| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Signaling in T Cells Prevents the Development of Experimental Glomerulonephritis1
*
Allergy Research Center,
Division of Nephrology Juntendo University School of Medicine, Tokyo, Japan
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
signaling, in mature T cells, where signaling by TGF- was blocked
specifically in T cells. In this study, we showed that anti-GBM
Ab-induced GN was suppressed in several measures in the transgenic mice
including the severity of glomerular changes, proteinuria, renal
function, and CD4 T cell infiltration into the glomeruli without
down-regulation of CD62 ligand (CD62L) (L-selectin) expression on CD4 T
cells. Furthermore, treatment with the soluble fusion protein of CD62L
and IgG enhanced anti-GBM Ab-induced GN. These findings indicated
that blockade of TGF- signaling in T cells prevented the development
of anti-GBM Ab-induced GN. Because CD62L on T cells appears to be
inhibitory for the development of anti-GBM Ab-induced GN,
persistent expression of CD62L on CD4 T cells may explain, at least in
part, the suppression of anti-GBM Ab-induced GN in the transgenic
mice. Our findings suggest that the development of anti-GBM
Ab-induced GN requires TGF-/Smad signaling in T
cells. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Recent evidence has suggested that anti-GBM Ab-induced GN is mediated by T cell-dependent fashion (2, 3, 4, 5). Huang et al. reported that CD4 T cells were accumulated in glomeruli of rats developing anti-GBM Ab-induced GN, and depletion of CD4 T cells prevented glomerular damage and proteinuria observed in the GN (2). Thus, in the current model, T cell-mediated responses are thought to be essential for the development of anti-GBM Ab-induced GN. However, it remains unclear regarding signaling pathways of T cells that are involved in the development of anti-GBM Ab-induced GN.
TGF- is a multifunctional cytokine that has diverse effects on a
variety of cell types (8). TGF- transduces signals from
the receptors to the nucleus through the Smad family of proteins
(9, 10). We have recently established transgenic mice
expressing Smad7, an intracellular antagonist of TGF-/Smad signaling
(11), under the control of a distal lck promoter that
directed high expression in peripheral T cells (12).
Therefore, we were able to block the TGF-/Smad signaling pathway
specifically in mature T cells. Peripheral T cells in the transgenic
mice showed high expression of Smad7 and were insensitive to TGF-,
but the development of the immune system was normal and the mice
survived into adulthood (13). Using the transgenic mice,
we determined whether TGF-/Smad signaling in mature T cells
regulated the development of GN. We used anti-GBM Ab-induced GN in
the transgenic mice and wild-type littermates by the injection of
heterologous (rabbit) anti-GBM Ab and compared the results. We
found that anti-GBM Ab-induced GN was suppressed in the transgenic
mice. Thus our findings suggested that the development of anti-GBM
Ab-induced GN required TGF-/Smad signaling in T cells.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Transgenic mice expressing Smad7 under control of a distal lck promoter were generated as previously described (13). Transgene-positive founders were backcrossed to B6 mice to establish lines. All experiments used 8- to 10-wk-old transgenic mice or the wild-type littermates, weighing 18–23 g, which were matched with sex.
Induction of anti-GBM GN
Rabbit anti-GBM Ab (nephrotoxic serum) was provided by Tanabe Pharmaceuticals (Tokyo, Japan) (14). Anti-GBM Ab-induced GN was developed by i.v. injection of the nephrotoxic serum through the tail vein in mice that had been preimmunized with rabbit IgG and CFA 4 days before administration of nephrotoxic serum. Nephrotoxic serum at a dose of 0.1 ml/20 g body weight was used in this study. Our pilot studies revealed that this dosage induced severe GN with functional deterioration, but was not sufficient to induce fatal damage (14).
Evaluation of proteinuria and blood urea nitrogen
Urine samples (10 µl) at each time point were evaluated as previously described (14). Serum samples at each time point were evaluated for the concentration of urea nitrogen by the Urease-Indophenol method. The Wako Urea NB kit (Wako Pure Chemical, Osaka, Japan) was used for the quantitative determination.
Histological analysis
Kidney sections were fixed in 10% formaldehyde and stained with periodic acid-Schiff’s (PAS) reagent to assess histological changes by light microscopy. Histology of the kidney sections was graded according to the criteria by Raij et al. (15). Briefly, the following light microscopic features were evaluated 1) intracapillary cellular proliferation; 2) capillary loop aneurysms characterized by dilatation of capillary loops two to three times greater than normal capillary diameter; 3) glomerulosclerosis, defined as the disappearance of cellular elements from the tuft, collapse of the capillary lumen, and folding of the GBM with entrapment of amorphous material; 4) cellular necrosis evidenced by loss of recognition of cellular membranes and by karyorrhexis; and 5) extracapillary cellular proliferation (crescent). Morphological changes (1, 2, 3, 4, 5) were quantitated on a scale of 1–4. A score of 1 was equivalent to 25% of the glomeruli affected by the particular morphologic change, and 4 represented involvement of 100% of the glomeruli. Intermediate values were assigned a value of 0.5. An injury score was then obtained by multiplying the severity of the change by the percentage of glomeruli with the same severity of the change. The extent of injury for each individual tissue specimen was then obtained by the addition of these scores. Twenty-five equatorially sectioned glomeruli per kidney were assessed.
Immunofluorescent study
Kidney sections were stained with FITC or rhodamine-labeled IgG of goat anti-mouse IgG (Cappel), goat anti-mouse complement C3 (Cappel, Aurora, OH), and FITC-labeled anti-CD4 Abs (PharMingen, San Diego, CA) as previously described (16). Glomerular CD4-positive T cell numbers were assessed using a blinded protocol. A minimum of 50 equatorially sectioned glomeruli per animal were assessed per animal, and the results were expressed as cells per glomerular cross section (cells/gcs).
Proliferation assay
The proliferation assay was performed as previously described (13). Splenocytes were isolated from transgenic mice and wild-type littermates at day 5 after injection of rabbit IgG as preimmunization, followed by [3H]thymidine uptake assay.
Purification of T cells
Mouse CD4 T cells were purified from splenocytes harvested from the transgenic or wild-type mice by a magnetic cell sorting using MACS anti-CD4 microbeads (Miltenyi Biotec, Gladbach, Germany) following the manufacturer’s recommendation. The purity of mouse CD4 T cells was confirmed by FACScan (Becton Dickinson, Mountain View, CA) and was consistently >99%.
Stimulation of T cells
Purified mouse CD4 T cells (1 x 106 cells/ml) were
stimulated with plate-bound anti-CD3 Ab (2C11) (10 µg/ml)
(PharMingen) in the presence or absence of recombinant human TGF-1
(10 ng/ml) (R&D Systems, Minneapolis, MN) and were cultured for 3 days
in RPMI 1640 with 10% heat-inactivated FCS (Life Technologies, Grand
Island, NY) in humidified 5% CO2 at 37°C,
followed by FACS analysis.
Flow cytometry
Mouse CD4 T cells suspended in PBS containing 0.1%
NaN3 and 1% FCS were incubated on ice with
PE-labeled anti-CD4, anti-LFA-1, anti-ICAM-1, anti-very
late Ag (VLA)-4,
anti-
47, and
anti-CD62 ligand (anti-CD62L) Ab (MEL14) (PharMingen). After
washing, the cells were analyzed on a FACScan flow cytometer (Becton
Dickinson) using CellQuest software (Becton Dickinson).
Treatment with CD62L and IgG chimeric molecule
To determine whether CD62L was involved in the development of anti-GBM Ab-induced GN, mice that had been preimmunized as described above were pretreated with the soluble fusion protein of human CD62L and human IgG (CD62L-IgG) (200 µg/mouse) or human IgG (200 µg/mouse) 4 h before the injection of the nephrotoxic serum (0.1 ml/20 g body weight). The CD62L-IgG chimeric protein was made at Tokyo Research Laboratory, Kyowa Hakko Kogyo (Mishima, Japan) as described previously (17). CD62L-IgG chimera was shown to act as an antagonist for CD62L-mediated responses (18). CD62L-IgG or control human IgG was injected i.v. and repeated three times every 24 h (total of four injections). Mice were sacrificed at day 10 after the injection of the nephrotoxic serum for evaluation of the treatment.
Data analysis
Data are summarized as mean ± SD. The statistical analysis of the results was performed by the amount of variance using Fisher’s least significant difference test for multiple comparisons. Values of p < 0.05 were considered to be significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Wild-type mice given rabbit anti-GBM Ab produced detectable
levels of urinary protein at day 4, which increased and peaked at day
10 after the injection of anti-GBM Ab (Fig. 1
A). In contrast, transgenic
mice expressing Smad7 selectively in mature T cells produced
detectable, but little levels of urinary protein at day 4 with a
significant reduction to nearly undetectable levels at later time
points (Fig. 1A). In addition, we observed a significant
reduction in blood urea nitrogen in the transgenic mice compared with
that in wild-type mice at day 10 after the injection of anti-GBM Ab
(Fig. 1B). There was no significant difference in baseline
blood urea nitrogen levels between the wild-type and transgenic mice
(wild-type: 13.4 ± 8 1.5 mg/dl vs transgenic: 14.0 ± 8 2.5
mg/dl, n = 4, mean ± SD).
|
, A and B).
Scoring of the histological findings showed significant reduction of
glomerular damage in the transgenic mice (Fig. 2C). These
results indicated that the blockade of TGF-/Smad signaling in T
cells suppressed the development of anti-GBM Ab-induced GN in
mice.
|
Because previous studies suggested a role of helper T cells as
local effectors of glomerular injury in anti-GBM Ab-induced GN
(2, 3, 4, 5), we assessed T cell infiltration into the kidney.
Wild-type mice showed the increase of infiltrating CD4-positive T cells
in glomeruli at day 10 and 21 after the injection of anti-GBM Ab
(Fig. 2
D). In contrast, the transgenic mice showed a marked
reduction in the infiltration of CD4-positive T cells into glomeruli
(Fig. 2D). Suppression of CD4 T cell infiltration was
observed not only in glomeruli, but also in periglomerular region and
interstitial tissue in the transgenic mice (Fig. 3, and data not shown). There was no
significant difference in the basal number of peripheral blood T cells
between Smad7-transgenic mice and the wild-type littermates (data not
shown). These findings indicated that CD4 T cell infiltration into the
kidney was suppressed in Smad7-transgenic mice.
|
Immunofluorescence at day 21 after the injection of anti-GBM
Ab revealed that binding of anti-GBM Ab was observed equally in the
transgenic mice and wild-type littermates (data not shown). Autologous
Abs (mouse anti-rabbit Igs) bound to the GBM were also equally
confirmed in both mice (Fig. 4, A and B). In addition, complements (C3) bound to
GBM in a granular fashion equally in the transgenic mice and the
wild-type littermates (Fig. 4, C and D). The
transgenic mice remained healthy and did not develop any sign of GN,
despite the equivalent binding of heterologous and autologous Abs as
well as complements to wild-type mice, indicating that the glomerular
deposition of these Abs and complements was not sufficient to trigger
GN. In addition, proliferation studies showed that splenic T cells
isolated from wild-type and transgenic mice 5 days after the
preimmunization with rabbit IgG responded equally to rabbit IgG (Fig. 4E), suggesting that there was no difference in the initial
sensitization to rabbit IgG between wild-type and transgenic
mice.
|
A role of helper T cells as local effectors of glomerular injury
in anti-GBM Ab-induced GN has been suggested (2, 3, 4, 5).
In addition, decreased T cell infiltration into glomeruli was observed
in Smad7-transgenic mice (Fig. 3). Thus it was possible that the
inhibition of T cell infiltration into glomeruli was attributed to the
suppression of anti-GBM Ab-induced GN in Smad7-transgenic mice. We
then examined surface expression levels of adhesion molecules including
LFA-1, ICAM-1, VLA-4,
47, and CD62L that
were involved in T cell infiltration into the tissue (19)
to address the mechanisms underlying the suppression of anti-GBM
Ab-induced GN in the transgenic mice. Basal expression levels of these
molecules on splenic CD4 T cells were not significantly different
between wild-type and transgenic mice at the age of 8–10 wk
(data not shown). We then asked whether expression levels of these
molecules on splenic CD4 T cells were affected by TGF-. Expression
levels of LFA-1, ICAM-1, VLA-4, and
47 were not changed
on splenic CD4 T cells from wild-type mice activated by immobilized
anti-CD3 Ab in the presence or absence of TGF- (data not shown).
As shown in Fig. 5, splenic CD4 T cells
from wild-type mice consisted of two distinct populations, CD62L
(L-selectin)low and
CD62Lhigh, when activated by immobilized
anti-CD3 Ab. The CD62Lhigh population was
significantly reduced in the presence of TGF- (Fig. 5). In contrast,
the CD62Lhigh population of splenic CD4 T cells
from Smad7-transgenic mice was not affected in the presence of TGF-
(Fig. 5). These findings indicated that TGF- down-regulated CD62L
expression on splenic CD4 T cells from wild-type mice, but not from
Smad7-transgenic mice.
|
, A–E). Most
notably, mice receiving CD62L-IgG died around day 10 after the
injection of anti-GBM Ab, which was not seen in mice receiving
control human IgG (Fig. 6A). These findings suggested that
CD62L functioned as inhibitory in the development of anti-GBM
Ab-induced GN. Taken together, the suppression of anti-GBM
Ab-induced GN in Smad7-transgenic mice might be attributed, at least in
part, to the persistent expression of CD62L on CD4 T cells in
Smad7-transgenic mice.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
signaling in T
cells in the development of anti-GBM Ab-induced GN, which have
extended the previous studies. In contrast, Fc receptors are recently
reported to be critical for induction of GN. In Fc receptor-deficient
mice, initial reaction of polymorphonuclear cells after the injection
of nephrotoxic serum was impaired, and subsequent renal damages were
suppressed (14, 16). Taken together, we could propose a
model for anti-GBM Ab-induced GN consisting of two phases: 1) an
early induction phase (until 3 days after the injection of anti-GBM
Ab) characterized by infiltration of polymorphonuclear cells into
glomeruli, where Fc receptor-mediated responses are critical; and 2) a
later nephritic phase (that follows the early phase), where T
cell-mediated responses are crucial. TGF- signaling in T cells is
likely to be essential for the development of the later nephritic stage
(T cell-mediated stage) of GN in our current protocol because the early
phase of anti-GBM Ab-induced GN (infiltration of polymorphonuclear
cells) was observed in the transgenic mice to the same degree as in
wild-type mice (data not shown). It appeared that the pathophysiology of anti-GBM Ab-induced GN was affected by the dosage of anti-GBM Ab (nephrotoxic serum). We found that Smad7-transgenic mice showed severe proteinuria, elevated blood urea levels, crescent formation, and decreased survival rate that were comparable to the wild-type littermates when the dose of anti-GBM Ab was increased sufficiently to affect mouse survival (0.2 ml/20 g body weight) (data not shown). Previously, we reported that the high dose of anti-GBM Ab (0.2 ml/20 g body weight) induced fatal GN in wild-type mice, but not in Fc receptor-deficient mice (14). Thus it appears that Fc receptor-mediated responses are more crucial for GN induced by the high-dose of anti-GBM Ab than T cell-mediated responses. We speculate that the Fc receptor-dependent early phase of GN was severely induced in the transgenic mice, resulting in fatal GN when using the high dose of anti-GBM Ab.
The mechanisms underlying the suppression of anti-GBM Ab-induced GN
in the transgenic mice remain to be determined. As shown in Fig. 5, we
found that TGF- down-regulated expression of CD62L on CD4 T cells in
wild-type mice, but not in the transgenic mice. In vivo experiments
using blocking fusion protein (CD62L-IgG) (Fig. 6) suggested that CD62L
might be involved in the suppression of anti-GBM Ab-induced GN.
Taken together, it is possible that persistent expression of CD62L on
CD4 T cells could be attributed, at least in part, to the suppression
of anti-GBM Ab-induced GN in Smad7-transgenic mice.
CD62L (L-selectin) is a well-characterized homing receptor, a carbohydrate-binding protein detected by the MEL-14 Ab in mouse (20), that belongs to the three-member (the other two are P- and E-selectin) selectin family of unique adhesion molecules. CD62L expressed on T cells and other leukocytes is mainly involved in the adhesion of T cells to the high endothelial venules of peripheral lymph nodes and is thought to mediate the adhesion of naive T cells to high endothelial venules and subsequent extravasation in peripheral lymph nodes (21). Previous studies using CD62L blocking Ab or CD62L-deficient mice suggested that CD62L was also crucial for migration of lymphocytes to sites of inflammation (22, 23), which would be inconsistent with our findings. However, recent evidence suggested that CD62L-negative (or low) subset of T cells migrated to sites of inflammation markedly better than CD62L-positive (or high) subset of T cells (24, 25, 26). Low CD62L expression could reduce the capacity of T cells to recirculate through lymph nodes and redirect them toward the inflamed lung tissue (26). Similar phenomena might occur in the inflamed kidney. In addition, P-selectin deficiency was recently shown to exacerbate anti-GBM Ab-induced GN in mice (27). These studies, in contrast to previous ones, suggested an inhibitory role for the selectin family of proteins in migration of lymphocytes to sites of inflammation. Thus, it appears that regulatory mechanisms of lymphocyte migration by the selectin family of proteins are more complex than we ever thought. Further studies are definitely needed to address the precise role of CD62L in lymphocyte migration to sites of inflammation.
TGF- has been implicated as a negative regulator of the immune
system and the systemic administration of TGF- suppressed
inflammation in some experimental models (28) in contrast
to our current study. Different experimental systems may explain the
different results. It is important to note that our experimental
approach using transgenic mice expressing Smad7 only in T cells has
advantage of avoiding multiple effects of TGF- on other cell types
and can specifically address the role of TGF- signaling in T cells
in GN. Systemic administration of TGF- or neutralizing Ab against
TGF- affects various functions in a variety of TGF--responsive
cells and may mislead results of the experiments.
We have previously shown that Ag-induced airway inflammation (murine
model of asthma) is enhanced in Smad7-transgenic mice compared with the
wild-type littermates (13); this appears to be opposite to
the current study in the GN model. In the murine model of asthma,
cytokines such as IL-4, IL-5, and IL-13 and chemokines such as eotaxin
were immediately produced in the mouse airways upon Ag challenge and
were shown to be important for induction of airway inflammation
(29). TGF- levels in the mouse airways were gradually
increased and reached a peak at the chronic phase of the airway
inflammation (our unpublished data), suggesting that TGF- was not
important for induction of airway inflammation in the asthma model. In
contrast, TGF- was immediately secreted upon injured glomeruli in GN
(30), suggesting that TGF- may be a principal cytokine
that initiates GN. In fact, systemic administration of neutralizing Ab
against TGF- suppressed glomerular sclerosis in rats
(31). Therefore, the different phenotypes observed between
asthma model and GN model in Smad7-transgenic mice may result from
distinct roles of TGF- (anti-inflammatory vs proinflammatory) in
the two disorders.
In summary, we demonstrated that anti-GBM Ab-induced GN was
suppressed in the transgenic mice expressing Smad7 selectively in
mature T cells where TGF-/Smad signaling was blocked specifically in
T cells. Our results narrowed down TGF-/Smad signaling in T cells as
an essential component for the development of anti-GBM
Ab-induced GN.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Atsuhito Nakao, Allergy Research Center, Juntendo University, School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
3 Abbreviations used in this paper: GN, glomerulonephritis; GBM, glomerular basement membrane; CD62L, CD62 ligand; VLA, very late Ag.
Received for publication October 3, 2000. Accepted for publication December 4, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
. M. B. Sporn, and A. B. Roberts, eds. In Handbook of Experimental Pharmacology Vol. 95:418. Springer-Verlag, Heidelberg.
signalling from cell membrane to nucleus through SMAD proteins. Nature 390:465.[Medline]
signal transduction. Annu. Rev. Biochem. 67:753.[Medline]
-inducible antagonist of TGF- signaling. Nature 389:631.[Medline]
/Smad signaling by overexpression of Smad7 in T cells enhances antigen-induced airway inflammation and airway reactivity. J. Exp. Med. 192:151.. Annu. Rev. Immunol. 16:137.[Medline]
: a novel approach to treatment of glomerulonephritis and prevention of glomerulosclerosis. Kidney. Int. 41:566.[Medline]
1. Nature 346:371.[Medline]
This article has been cited by other articles:
|
|
 |
|
  S. H. Yang, S. J. Kim, N. Kim, J. E. Oh, J. G. Lee, N. H. Chung, S. Kim, and Y. S. Kim NKT Cells Inhibit the Development of Experimental Crescentic Glomerulonephritis J. Am. Soc. Nephrol., September 1, 2008; 19(9): 1663 - 1671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. R. Huang, A. C.K. Chung, L. Zhou, X. J. Wang, and H. Y. Lan Latent TGF-{beta}1 Protects Against Crescentic Glomerulonephritis J. Am. Soc. Nephrol., February 1, 2008; 19(2): 233 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Mitsuo, S. Morimoto, Y. Nakiri, J. Suzuki, H. Kaneko, Y. Tokano, H. Tsuda, Y. Takasaki, and H. Hashimoto Decreased CD161+CD8+ T cells in the peripheral blood of patients suffering from rheumatic diseases Rheumatology, December 1, 2006; 45(12): 1477 - 1484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kanamaru, L. Scandiuzzi, M. Essig, C. Brochetta, C. Guerin-Marchand, Y. Tomino, R. C. Monteiro, M. Peuchmaur, and U. Blank Mast Cell-Mediated Remodeling and Fibrinolytic Activity Protect against Fatal Glomerulonephritis J. Immunol., May 1, 2006; 176(9): 5607 - 5615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Suzuki, Y. Suzuki, T. Yamanaka, S. Hirose, H. Nishimura, J. Toei, S. Horikoshi, and Y. Tomino Genome-Wide Scan in a Novel IgA Nephropathy Model Identifies a Susceptibility Locus on Murine Chromosome 10, in a Region Syntenic to Human IGAN1 on Chromosome 6q22-23 J. Am. Soc. Nephrol., May 1, 2005; 16(5): 1289 - 1299. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Wang, X. R. Huang, A. G. Li, F. Liu, J.-H. Li, L. D. Truong, X. J. Wang, and H. Y. Lan Signaling Mechanism of TGF-{beta}1 in Prevention of Renal Inflammation: Role of Smad7 J. Am. Soc. Nephrol., May 1, 2005; 16(5): 1371 - 1383. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hertig and E. Rondeau Role of the Coagulation/Fibrinolysis System in Fibrin-Associated Glomerular Injury J. Am. Soc. Nephrol., April 1, 2004; 15(4): 844 - 853. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. N. Lai, S. C. W. Tang, J.-Y. Guh, T.-D. Chuang, M. F. Lam, L. Y. Y. Chan, A. W. L. Tsang, and J. C. K. Leung Polymeric IgA1 from Patients with IgA Nephropathy Upregulates Transforming Growth Factor-{beta} Synthesis and Signal Transduction in Human Mesangial Cells via the Renin-Angiotensin System J. Am. Soc. Nephrol., December 1, 2003; 14(12): 3127 - 3137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Mizobuchi, K. Yasufuku, Y. Zheng, M. A. Haque, K. M. Heidler, K. Woods, G. N. Smith Jr., O. W. Cummings, T. Fujisawa, J. S. Blum, et al. Differential Expression of Smad7 Transcripts Identifies the CD4+CD45RChigh Regulatory T Cells That Mediate Type V Collagen-Induced Tolerance to Lung Allografts J. Immunol., August 1, 2003; 171(3): 1140 - 1147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Suzuki, C. Gomez-Guerrero, I. Shirato, O. Lopez-Franco, P. Hernandez-Vargas, G. Sanjuan, M. Ruiz-Ortega, T. Sugaya, K. Okumura, Y. Tomino, et al. Susceptibility to T Cell-Mediated Injury in Immune Complex Disease Is Linked to Local Activation of Renin-Angiotensin System: The Role of NF-AT Pathway J. Immunol., October 15, 2002; 169(8): 4136 - 4146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kanamaru, A. Nakao, I. Shirato, K. Okumura, H. Ogawa, Y. Tomino, and C. Ra Chronic Graft-versus-Host Autoimmune Disease in Fc Receptor {gamma} chain-deficient Mice Results in Lipoprotein Glomerulopathy J. Am. Soc. Nephrol., June 1, 2002; 13(6): 1527 - 1533. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
