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Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) that are more often associated with asthma. In an experimental
animal model of allergic inflammation, IL-4 and IL-5 but not IFN-
mRNAs were up-regulated among bronchoalveolar lavage
(BAL)3 cells, and the
increase of IL-4 and IL-5 was T cell-dependent (4). Furthermore, both
the constitutive transgenic expression of IL-4 in the lung (5) and a
tracheal injection of high levels of IL-5 (6) are associated with lung
eosinophilia. In humans, allergen-specific T cell clones that were
isolated from atopic subjects produced Th2 cytokines when stimulated in
vitro (7), and Th2 cells were present among the BAL cells and airway
mucosa of asthma patients (8, 9). Furthermore, it was demonstrated
recently that adoptively transferred Th2 cells, either through i.v.
(10) or intranasal (i.n.) (11) administration, induced asthma-like lung
inflammatory responses when stimulated with Ag. Taken together, these
results support the concept that Th2 cells and their cytokines play a
central role in inflammatory responses in asthma; however, an increase
of IFN--producing T cells has also been reported in a clonal
analysis of activated T cells in asthma (12). This finding raises the
possibility that Th1 cells are also involved in asthma, although the
specific role of Th1 cells in lung inflammation during asthma is not
clear.
It is evident that T cell-produced cytokines are not necessarily the
primary mediators of inflammatory cell recruitment; eosinophils and
other leukocytes are more directly drawn into tissues by the production
of chemokines by monocytes and parenchymal cells (13). The chemokines
that have been implicated in asthma include RANTES, macrophage
inflammatory protein (MIP)-1
, and monocyte chemotactic protein
(MCP)-3 (14). In a lung granuloma model, MIP-1 and RANTES were
associated with eosinophil accumulation (15). Furthermore, the recently
identified eosinophil chemoattractant, eotaxin, has been detected in
rodent models of allergic inflammation (16, 17) and was determined to
be one of the molecules linking T cell activation and the recruitment
of eosinophils into the airway (18). The potential direct regulation of
chemokine production in the lung by Th1 and Th2 cytokines has not been
elucidated; therefore, the present study was initiated to establish the
relationship between Th subsets and the Ag-dependent induction of
chemokine production leading toward eosinophilia.
We adoptively transferred Ag-specific Th1 and/or Th2 cells into naive mice and challenged the mice i.n. with Ag. We found that the Ag-specific activation of Th1 and Th2 cells induced different patterns of chemokines leading to different types of cellular infiltration. The activation of Th2 cells was sufficient to induce both eotaxin expression and lung eosinophilia; however, the cotransfer of Th1 cells did not significantly inhibit Th2 cell activation, nor did it suppress Th2 cell-induced eotaxin expression and eosinophilia in the lung. These results were obtained regardless of whether Ag was provided as synthetic peptide or by infectious influenza virus infection. We conclude from these studies that Th1 and Th2 cell-induced responses are codominant at the effector stage of lung inflammation regardless of the nature of the Ag stimulus.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TCR-SFExBALB/c transgenic mice have been described previously (19). These mice are transgenic for a TCR that is specific for influenza PR8 hemagglutinin peptide 110–119 (SFERFEIFPK) presented on I-Ed. Naive BALB/c mice (6–8 wk of age) were provided by the Rodent Breeding Colony of The Scripps Research Institute (TSRI). The BALB/c and TCR-SFExBALB/c mice were maintained under specific pathogen-free conditions in the TSRI rodent colony in accordance with National Institutes of Health (Bethesda, MD) and TSRI institutional guidelines.
Generation and testing of Th1 and Th2 cells
Th1 and Th2 cells were generated from naive lymph node T cells (sorted CD4+ Mel-14high) (PharMingen, San Diego, CA) that had been obtained from TCR-SFExBALB/c mice. A total of 106 T cells were cultured with 5 x 106 irradiated (2500 rad) spleen cells under Th1 (20 ng/ml IL-12; Genzyme, Cambridge, MA) or Th2 (25 ng/ml IL-4; PeproTech, Rocky Hill, NJ) and 100 µg/ml of anti-IL-12 (monoclonal rat IgG, clone C17.8.20; a kind gift of Dr. G. Trinchieri, The Wistar Institute Philadelphia, PA) conditions with 0.5 µg/ml of SFE peptides. The media was changed every 2 to 3 days, and 50 U/ml of IL-2 (PeproTech) was added to all the culture from day 3 on. Cells that had been cultured for 9 days were used for adoptive transfer. At 7 days after the culture, an aliquot of Th1 or Th2 cells (105/well) was stimulated with Con A (5 µg/ml), and cytokines in the supernatants were tested by ELISA (PharMingen). Aliquots of T cells were also stained for CD4-phycoerythrin and Vß8.1/8.2-FITC (PharMingen) and analyzed by flow cytometry. Th1 or Th2 cells (5 x 104/well) were stimulated with irradiated (2500 rad) syngeneic spleen cells (1.5 x 105/well) in the presence of different concentrations of SFE peptide, and their in vitro proliferation was assessed by [3H]thymidine incorporation.
Induction of lung inflammations
Th1 or Th2 cells (5 x 106/mouse) or Th1 plus Th2 cells (5 x 106 of each type per mouse) were transferred i.v. into naive BALB/c mice. Mice were challenged i.n. at 24 h posttransfer with 100 µg of SFE peptide daily for 3 days. Control mice were either transferred with Th1 or Th2 cells but challenged with PBS or challenged with SFE without cell transfer. Mice were sacrificed at 3 h after the last challenge, and their blood was taken for the testing of serum IgE levels. The lung was then perfused from the right ventricle using PBS until it turned white, and BAL was collected by washing the lung through the trachea three times with 5 ml of RPMI 1640 plus 2% horse serum. Cytospins were prepared for BAL cells from each mouse. The upper right lobe of the lung was then frozen in Trizol reagent (Life Technologies, Grand Island, NY) at -70°C for RNA extraction. One-half of the left lung was fixed in Bouins’ solution for hematoxylin and eosin staining, while the other half was frozen in OCT compound (Miles, Elkhart, IN) for immunohistochemical staining.
In cases of virus infection, Th1 or Th2 cells (6 x 106/mouse) or Th1 plus Th2 cells (6 x 106/mouse of each type) were transferred i.v. into naive BALB/c mice. These mice were infected i.n. with 25 µl (2.5 hemagglutinating units) of influenza virus (influenza A/PR/8/34/Mt. Sinai, as described in 20 at 24 h after cell transfer. The mice were sacrificed after 3 days, and BAL and tissue were processed as described above.
Histology
Cytospins of BAL cells were fixed with methanol and stained with eosin and methylene blue (Fisher, Pittsburgh, PA). Leukocytes were analyzed by a differential count of 200 to 300 cells on coded slides. Bouins’ solution-fixed lung tissues were embedded in paraffin, and sections were stained with hematoxylin and eosin (Sigma). Frozen lung sections were fixed with cold acetone (Fisher) and stained with rat anti-mouse CD4 (PharMingen) followed by biotin-F(ab)2 mouse anti-rat IgG (Jackson ImmunoResearch, West Grove, PA) and streptavidin-horseradish peroxidase (Jackson ImmunoResearch). CD4+ cells were visualized by 3-amino-9-ethylcarbazole (AEC) substrate (Sigma). Eosinophils were stained for cyanide-resistant eosinophil peroxidase activity as described previously (21). Briefly, frozen lung sections were fixed with 1% formalin (Fisher) in acetone. Tissues were subsequently stained for 10 min with 0.4 mg/ml sodium cyanide (Sigma), 3 µl/ml H2O2 (Fisher), and 0.75 mg/ml diaminobenzidine (Sigma) substrate in PBS and then counterstained with hematoxylin.
Detection of cytokines from BAL
Both mice that had been transferred with Th1 and/or Th2 cells
and control mice that did not receive any cells were sacrificed and
perfused at 2 days after SFE challenge. The BAL was subsequently
collected by washing the lung through the trachea with 1 ml of RPMI
1640 plus 2% horse serum. BAL was kept at 37°C for 45 min, and the
media were collected by spinning down the cells. Levels of IL-4, IL-5,
and IFN- levels in the BAL media were detected by ELISA
(PharMingen).
RNase protection assay
Total RNA was isolated using Trizol reagent. The probes for a
panel of chemokines have been described previously (22) or were
purchased from PharMingen. The assay was performed as described
previously (23). Briefly, RNA was dissolved in 80% formamide, 0.4 M
NaCl, 1 mM EDTA, and 40 mM PIPES; heated to 85°C for 5 min; and
hybridized for 10 h with corresponding
[-32P]uridine triphosphate-labeled antisense
probes at 55°C. The unhybridized RNA was digested with 50 U/ml of
RNase T1 (Life Technologies) and 24 µg/ml of RNase A (Sigma) for
1 h at 30°C. After phenol-chloroform extraction and sodium
acetate-ethanol precipitation, the protected, hybridized RNA was
denatured and electrophoresed on 10% polyacrylamide gel. The gel was
dried and exposed to film.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To characterize the lung inflammatory responses induced by Th1 or
Th2 cells, bulk Th1 and Th2 cells were generated from naive CD4 T cells
of influenza hemagglutinin-specific TCR-SFExBALB/c transgenic mice
under Th1- and Th2-favoring conditions. In vitro, the established Th1
and Th2 cell lines produced their corresponding cytokines when
stimulated with either SFE peptide (data not shown) or Con A (Fig. 1
A). Both Th1 and Th2 cells
were CD4+ and expressed the Vß8.2 chain of the TCR
transgene (Fig. 1B). Furthermore, Th1 and Th2 cells showed
similar Ag-specific proliferative responses after stimulation with
syngeneic APCs plus SFE peptides (Fig. 1C). These Th1 or Th2
cells were adoptively transferred into unmanipulated naive BALB/c mice,
and the mice were given three daily i.n. challenges with SFE peptide.
Similar numbers of CD4+Vß8.1/8.2+ T cells
were detected in the BAL of Th1- and Th2-injected mice after the last
challenge (12.4 ± 2.4 x 104 in Th1 mice vs
14.8 ± 7.2 x 104 in Th2 mice; n
= 8), which suggests a similar recruitment of these lymphocytes to the
lung. In both cases, a high proportion of these cells appeared to be
activated, based on the expression of the T cell activation marker
CD25: 20 to 60% (average 43%) of total
CD4+Vß8.1/8.2+ cells were CD25+
in Ag-stimulated Th1- or Th2-injected mice compared with only 4 to 12%
(average 8%) in control mice.
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). On average, 
1.2 x
106 and 1.4 x 106 mononuclear cells
(mainly alveolar macrophages) vs 4.4 x 105 and
3.1 x 105 neutrophils were harvested from the BAL of
Th1- and Th2-injected mice, respectively, compared with only 0.5
x 106 mononuclear cells and 0.3 x 105
neutrophils in the control mice. Interestingly, significant numbers of
eosinophils were detected in the BAL of Th2-injected mice but not in
the BAL of Th1-transferred mice (Fig. 2). An average of 8.7 x
105 eosinophils were isolated from the BAL of
Th2-transferred mice compared with only 5 x 104
eosinophils in Th1-transferred mice or 7 x 103 in
control mice. Furthermore, despite active inflammation, total serum IgE
levels were not induced above background (data not shown). The failure
to induce IgE production under these conditions is presumably due to
the fact that Ag stimulation only used a short peptide that was
administered over a 3-day course. Histologically, perivascular
and peribronchial infiltration by mononuclear and polymorphonuclear
cells was detected, including CD4+ T cells, neutrophils,
and eosinophils (Fig. 3). Similar
patterns of CD4+ T cell infiltration were found in Th1- and
Th2-transferred mice. Eosinophils were absent or scattered in most of
the infiltrated areas in Th1 mice (Fig. 3 shows one of the most heavily
infiltrated areas), whereas massive eosinophil infiltration was present
in all of the infiltrated areas that were studied in Th2 mice (Fig. 3).
These results demonstrate that Th1 and Th2 cells cause different
patterns of Ag-dependent lung inflammation, and the activation of Th2
cells was sufficient to induce lung eosinophilia. Interestingly, we
were able to generate significant effects in these experiments by
transferring small numbers of T cells; it was not necessary to reduce
the pool of host T lymphocytes. This is in striking contrast to other
studies adoptively transferring inflammatory diseases such as diabetes
and graft-vs-host disease, in which it was required that recipient mice
be depleted by sublethal irradiation.
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Th1 and Th2 cells often show a reciprocal inhibition of functions
during immune responses; such inhibition has been observed in
Leishmania infection, experimental allergic
encephalomyelitis, and autoimmune diabetes (24). To study the effect of
Th1 cells on the lung eosinophilia induced by Th2 cells, Th1 and Th2
cells were cotransferred into naive BALB/c mice. After three daily SFE
challenges, mice that had received a mixture of Th1 and Th2 cells at a
1:1 ratio showed eosinophil infiltration in both the BAL and lung
tissue that was similar to that seen in mice that had received Th2
cells alone (Figs. 2
and Fig. 3). Approximately 6.5 ±
5.3 x 105 (n = 8) eosinophils were
collected from the BAL of Th1 plus Th2 cotransferred mice compared with
8.7 ± 6.2 x 105 (n = 11)
eosinophils in the mice that had been transferred with Th2 alone. The
difference is not significant when analyzed using ANOVA. In one
experiment, in which Th1 cells were cotransferred with Th2 cells at
both a 1:1 and 2:1 ratio, the total number of eosinophils collected
from the BAL were 3.7 x 105 and 6.8 x
105 per mouse, respectively, compared with an average of
4.9 x 105 eosinophils in the Th2-transferred mice.
These results suggested that at the effector stage, Th1 cells did not
significantly inhibit the lung eosinophilia induced by Th2 cells.
To confirm the absence of counterinhibition between Th1 and Th2 cell
activation in the lung, representative Th1 (IFN-) and Th2 (IL-4 and
IL-5) cytokines were assayed from the BAL of mice that had been
transferred with Th1 or Th2 cells alone or Th1 plus Th2 cells. IFN-
was detected from the BAL of Th1-transferred mice but not from the BAL
of Th2-transferred mice, while IL-4 and IL-5 were only found from Th2
cell transfer BAL (Fig. 4). This result
further confirmed that the transferred Th1 and Th2 cells were active in
vivo, and they retained their in vitro cytokine phenotypes in the
inflamed lung. Interestingly, a mixture of Th1 and Th2 cytokines were
detected from the BAL in the mice that had been cotransferred with both
Th1 and Th2 cells. Th2 cytokine levels were not inhibited compared with
the results obtained for single-cell-type-injected mice (Fig. 4).
Although the IFN- levels in mice that were given both Th1 and Th2
cells appeared to be slightly reduced in comparison with the levels
seen for mice given Th1 only, these effects were not statistically
significant. This finding suggested that Th1 and Th2 cells did not
efficiently counterinhibit each other’s cytokine production at the
effector phase of lung inflammation, which may provide an explanation
for the lack of cross-inhibition between Th1- and Th2-induced lung
inflammatory responses.
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Chemokines are directly responsible for cellular recruitment in
inflammatory responses. Using RNase protection assays, we tested a
panel of chemokines that were potentially involved in Th1 and Th2
cell-mediated lung inflammations. Two specific patterns of chemokines
were found in Th1- vs Th2-transferred lungs (Fig. 5). Eotaxin, which is an
eosinophil-specific chemokine, was mainly expressed in Th2-transferred
lungs; only low levels were seen in Th1-transferred lungs (Fig. 5A). This pattern correlated well with the eosinophilia that
was induced by Th2 but not Th1 cells. By contrast, lymphotactin (Ltn)
was mainly expressed in Th1-injected lungs, and higher levels of
IFN--inducible protein (IP-10), RANTES, MIP-1ß, and
MCP-1 and variably low levels of MIP-1 were found in Th1- compared
with Th2-transferred lungs (Fig. 5B). The major source of
eotaxin does not appear to be the injected Th cells, because equivalent
numbers of T cells produced almost undetectable amounts of chemokines
when activated in vitro by Con A. When using higher numbers of cells,
similar levels of Ltn, MIP-1, MIP-1ß, and T cell activation gene 3
were produced by Th1 and Th2 cells, but neither Th1 nor Th2 cells
expressed detectable eotaxin (Fig. 5C); this finding is in
contrast to a recent report (17). These results indicated that the
activation of Th1 and Th2 cells in the lung induced different patterns
of chemokine production, most likely by parenchymal cells in the lung.
Finally, the chemokines found in Th1 plus Th2 cotransferred lungs were
a combination of those that were expressed in the lungs when Th1 or Th2
cells were transferred alone (Fig. 5, A and B),
which correlated well with the additive effects on granulocyte
recruitment.
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Respiratory virus infection is often a trigger of allergic asthma,
despite the fact that Th1 responses are usually induced by viral
infection (25). To study the potential role of virus infection in lung
inflammation in mice that were biased to Th1 or Th2 responses,
influenza virus was used to infect mice that had been transferred with
Th1, Th2, or Th1 plus Th2 cells. In control mice that were given no
effector T cells, influenza infection produced significant neutrophil
inflammation at 3 days after infection (Fig. 6A) and induced the expression
of chemokines such as RANTES, IP-10, and MCP-1 (Fig. 6B)
compared with uninfected mice (Fig. 2). This neutrophil recruitment was
similarly evident in mice that were given Th1 or Th2 cells alone and
Th1 plus Th2 cells. However, the most striking observation was that in
mice given Th2 cells, eosinophilia and eotaxin production were also
induced (Fig. 6C). This was true regardless of
whether Th2 cells were administered alone or in a mix with Th1 cells.
On average, 8.7 x 105 and 11.9 x
105 eosinophils were collected from the BAL of both Th2 and
Th1 plus Th2 cell-transferred mice, respectively. Thus, with both forms
of the stimulus (either free peptide or infectious virus), Th2
activation by Ag in the lung results in eotaxin production and
eosinophilia that cannot be inhibited by Th1 cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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were detected in the lungs of those
mice. Thus, IFN- may not inhibit eotaxin production; indeed, two
recent studies suggest that in the presence of IL-1 or TNF-,
IFN- may even serve as a stimulator of the eotaxin that is expressed
by human dermal fibroblasts (26) and lung epithelial cells (27). The
observed production of both Th1 and Th2 cytokines in asthma (12, 28)
might therefore suggest a contributory role for Th1 cells in disease
pathogenesis. Curiously, the patterns of granulocyte recruitment described here were quite distinct from the lymphoid infiltration that was observed in a closely related model in which autoimmune diabetes was induced using the same Ag (expressed in islet ß cells) and TCR-transgenic T cells (19). This contrast illustrates the important principle that while Ag-mediated inflammation may be driven by a local activation of circulating T cells, tissue-specific responses by parenchymal cells (e.g., chemokine expression) can have a major influence on the character of the local inflammatory response. Further studies are in progress to identify these tissue-specific factors.
IgE induction and eosinophil rich inflammation are often associated with allergic asthma. The in vivo IgE depletion (29) and passive transfer of IgE (30) studies in mouse models suggest an important role for IgE in inducing lung eosinophilia and airway hypersensitivity. But despite the eosinophilia, IgE was not induced above background in Th2 mice or Th1 plus Th2 transferred mice (data not shown), presumably due to the brief duration of Ag challenge (3 days), and the fact that the Ag was only a very short (10 aa) synthetic peptide. This result suggested that IgE and IgE-mediated mast cell activation was not required for the induction of lung pathology in our model. Other recent studies have also shown that airway eosinophilic inflammation can occur in IgE- or B cell-deficient mice (31, 32, 33). It is important to note that our results may have no bearing on the issue of airway hypersensitivity in allergic responses; since airway hypersensitivity and eosinophilia can be considered two separate aspects of asthma (5, 34), our results only suggest that IgE may not be required in eosinophilia and late-phase airway injury in asthma.
In our model, the cotransfer of Th1 cells did not produce a significant
inhibition of Th2 cell activation and eotaxin expression in response to
Ag. This finding appears to contradict studies showing that the
administration of IL-12 (35, 36) or IFN- (37) can inhibit Ag-induced
Th2 responses, airway hypersensitivity, and lung inflammation. In those
studies, the most effective inhibition occurred when IL-12 was
administered at the immunization stage of the response or given at
least a few days before the challenge, at a point before the activation
of the Th2 cells (35, 36, 37). This timepoint presumably provided enough
time for the major effector of the suppression, IFN-, to effectively
inhibit the proliferation and activation of Th2 cells. In contrast,
when Th1 and Th2 cells are activated simultaneously, IFN- may have
little effect on the activated Th2 cells; thus Th1 cells would not
inhibit Th2 responses. Curiously, in mice that were treated with IL-12
during initial Ag challenge, both Th1 and Th2 cytokines were detected
from the BAL (36), suggesting that Ag-specific Th1 and Th2 cells may
already coexist in those animals. It is tempting to speculate that if
those mice were further challenged with Ag in the absence of any
cytokine treatments, Th1 and Th2 responses might both expand, leading
to the situation presented in our model.
It should be noted that, although the present paper provides some interesting correlations between Th1/Th2 cell activation in vivo and various patterns of chemokines, the correlations do not conclusively establish causative links between specific cytokines/chemokines and granulocyte recruitment. Thus, while eotaxin is consistently associated with eosinophilia, it is probably not exclusively required for the recruitment of eosinophils. For example, in recent studies, both an Ab blockade of eotaxin in vivo (13) and the targeted disruption of the eotaxin gene (38) caused only a 50% reduction in eosinophil recruitment in models of tissue eosinophilia. Moreover, in our preliminary studies, the neutralization of some Th2 cytokines was able to inhibit eosinophilia without blocking the induction of eotaxin, which suggests that several factors contribute to eosinophil recruitment (our unpublished observations).
Our study, when taken together with two recent reports (10, 11), shows the critical role of allergen-specific Th2 cells in late-phase asthma responses. The effect of the injected Th2 cells is even more impressive when the dilution of these cells by a large excess of recipient T cells that were not specific for the Ag is considered. Our results suggest that, while concomitant Th1 responses may be present in most situations, preexisting Th2 responses are most relevant to the generation of eosinophilia and associated pathology. Infection with influenza virus did not affect the activation of Th2 cells and eosinophilia despite its previously described preferential induction of Th1 cells and its regular induction of neutrophil infiltration. Given these observations, it is possible that although not all atopic individuals are asthmatic, they may all still be susceptible to some degree of Ag-induced lung eosinophilia; asthmatic patients might be distinguished only by unusual airway sensitivity to the eosinophilia. In sum, these results suggest that the treatment of allergic lung inflammation may depend upon the direct depletion of Th2 effector cells, since it may not be possible to establish regulatory interactions to suppress such cells.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. David Lo, Department of Immunology IMM-25, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037. E-mail address:
3 Abbreviations used in this paper: BAL, bronchoalveolar lavage; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; Ltn, lymphotacin; IP-10, IFN--inducible protein-10; i.n., intranasal(ly).
Received for publication March 16, 1998. Accepted for publication May 19, 1998.
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K. Raman, M. H. Kaplan, C. M. Hogaboam, A. Berlin, and N. W. Lukacs STAT4 Signal Pathways Regulate Inflammation and Airway Physiology Changes in Allergic Airway Inflammation Locally Via Alteration of Chemokines J. Immunol., April 1, 2003; 170(7): 3859 - 3865. [Abstract] [Full Text] [PDF]
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K. Irifune, A. Yokoyama, N. Kohno, K. Sakai, and K. Hiwada T-helper 1 cells induce alveolitis but do not lead to pulmonary fibrosis in mice Eur. Respir. J., January 1, 2003; 21(1): 11 - 18. [Abstract] [Full Text] [PDF]
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N. Mojtabavi, G. Dekan, G. Stingl, and M. M. Epstein Long-Lived Th2 Memory in Experimental Allergic Asthma J. Immunol., November 1, 2002; 169(9): 4788 - 4796. [Abstract] [Full Text] [PDF]
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 A M Butt, S H Murch, C-L Ng, P Kitching, S M Montgomery, A D Phillips, J A Walker-Smith, and M A Thomson Upregulated eotaxin expression and T cell infiltration in the basal and papillary epithelium in cows' milk associated reflux oesophagitis Arch. Dis. Child., August 1, 2002; 87(2): 124 - 130. [Abstract] [Full Text] [PDF]
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M. Surquin, A. Le Moine, V. Flamand, N. Nagy, K. Rombaut, F.-X. Demoor, P. Stordeur, I. Salmon, J.-C. Guery, M. Goldman, et al. Skin Graft Rejection Elicited by {beta}2-Microglobulin as a Minor Transplantation Antigen Involves Multiple Effector Pathways: Role of Fas-Fas Ligand Interactions and Th2-Dependent Graft Eosinophil Infiltrates J. Immunol., July 1, 2002; 169(1): 500 - 506. [Abstract] [Full Text] [PDF]
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