, R. J. Verburg, J. Henwood, S. H. Douglas, A. Masurel, P. Conaghan, et al. Dysregulated lymphocyte proliferation and differentiation in patients with rheumatoid arthritis Blood, December 15, 2002; 100(13): 4550 - 4556. [Abstract] [Full Text] [PDF]
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 D. L. Sodora, J. M. Milush, F. Ware, A. Wozniakowski, L. Montgomery, H. M. McClure, A. A. Lackner, M. Marthas, V. Hirsch, R. P. Johnson, et al. Decreased Levels of Recent Thymic Emigrants in Peripheral Blood of Simian Immunodeficiency Virus-Infected Macaques Correlate with Alterations within the Thymus J. Virol., August 28, 2002; 76(19): 9981 - 9990. [Abstract] [Full Text] [PDF]
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R. Terra, N. Labrecque, and C. Perreault Thymic and Extrathymic T Cell Development Pathways Follow Different Rules J. Immunol., July 15, 2002; 169(2): 684 - 692. [Abstract] [Full Text] [PDF]
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 C. L. Ortman, K. A. Dittmar, P. L. Witte, and P. T. Le Molecular characterization of the mouse involuted thymus: aberrations in expression of transcription regulators in thymocyte and epithelial compartments Int. Immunol., July 1, 2002; 14(7): 813 - 822. [Abstract] [Full Text] [PDF]
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T. J. Fry and C. L. Mackall Interleukin-7: from bench to clinic Blood, May 13, 2002; 99(11): 3892 - 3904. [Full Text] [PDF]
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Y. Okamoto, D. C. Douek, R. D. McFarland, and R. A. Koup Effects of exogenous interleukin-7 on human thymus function Blood, April 15, 2002; 99(8): 2851 - 2858. [Abstract] [Full Text] [PDF]
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S. L. Butler, E. P. Johnson, and F. D. Bushman Human Immunodeficiency Virus cDNA Metabolism: Notable Stability of Two-Long Terminal Repeat Circles J. Virol., March 19, 2002; 76(8): 3739 - 3747. [Abstract] [Full Text] [PDF]
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T. J. Fry, E. Connick, J. Falloon, M. M. Lederman, D. J. Liewehr, J. Spritzler, S. M. Steinberg, L. V. Wood, R. Yarchoan, J. Zuckerman, et al. A potential role for interleukin-7 in T-cell homeostasis Blood, May 15, 2001; 97(10): 2983 - 2990. [Abstract] [Full Text] [PDF]
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J.-i. Yasunaga, T. Sakai, K. Nosaka, K.-i. Etoh, S. Tamiya, S. Koga, S. Mita, M. Uchino, H. Mitsuya, and M. Matsuoka Impaired production of naive T lymphocytes in human T-cell leukemia virus type I-infected individuals: its implications in the immunodeficient state Blood, May 15, 2001; 97(10): 3177 - 3183. [Abstract] [Full Text] [PDF]
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G. C. Koo, C. Huang, R. Camacho, C. Trainor, J. T. Blake, A. Sirotina-Meisher, K. D. Schleim, T.-J. Wu, K. Cheng, R. Nargund, et al. Immune Enhancing Effect of a Growth Hormone Secretagogue J. Immunol., March 15, 2001; 166(6): 4195 - 4201. [Abstract] [Full Text] [PDF]
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G. D. Sempowski, J. R. Thomasch, M. E. Gooding, L. P. Hale, L. J. Edwards, E. Ciafaloni, D. B. Sanders, J. M. Massey, D. C. Douek, R. A. Koup, et al. Effect of Thymectomy on Human Peripheral Blood T Cell Pools in Myasthenia Gravis J. Immunol., February 15, 2001; 166(4): 2808 - 2817. [Abstract] [Full Text] [PDF]
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 H. J. Cohen Editorial: In Search of the Underlying Mechanisms of Frailty J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2000; 55(12): 706M - 708. [Full Text]
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