| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Departments of
*
Anatomy and
Gastroenterology and Hepatology, Medical School of Hannover, Hannover, Germany; and
Immunology Research Group, University of Manchester, Manchester, United Kingdom
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
From animal studies it is well known that T cells continuously migrate through lymphoid and nonlymphoid organs, including the liver (6, 7, 8). Interestingly, about as many lymphocytes migrate into the liver as into the lymph nodes (LNs)3 (6, 8, 9, 10, 11, 12). Furthermore, T cells leave the liver both via the hepatic veins into the blood (13), and via the afferent lymphatics into the draining celiac LN (12). Upon activation, the distribution of migrating T cells changes, and many of them are found in the liver (6, 14). It is very likely that the situation in humans is comparable with that in animal models. Even the normal human liver contains significant numbers of T cells (15, 16). In addition, following liver transplantation, many donor-derived lymphocytes are found in the blood, showing that human liver lymphocytes are able to leave the liver (13, 17).
To date, it is not known whether, even under nonpathological conditions, T cells migrate in comparable numbers and with similar kinetics through the two compartments of the liver, the parenchyma and the periportal field. In addition, it is unclear whether naive, activated, and memory T cells are different in this respect. This would be important to know since they differ in their activation requirements and the cytokines they secrete into the tissue. Understanding the migration of T cell subsets under physiological conditions through the compartments of the liver could help to elucidate why many immunological liver diseases initiate and perpetuate primarily in the periportal field. Therefore, in the present study, naive, activated, and memory T lymphocytes were separated, labeled, and injected i.v. into rats. Using quantitative immunohistology (18, 19), the migration of these T cell subsets through the parenchyma and periportal field of the liver and into the draining lymph node was investigated. Furthermore, the present study analyzes both the rate of proliferation (BrdU incorporation) and apoptosis (TUNEL technique) among activated T cells that have migrated either into the parenchyma or the periportal field of the liver.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
T cells were prepared by two methods, depending on whether naive and memory T cells or activated T cells were studied. To obtain naive and memory T cells, thoracic duct CD4+ T cells were separated into naive and memory phenotype according to the high and low molecular isoform of CD45R, respectively. Activated T cells were generated in vitro by stimulating lymphocytes from pLNs and mLNs via the TCR and CD28.
Naive (CD45RC+) and memory (CD45RC-) CD4+ T cells
Congenic rats from the inbred PVG.7A (RT7a) and PVG.7B (RT7b) strains were bred and maintained under barrier conditions in the Animal Unit at the University of Manchester Medical School. Details of the purification procedure were described previously (7). Briefly, thoracic duct lymphocytes from PVG.7B donors (6–13 wk old) were depleted of B cells, CD8+ T cells, and CD90+ recent thymic emigrants using a mixture of specific mouse mAbs and anti-mouse Ig-conjugated immunomagnetic particles (20). The resulting population (>99% CD4+) was 80% CD45RC+. The CD45RC- subset was prepared as above, but with the additional depletion of CD45RC+ cells. Cell purity was routinely >97%. After i.v. injection of naive (CD45RC+) or memory (CD45RC-) T cells (20 x 106 cells), the livers of recipients were removed at various time intervals.
In addition, purified subsets of CD4+ T cells from the thoracic duct were labeled with 51Cr (sodium chromate CJS 1P; Amersham, Amersham, U.K.) using 10 µCi (0.37 mBq) per 108 subsetted cells. The liver was removed at various time points after injection, and the number of injected cells present in the whole liver was determined by gamma counting, as described (21). It is known that memory cells (CD45RC-) may revert back to the CD45RC+ phenotype and reexpress the high m.w. isoform of CD45R (22, 23). Nevertheless, linking CD45RC+ and CD45RC- with naive and memory is a useful division; it distinguishes T cells waiting to encounter Ag (naive) from those that have recently seen Ag (memory) (22).
In vitro activated T cells
Cell suspensions were prepared from LEW.7B
(RT7b) rat pLNs (pooled axillary, brachial, and
cervical LNs) and mLNs (24). The cells were stimulated in
vitro via the TCR-
ß (mAb R73) and CD28 (mAb JJ319), as described
(25). During the activation period, the cells were
cultured in the presence of 5 µM BrdU for 72 h
(26). BrdU is incorporated into the DNA during the S phase
of the cell cycle and can be detected in cytological and histological
preparations with specific Abs (summarized in Ref. 27).
Cytopreparations were made from pLN and mLN cells after stimulation
(before injection), and the incorporated BrdU was detected in T cells
(Ab R73) using the APAAP and peroxidase antiperoxidase techniques
(27), showing that 79 ± 5% had incorporated BrdU
and that 81 ± 3% of them are T cells (n = 10).
There was no difference in the incorporation of BrdU or the proportion
of T cells between pLN and mLN cells. In addition, our group recently
showed that the expression of L-selectin, LFA-1, ICAM-1, LFA-2, and
CD44 is similar for activated pLN and mLN (26, 28). Among
the T cells, 47.5 ± 5.7% were CD8+ and
52.5 ± 5.7% were CD4+. Then a mean of
60 x 106 BrdU+ T
cells originating from pLN or mLN was injected over 2 min i.v. into
LEW.7A (RT7a) rats (5–6 wk old)
(26). At various time points after injection, the liver,
the celiac LN draining the liver, and the axillary LN draining the skin
were removed.
Preparation and injection of T cells activated in vitro to test for proliferation in vivo
To study the local proliferation of activated T cells in the liver compartments, congenic donor cells from LEW.7B (RT7b) rats were activated as described, but in the absence of BrdU. Three days after injection of the activated cells into LEW.7A (RT7a) rats, the animals received 5 mg BrdU/100 g body weight i.v., and 1 h later the liver and the celiac LN draining the liver and the axillary LN draining the skin were removed. Thus, only those lymphocytes that were in the S phase of the cell cycle due to local stimulation within the respective microenvironment were labeled.
Detection of donor cells in the recipient organs
At various times after injection, the rats were anesthetized with ether and exsanguinated. The liver and the celiac and axillary LNs draining the liver and skin, respectively, were removed, frozen in liquid nitrogen, and stored at -80°C. Cryostat sections were made (thickness = 5 µm), air dried, wrapped in aluminum foil, and stored at -20°C. Regarding the distribution of naive, activated, and memory T cells, no differences were found in the various lobes of the liver. Therefore, the same part of the right lobe was always removed for further analysis.
To localize naive and memory cells in the organ, the sections were incubated with a mAb directed against the injected cells (LEW.7B phenotype; HIS 41 (29)). After washing with Tris-buffered saline containing 0.05% Tween-20 (TBS/Tween), the bound Ab was revealed using a second Ab (rabbit anti-mouse; Dako, Hamburg, Germany) and a mouse Ab complex (APAAP; Dako) for 30 min. Each of the last two steps was repeated for 15 min. To visualize the Abs, a mixture of APAAP substrate (Dako) and fast blue (Sigma, St. Louis, MO) in Tris buffer, pH 8.2, was utilized. The naive and memory cells appeared blue.
Activated lymphocytes were identified by revealing their incorporated
BrdU. In addition, their phenotype was determined with one of the
following mAb: T cells, R73 (30);
CD8+ cells, OX8 (31);
IL-2R-expressing cells, OX39 (32); MHC class
II-expressing cells, OX6 (33); B cells, HIS 14
(34). In brief, the slides were fixed for 10 min in equal
parts of methanol and acetone at -20°C, washed in TBS/Tween, and
incubated for 30 min at room temperature in a moist chamber with the
respective primary mAbs. Then the slides were incubated with the second
Ab (rabbit anti-mouse; Dako) and the mouse Ab complex (APAAP; Dako)
for 30 min. Each of the last two steps was repeated for 15 min. To
visualize the Abs, a mixture of APAAP substrate (Dako) and fast blue
(Sigma) in Tris buffer, pH 8.2, was utilized. The positive cells
appeared blue. Next the slides were washed in TBS/Tween, incubated in
70% ethanol for 30 min, and then air dried for at least 30 min. To
detect incorporated BrdU in activated lymphocytes, DNA was denatured
with formamide (Sigma) and NaOH (18). Formamide (190 ml)
was warmed to 70°C, and 1 N NaOH (10 ml) was added. The solutions
were then mixed for 8 min. The slides were immersed in this solution
for 30 s. After washing with TBS/Tween, the slides were immersed
in formamide containing 7.5 mM trisodium citrate for 15 min. These
steps were done at 70°C. After this, the cells were washed in
ice-cold TBS/Tween and fixed in 1% formaldehyde (30 min) and 0.2%
glutaraldehyde (10 min). Slides were incubated overnight with the mAb
anti-BrdU (Becton Dickinson, Mountain View, CA) dissolved in
TBS/Tween. After washing with TBS/Tween, the bound Ab was revealed
using rabbit anti-mouse (Dako) and the mouse Ab complex (APAAP;
Dako) for 30 min. Each of the last two steps was repeated for 15 min.
Then the organ sections were incubated with a mixture of APAAP
substrate (Dako) and fast red for 25 min, resulting in red staining of
the BrdU+ cells (27). The slides
were counterstained with hematoxylin and mounted in glycergel (Dako).
To test for proliferation of injected cells in the organs, first the
injected cells were identified by using a mAb directed against the
congenic LEW.7B phenotype (HIS 41), and visualized in blue, as
described above. BrdU incorporation was demonstrated in red.
Proliferating donor cells appeared blue and red. Before the LN sections
were stained for BrdU, they were stained with low concentrations of a
mAb against B cells (HIS 14) concomitantly with HIS 41. Using the APAAP
method with fast blue, the B cell areas appeared in light blue, and the
injected cells in dark blue. This allowed a clear identification of the
injected cells in the different organ compartments of the LN. Since
both the applied Abs and the activity of the alkaline phosphatase were
destroyed by the denaturation procedure, the incorporated BrdU could be
revealed using the same system without leading to unwanted
cross-reaction. At each time point, both the number and the phenotype
of the injected cells were determined in the parenchyma and the
periportal field (excluding the lumen of the vessels) of liver.
Identification of apoptotic cells in the liver
Cryostat sections were fixed with 4% paraformaldehyde (pH 7.4 in PBS) for 20 min. To localize donor cells in the liver, the sections were incubated with mAb directed against the congenic LEW.7B phenotype (HIS 41) and visualized in blue by the APAAP technique, as described (18). To detect apoptotic cells by the TUNEL method (26, 35), the sections were incubated with 70% ethanol for 30 min at room temperature. After washing (0.05% Tween in Tris-buffered saline), the sections were incubated with digoxigenin-labeled UTP (1.7 nM) and TdT (12.5 U) in the TdT buffer (200 mM potassium cacodylate, 25 mM Tris-HCL, 1.25 mg/ml BSA, pH 6.6, 5 mM cobalt chloride solution) for 60 min at 37°C. After washing, the incorporated UTP was revealed by a peroxidase-conjugated anti-digoxigenin Fab fragment Ab (Boehringer Mannheim, Indianapolis, IN) and subsequent immunohistology. Diaminobenzidine was used as a substrate. Therefore, injected cells appeared blue and apoptotic cells brown.
Statistics
The data were analyzed using SPSS for Windows. The number of T cell subsets per area of the respective compartment was determined and expressed as means ± SDs. Differences between time points, compartments, or organs were analyzed using either the Mann-Whitney U test or the Wilcoxon matched-pairs signed ranks test. p < 0.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The different compartments of the liver, parenchyma and periportal
field, could be clearly identified (Fig. 1
A). When determined
morphometrically (18), they made up 95 ± 1% and
5 ± 1% of a liver section, respectively (n =
10). In addition, within the different compartments both individual
injected cells and their phenotype could be identified (Fig. 1A). Furthermore, it could be analyzed whether the injected
cells were in the S phase of the cell cycle (Fig. 1B) or
were dying by apoptosis (Fig. 1C).
|
CD4+ T cells showed different kinetics in
the parenchyma and the periportal field of the liver. Although naive T
cells entered the parenchyma and periportal compartments in about
similar numbers (0.5 h), after 2 h naive T cells left the
parenchyma (Fig. 2). In contrast, the
number of naive T cells in the periportal field remained constant. A
comparable pattern was seen for memory T cells (Fig. 2). Using
51Cr-labeled subsets, it was further confirmed
that the numbers of naive and memory CD4+ T cells
in the liver were comparable at each time point after injection (Table I). Since the liver of these rats weighed
10 g (9), our data show that the liver contained at
least 20% of the injected cells at each time point.
|
|
Activated T cells were generated in vitro by stimulating the TCR
and CD28. They were injected i.v. and the distribution in the liver was
studied over time. At 1h, the number of activated T cells in the
parenchyma and the periportal field of the liver was comparable (Fig. 3). Then the activated T cells left the
parenchyma, a pattern that was also observed with naive and memory
CD4+ T cells. However, the kinetics of migration
within the periportal field was very different. After 9, 24, and
96 h, the number of T cells in the periportal field was
significantly higher (up to 10-fold) compared with the number of cells
at 1 h after cell injection.
|
ß. These cells were
53 ± 8% CD8+ (n = 10) and
47 ± 8% CD4+ (n = 10).
There was no difference in the cell subset distribution between the
parenchyma and the periportal field. However, there were differences in
the expression of T cell activation markers between the liver
compartments. At all time points, there were significantly more
activated cells expressing IL-2R in the periportal field (Table II). Similarly, the periportal field also
contained significantly increased numbers of activated cells expressing
MHC class II.
|
Next it was investigated whether the expression of IL-2R on
activated T cells resulted in proliferation of injected T cells in situ
in the liver. Three days after injection of activated T cells, BrdU was
injected i.v. The percentage of activated T cells that had incorporated
BrdU either in the parenchyma or the periportal field was analyzed
(Fig. 1
B). The proliferation of injected cells was
significantly higher in the periportal field (Fig. 4). Furthermore, the degree of
proliferation was linked to the origin of the donor cells in both
compartments. Cells from the mLNs showed a proliferation level that was
3 times higher than cells from pLNs. In control animals, it was shown
that the endogenous T cell proliferation was also different in the
parenchyma and the periportal field of the liver (parenchyma, 1.7%, 91
BrdU+ cells among 5408 cells; periportal field,
7%, 27 BrdU+ cells among 385 cells; data pooled
from five animals), and there was no difference between CD8+
and CD4+ T cells (data not shown). These data are
comparable with the proliferation of injected pLN cells in the liver.
In contrast, the origin of the donor cells was not important when in
vivo proliferation was monitored after entry into the celiac LN
draining the liver, and the same held for the axillary LN draining the
skin (Table III).
|
|
To study the fate of T cells in the liver, we investigated whether
the injected T cells die in situ. The rate of apoptosis among injected
cells (Fig. 1C) was about 0.5% in the liver (among 2912
donor cells from mLN, 16 cells were TUNEL positive; data pooled from
eight animals).
The question arose as to whether most donor T cells die there or
whether some activated T cells also leave the liver. Therefore, the
number of donor lymphocytes in the celiac LN draining the liver was
studied. As a control for the entrance via blood, the number of cells
in the celiac LN was compared with that of the axillary LN draining the
skin. Under normal circumstances, only very few lymphocytes reach the
axillary LN via afferent lymph (14, 36). Many more
injected cells were found in the celiac LN with time than in the
axillary LN (Fig. 5A). This
was true for both CD4+ and
CD8+ T cells (data not shown). When the values
were expressed as a ratio (Fig. 5B), about 2 times as many
donor cells were found in the T cell region of the celiac LN draining
the liver at 1 h. This increased to a factor of 10 at 9 h and
12 at 24 h. Comparable observations were made when comparing the B
cell region and the medulla of both LNs (data not shown). The
difference in the two LNs most likely suggests that the greater number
of injected T cells in the celiac LN draining the liver is due to their
exit from the liver via the lymphatics.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
T cell subsets migrate with different kinetics through the parenchyma and periportal field of the liver
Previous investigations reported that T cells recirculate through the liver (6, 11, 12). However, these studies did not consider the liver compartments that are differently affected in various immunological liver diseases. The present study demonstrates that T cells migrate through both the parenchyma and the periportal field. Although it is known that damaged cells are retrieved in the liver (10, 39, 40), the donor cells we found were clearly intact, as seen by immunohistology. With the method that was applied it was not possible to differentiate where precisely the donor T cells are located in the parenchyma: in the sinusoids, between the endothelium and the hepatocytes, or between the hepatocytes. However, it is unlikely that they are in the sinus since both kinetics and proliferation rate of injected T cell subsets in the blood were different from those of donor T cells in the parenchyma (data not shown). T cells leave the parenchyma quickly, but accumulate in the periportal field of the liver. The mechanisms that are involved are unclear. It is known that the liver receives its blood from the hepatic artery (one-third) and the portal vein (two-thirds) (41), which preferentially supply the periportal field and the parenchyma, respectively (42). This might partly explain the different migration kinetics of the periportal field and parenchyma. In addition, adhesion molecules are constitutively expressed mainly in the periportal field of the liver (43). Whatever the mechanism, our study demonstrates that in vivo the periportal field of the liver receives relatively more T cells than the parenchyma, which could partially explain the initiation and manifestation of immunological liver diseases in this region compared with that of the parenchyma.
Naive and memory CD4+ T cells migrate with comparable kinetics through the liver compartments
Interestingly, we found that both naive and memory
CD4+ T cells migrate through the liver. This is
in agreement with reports that naive and memory T cells are also
present in the human liver (2, 44, 45), and together this
clearly demonstrates that naive T cells continuously migrate through
nonlymphoid organs such as the liver. In our study, the injected naive
T cell suspension contained some memory T cells (20%), because we
opted to tolerate this contamination to avoid purification by positive
selection, a procedure that would coat the
CD45RC+ subset with mAb. It is unlikely, however,
that the cells found in the liver after naive cell injection all belong
to the contaminating memory T cell population, because if this were
true, the absolute number of cells we would have found would have been
only one-fifth of the number of memory T cells. This was clearly not
the case, since we found no difference in migration of naive or memory
CD4+ T cells through the liver (Fig. 2). Tietz
and Hamman (14) reported that memory
CD4+ T cells have a preference for the liver
similar to that of activated lymphocytes. However, they did not exclude
activated T cells from their memory cell preparation. Thus, when the
migration of naive and memory T cells was followed directly through the
parenchyma and the periportal field, we found no evidence to indicate
that there are different pathways. This underlines the importance of
directly following the traffic of labeled lymphocyte subsets to define
their migration routes in vivo (8, 19, 46, 47) and shows
that the notion that naive T cells preferentially migrate through
lymphoid organs and memory T cells preferentially through nonlymphoid
organs is not as strict as previously thought (48, 49). In
addition, since the liver contains dendritic cells (42, 50, 51) capable of presenting Ag to naive CD4+
T cells, the liver may not merely be an effector site (immigration of
memory CD4+ T cells), but may also be a site of
primary immune responses (immigration of naive
CD4+ T cells). Further studies must show whether
similar kinetics apply to naive and memory CD8+ T
cells.
Preferential proliferation of activated T cells in the periportal field
After injection and migration, activated T cells of both
phenotypes (CD4+ and CD8+)
are found in the liver and are able to proliferate in situ. The
proliferation rate is comparable or even higher than in the T cell area
of LNs. The liver sections from rats injected with donor cells,
however, are histologically indistinguishable from normal livers and do
not contain readily detectable cell infiltrates. This shows that it is
necessary to analyze BrdU incorporation at the single cell level within
the respective compartments to demonstrate the proliferation of
activated T cells in the liver. Thus, in addition to preferential
migration into the periportal field, the differential proliferation of
activated T cells in the liver compartments, which is more pronounced
than that for naive and memory T cells, is also responsible for the
accumulation of activated T cells in the periportal field compared with
the parenchyma. This correlates well with the higher activation state
of these cells in the former compartment (IL-2R and MHC class
II).
T cells derived from mLNs show a proliferation rate in the periportal
field that was 3 times as high as cells originating from pLNs and 3
times as high as endogenous proliferation. This augmented proliferation
of mLN T cells is apparently governed by the periportal
microenvironment, for when these same mLN and pLN T cells were examined
before injection (26) and after injection in the celiac LN
draining the liver (present study), there was no difference in the rate
of proliferation between these two sources of T cells. In accordance
with the preferential proliferation in the liver, it was recently shown
that in the mLNs, activated donor T cells show enhanced proliferation
if the cells originated from the same tissue (26). This
also indicates that the presence of characteristic accessory molecules
such as B7.1 and B7.2 (52, 53), various adhesion molecules
(16), and different concentrations of various cytokines
(54, 55) may drive the preferential proliferation of
activated T cells in a microenvironment-specific fashion (28, 47). This is in line with recent observations in mice, in which
it was shown that lymphocytes from pLN and Peyer’s patches
significantly differ in the amount and ratio of IL-2, IL-4, and IFN-
they produce (56, 57). In addition, extracellular matrix
compounds, dendritic cell subsets (58), adhesion molecules
(43), and even innervation by the central nervous system
(59, 60) might play a role in the
microenvironment-characteristic regulation of the proliferation of
activated T cells.
Taken together, activated T cells have an even greater preference for the periportal field of the liver than naive or memory T cells, and they preferentially proliferate there. This could partly explain the preferential initiation and manifestation of some immunological liver diseases in the periportal field.
Activated T cells survive in and are able to leave the liver
Our study suggests that the preferential proliferation of activated T cells in the periportal field of the liver contributes to the accumulation of these cells in this compartment. However, other possibilities such as an increased entry or reduced cell death and exit should be considered. Entry into the liver does not seem to be important for the preferential accumulation in the periportal field, since regardless of whether they are naive, activated, or memory T cells, the number found initially (0.5–1 h after injection) in both compartments is comparable.
Injected cells die by apoptosis in the liver, showing that not only hepatocytes die by this pathway during viral hepatitis and primary biliary cirrhosis (61), but also activated T cells after migration into the normal liver. In a recent study, it was found that after antigenic stimulation many Ag-specific T cells accumulate in the liver, where they undergo apoptosis (39, 62). Due to the low number of apoptotic cells among the injected T cells in the liver, we can neither confirm nor exclude that preferential apoptosis in the parenchyma may be involved in the accumulation of activated T cells in the periportal field. In addition, the amount of cell death among activated T cells in the liver caused by apoptosis is unknown. However, the present study shows that a substantial number of activated T cells survives, and both CD4+ and CD8+ T cells are able to leave the liver. This is demonstrated by the fact that about 10 times more activated T cells are found in the celiac LN draining the liver than in the axillary LN draining the skin 9, 24, and 96 h after injection. It is known that under normal circumstances only very few lymphocytes reach the axillary LN via the afferent lymphatics (14). When assuming that the number of activated T cells entering the celiac and axillary LN via the high endothelial venules is roughly similar (19, 26), then a large difference in the number of activated T cells found in both LNs must be due to the arrival of activated T cells via the afferent lymphatics, a route that was previously described for dendritic cells (63).
Conclusions
Naive, activated, and memory T cells continuously migrate through the parenchyma and the periportal field of the liver. All migrating T cell subsets investigated in the present study have a preference for the periportal field of the normal liver, and activated T cells mainly proliferate there. Together, this may partly explain why many immunologically mediated diseases predominantly affect the periportal field and not the parenchyma. Future studies should aim at identifying the as yet unknown factors that are involved in regulating the compartment-characteristic migration and proliferation. In addition, it is necessary to analyze how these subsets migrate through the compartments of the liver during various diseases. Modifying migration and proliferation of the different T cell subsets may represent a way to increase or decrease their numbers in the liver, and could have clinical relevance for the treatment of immunologically mediated diseases of the liver.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Juergen Westermann, Zentrum Anatomie 4120, Medizinische Hochschule Hannover, D-30623 Hannover. E-mail address:
3 Abbreviations used in this paper: LN, lymph node; APAAP, alkaline phosphatase antialkaline phosphatase; BrdU, 5-bromo-2-deoxyuridine; mLN, mesenteric lymph node; pLN, peripheral lymph node.
Received for publication May 12, 1999. Accepted for publication July 29, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
4 integrin-VCAM-1 interaction. Int. Immunol. 7:1861.24-JQ and 
T cell receptor bearing cells. Hum. Immunol. 28:20.
This article has been cited by other articles:
|
|
 |
|
  M. Fedrowitz, K. Kamino, and W. Loscher Significant Differences in the Effects of Magnetic Field Exposure on 7,12-Dimethylbenz(a)anthracene-Induced Mammary Carcinogenesis in Two Substrains of Sprague-Dawley Rats Cancer Res., January 1, 2004; 64(1): 243 - 251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Djilali-Saiah, P. Lapierre, S. Vittozi, and F. Alvarez DNA Vaccination Breaks Tolerance for a Neo-Self Antigen in Liver: A Transgenic Murine Model of Autoimmune Hepatitis J. Immunol., November 1, 2002; 169(9): 4889 - 4896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fedrowitz, J. Westermann, and W. Loscher Magnetic Field Exposure Increases Cell Proliferation but Does Not Affect Melatonin Levels in the Mammary Gland of Female Sprague Dawley Rats Cancer Res., March 1, 2002; 62(5): 1356 - 1363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M. Milicevic, B. Luettig, C. Trautwein, T. Wustefeld, M. Mahler, P. Jecker, K. Wonigeit, and J. Westermann Splenectomy of rats selectively reduces lymphocyte function-associated antigen 1 and intercellular adhesion molecule 1 expression on B-cell subsets in blood and lymph nodes Blood, November 15, 2001; 98(10): 3035 - 3041. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Luettig, M. Kaiser, U. Bode, E. B. Bell, S. M. Sparshott, M. Bette, and J. Westermann Naive and Memory T Cells Migrate in Comparable Numbers through the Normal Rat Lung . Only Effector T Cells Accumulate and Proliferate in the Lamina Propria of the Bronchi Am. J. Respir. Cell Mol. Biol., July 1, 2001; 25(1): 69 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-X. Liu, S. Govindarajan, S. Okamoto, and G. Dennert Fas-Mediated Apoptosis Causes Elimination of Virus-Specific Cytotoxic T Cells in the Virus-Infected Liver J. Immunol., March 1, 2001; 166(5): 3035 - 3041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Reome, D. S. Johnston, B. K. Helmich, T. M. Morgan, N. Dutton-Swain, and R. W. Dutton The Effects of Prolonged Administration of 5-Bromodeoxyuridine on Cells of the Immune System J. Immunol., October 15, 2000; 165(8): 4226 - 4230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Voehringer, C. Blaser, A. B. Grawitz, F. V. Chisari, K. Buerki, and H. Pircher Break of T Cell Ignorance to a Viral Antigen in the Liver Induces Hepatitis J. Immunol., September 1, 2000; 165(5): 2415 - 2422. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Schmitz, M. J. Kuroda, R. S. Veazey, A. Seth, W. M. Taylor, C. E. Nickerson, M. A. Lifton, P. J. Dailey, M. A. Forman, P. Racz, et al. Simian Immunodeficiency Virus (SIV)-Specific CTL Are Present in Large Numbers in Livers of SIV-Infected Rhesus Monkeys J. Immunol., June 1, 2000; 164(11): 6015 - 6019. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. O. Farah, P. W. Mola, T. M. Kariuki, M. Nyindo, R. E. Blanton, and C. L. King Repeated Exposure Induces Periportal Fibrosis in Schistosoma mansoni-Infected Baboons: Role of TGF-{beta} and IL-4 J. Immunol., May 15, 2000; 164(10): 5337 - 5343. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||
