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From the Department of Bacteriology and Immunology,*
the
Department of Pathology,
and the
Transplantation Laboratory,§
Haartman
Institute; and the Department of Internal
Medicine,
University of Helsinki and The
Helsinki Universital Central Hospital, Helsinki, Finland
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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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2,3-sialylated, 1,3-fucosylated, and sulfated
lactosamines.6-8
We and others have shown that
high endothelial cells in lymph nodes express glycans fulfilling
all or most of the above-listed requirements, the prototype decoration
being sulfated sialyl Lewis x (sLex) for L-selectin.9-12
Importantly, endothelial cells under normal conditions in other
locations do not express proper glycoforms of L-selectin ligands.
However, proinflammatory stimuli in in vitro and animal
studies have shown that endothelium can be induced to express these
glycans de novo and to promote leukocyte
extravasation.2,13,14
Likewise, the endothelial E- and
P-selectins have been shown to be inflammation-inducible
molecules, both in animal models and in human
patients.15-19
A novel approach to increase
immunosuppressive efficacy, without targeting activation and
proliferation of T cells, would be to inhibit the
carbohydrate-dependent entry of lymphocytes into the graft. Experimental animal work has demonstrated that free sLex-containing glycans can prevent short-term selectin-dependent inflammation, for example, after reperfusion injury.20-23 These glycans target mainly the endothelial P-selectin-dependent extravasation of granulocytes.20 To investigate the relevance of inducible, properly decorated endothelial L-selectin ligands on lymphocyte extravasation to the sites of inflammation, we initiated experiments in allografts where the inflammatory event is composed of lymphocytes and monocytes but not of granulocytes. With rat heart and kidney allograft models, we have shown a strong induction of sLex-decorated L-selectin ligands on only microvascular endothelium occurring concomitantly with the accumulation of lymphocytes and mononuclear phagocytes into the grafts.2,24 Furthermore, the L-selectin-dependent leukocyte-endothelial recognition could be inhibited by enzymatically synthesized multivalent sLex glycans.2,25 We therefore wanted to investigate whether the expression of endothelial L-selectin ligands in human heart allograft rejection follows the same patterns as in the rat. In this study we used a large selection of endomyocardial biopsies (EMBs) from human heart transplants at different stages of rejection to demonstrate the point.
Our results show that although normal heart endothelium does not practically express sulfated sLex decorations, these epitopes are readily detectable on capillaries and venules during acute rejection. Furthermore, although the level of endothelial L-selectin ligand expression increased at the onset and during progression of the rejection, it decreased as the rejection episode resolved. There was a significant correlation between the intensity of expression of endothelial sulfated sLex-decorated L-selectin ligands and the histological severity of the rejection episodes. These data suggest that the strong up-regulation of the endothelial L-selectin ligands is a key factor in the initiation of lymphocyte extravasation to the heart allografts, and therefore also provide a putative target for new immunosuppressive and anti-inflammatory agents in organ transplantation.
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Materials and Methods |
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The study plan was approved by the Review Board of the Helsinki University Central Hospital (HUCH). Searching through over 600 EMBs from the archives of the Transplantation Laboratory of the University of Helsinki's Haartman Institute from 1992 to 1997, we identified 91 biopsies as having unequivocal histological signs of acute rejection of various degrees. These, together with the nonrejection control biopsies, were further analyzed with immunohistochemistry for the presence of endothelial L-selectin ligands (see below). The tissue specimens were formalin-fixed, paraffin-embedded, and processed for routine histological diagnosis.
Transplant recipients received triple drug immunosuppressive therapy consisting of cyclosporine, methylprednisolone, and azathioprine; acute episodes of rejections were treated with a high dose of methylprednisolone, either alone or, in the most severe cases, combined with antithymocyte globulin. All recipients also received acyclovir prophylaxis against herpesvirus infections for the first 3 months. The histological evidence of rejection was diagnosed by one pathologist and graded according to the Working Formulation of the International Society for Heart and Lung Transplantation.26 Normal histology did not present any signs of rejection. The diagnosis of an intermediate rejection (ie, a borderline or a resolving rejection) was referred to small perivascular lymphocytosis, lymphocyte activation, edema, and fibrosis, ie, signs of very mild acute rejection that did not fulfill the criteria of either grade 1A or normal histology. Grade 1A rejection represented a focal lymphocytic infiltrate; grade 1B was characterized by diffuse, but spare infiltrate; grade 2 consisted of myocyte necrosis in association with a focal infiltrate; grade 3A possessed multifocal infiltrates with myocyte necrosis; grade 3B had diffuse infiltrate with myocyte necrosis; and grade 4 represented diffuse infiltrate with vasculitis, hemorrhage, and edema. No EMBs with a grade 4 rejection were found in our material.
Fifty-four biopsies represented normal histology, 27 biopsies represented intermediate diagnoses, and 91 cases had various grades of rejection (grade 1A, n = 49; 1B, n = 26; 2, n = 3; 3A, n = 7; 3B, n = 6). For further analysis the most severe rejections with myocyte necrosis, ie, grades 2 through 3B, were grouped together due to the small number of specimens.
Antibodies
The glycan epitopes on L-selectin ligands identified by the
monoclonal antibodies (mAbs) used in the present study are described in
Table 1
.27
Both mAbs 2F3 (5
µg/ml,28
kindly provided by R. Kannagi, Aichi Cancer
Center, Nagoya, Japan) and HECA-452 (15 µg/ml,29
kindly
provided by S. Jalkanen, University of Turku, Turku, Finland) are
anti-sLex mAbs, requiring both the presence of 2,3 sialylation and
1,3 fucosylation of the lactosamine, whereas MECA-79 (1: 100 culture
supernatant,30,31
also from S. Jalkanen) recognized
6-sulfation of the GlcNAc-residue of N-acetyllactosamine on a family of
endothelial proteins for proper recognition. Polyclonal anti-murine
Fuc-TVII antibody shown to cross-react with the human 1,3
fucosyltransferase VII (Fuc-TVII) was a generous gift from J. B.
Lowe (1:10 dilution,32
Howard Hughes Medical Institute,
Ann Arbor, MI). Isotype-matched mouse and rat IgMs (15 µg/ml,
Pharmingen, San Diego, CA) as well as rabbit IgG (15 µg/ml) were used
as control reagents.
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EMB sections 5 µm thick were deparaffinized and rehydrated by rinsing with xylene (5 minutes x 5), 100% ethanol (5 minutes x 2), 96% and 70% ethanol (5 minutes each), and aqua (5 minutes x 2). The slides were then incubated for 60 minutes at 37°C with 0.5% trypsin in phosphate buffered saline (PBS), pH 7.5. The trypsin was rinsed quickly with PBS and then washed 3 times for 10 minutes each time. We used a Histostain-plus kit (Zymed Laboratories Inc, San Francisco, CA) for immunoperoxidase staining according to instructions.
The levels of reactivity of mAbs 2F3, HECA-452, MECA-79, and rabbit anti-mouse Fuc-TVII antibody were scored by two observers who had no knowledge of the previously given pathological diagnosis of the specimens. The analysis was done by scoring the staining intensity of arterioles, capillaries, and venules with a semiquantitative staining score: normal, 0; mild, 1; moderate, 2; and intense, 3. At the site of a given rejection the intensity of endothelial staining was homogeneous and all identified vessels (from 4 to >20) within the rejection focus were included in the analysis.
Statistical Analysis
We used the nonparametric Kruskal-Wallis test to determine the differences in staining intensities between groups of different histological diagnosis (normal, intermediate, 1A, 1B, and 2–3B). P values <0.05 were considered significant. This test is basically a comparison of the medians of several unpaired groups and the null hypothesis is that the medians are all equal. We used also the nonparametric Spearman rank correlation test to determine whether the rank of the staining intensity was correlated with the rank of the groups of histological diagnosis. P values <0.05 were considered significant. Unpaired Student's t-test was used to analyze the significance between the endothelial staining intensity and different time groups during the progression of rejection and P values <0.05 were considered significant.
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Results |
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, 2F3 and HECA-452
mAbs detect 2,3 sialylation and 1,3 fucosylation of lactosamine
and do not distinguish between sulfation and
nonsulfation.29,30
On the other hand, MECA-79 needs
sulfation of its epitope for proper recognition.31,32
The
best ligands, ie, ligands with highest relative binding affinity toward
L-selectin, would possess all these decorations, as shown in lymphatic
tissue.4 First we performed immunohistochemical analysis of the EMBs with the three mAbs detecting different decorations of L-selectin ligands and correlated the intensity of endothelial staining, given as a semiquantitative score of 0 to 3, with the histological severity of acute graft rejection, as judged by quantitative histology from normal to grade 2–3B. The analysis was performed separately from all vascular endothelia present in endomyocardial biopsies, ie, from arterioles, intramuscular capillaries, and venules. Arterioles never reacted with the tested antibodies. The expression of L-selectin ligands was observed in the intermuscular capillaries as well as venules during rejection episodes. As these compartments of the vasculature gave similar results, only the results of stainings in the capillaries are presented for clarity in this study.
The anti-sLex mAb 2F3 reacted with normal nonrejection biopsies;
approximately 60% of the biopsies were positive. However, the staining
intensity was weak (Figure 1)
. Along with
increasing histological severity of rejection, the percentage of
positively reactive specimens increased from 60% to >90%, and over
half of the specimens gave intermediate or strong staining reaction.
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. The proportion of
positively reactive specimens increased up to 30% in intermediate
grade rejections and to 60 to 75% in grade 1A, 1B, and 2–3B rejection
biopsies. Concomitantly, an increased intensity of staining was
observed, and in grades 2–3B rejections up to 60% of the samples
demonstrated intermediate or strong staining intensity.
The background staining of mAb MECA-79 in normal biopsies was
negligible, ie, below 5%. The proportion of positive specimens
increased to 15% in intermediate grade biopsies and to 50% in grade
1A, 1B, and 2–3B rejection biopsies. Virtually all specimens reacting
with MECA-79 displayed a strong staining intensity (Figure 1)
.
The statistical correlation between the intensity of endothelial
L-selectin ligand expression and the severity of graft rejection was
shown using two separate and independent tests. The Kruskal-Wallis test
was used to analyze the distribution of the mAb staining intensity in
different histological groups, ie, normal, intermediate and grades 1A,
1B, and 2–3B, representing different histological severities of
rejections. P values for all tested antibodies were <0.001,
indicating that the observed distribution of intensity of staining was
significantly different between specimens of different histological
severities (Figure 1)
.
To test whether the intensity of endothelial L-selectin ligand
expression correlated with the severity of the histological grade of
the rejection, we also performed the Spearman rank correlation test.
The correlation curves obtained indicated a strong and significant
positive correlation between the staining intensity with antibodies
reacting with various glycodecorations of L-selectin ligands on one
hand and the histological severity of rejection on the other hand
(P < 0.0001, Figure 2
). These observations demonstrate at the
population-based level that, when more functionally decorated
L-selectin ligands are expressed on the graft endothelium during
rejection, the more severe is the histological severity of rejection
episodes.
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,
the endothelial staining intensity with 2F3, HECA-452, and MECA-79 was
significantly increased when the rejection specimens were compared to
prerejection specimens. The staining remained elevated throughout the
rejection episode. As the rejection episode resolved, concomitantly
with the intensified immunosuppressive therapy, the endothelial
expression of L-selectin ligands decreased until it was close to or at
background levels.
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1,3
fucosyltransferase. Previous data have indicated that of the five
different human 1,3 fucosyltransfereases, Fuc-TVII, might be the
most important in the synthesis of sLex in endothelial
cells.34
Therefore, we also analyzed the expression
pattern of Fuc-TVII with a specific polyclonal rabbit antibody during
the progression of acute rejection and correlated this to the
expression pattern of L-selectin ligands. The prerejection samples did
not show any reactivity with Fuc-TVII, whereas the level of expression
was significantly elevated in samples representing rejection. As the
rejection episode resolved, the expression of endothelial Fuc-TVII also
decreased to background levels (Figure 3)
. In Figure 4
representative
microphotographs are shown from various immunohistochemical stainings.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The high correlation between the intensity of endothelial cell expression of sulfated and/or sLex decorated ligands and presence of acute rejection, suggest that endothelial cells up-regulate the expression of these inflammation-promoting glycoforms of L-selectin ligands at the onset of rejection thus leading to increased lymphocytic traffic into the human heart allografts. This is in accordance with our previously published results in rodent models of heart and kidney allograft rejection.2,13 The de novo induction/up-regulation of endothelial sLex glycans at the onset of both animal and human rejection, suggest that this pattern of regulation is crucial in the initiation of site-directed lymphocyte extravasation into the allograft and, therefore, in the generation of local inflammation. Furthermore, the down-regulation of the expression of the same glycoforms at the time the rejection resolves is linked with the decrease of lymphocytic infiltrate in the allograft, suggesting that the graft endothelium has the machinery to induce the synthesis of these glycans as well as the capacity to decrease the expression by enzymatic degradation or other mechanisms.
Tethering of lymphocytes to and rolling of lymphocytes on endothelium is dependent on interactions between selectins and their glycosylated ligands and is in most cases imperative to the generation of inflammatory reactions. Thus, our data presented here suggest that the strong up-regulation of the endothelial L-selectin ligands is a key factor in the initiation of lymphocyte extravasation to heart allografts and thus provides a putative target for new immunosuppressive/anti-inflammatory drug therapy. Experimental animal work has already shown the effect of sLex glycans on rejection and reperfusion injury after lung transplantation.19
The reason for using a panel of antibodies detecting various parts of posttransplantation decoration of L-selectin ligands was that no single antibody has been shown to detect solely all these glycoforms. We selected our anti-sLex antibody panel according to the following evaluations. We first used a larger panel of mAbs including clones 2H5, CSLEX-1, 2F3, and HECA-45212 on representative histological specimens. Although all these mAbs stained high endothelial venules (HEV) in frozen sections prepared from lymph nodes, only 2F3 and HECA-452 were able to do so in formalin-fixed and paraffin-embedded tissues, normally obtained from EMBs, and therefore we selected these antibodies for this study.
The original antigens in 2F3 and HECA-452 preparation were a sLex containing glycolipid and stromal components of human lymph nodes, respectively. The mAb 2F3 is able to inhibit in vitro the L-selectin-dependent adhesion of lymphocytes to human lymph node HEV, whereas HECA-452 did not block this.29 The HECA-452 epitope has also been termed a cutaneous lymphocyte antigen (CLA).35,36 This CLA is a sLex-decorated variant of a P-selectin ligand glycoprotein, present on the skin-homing lymphocytes.37 The glycans of P-selectin ligand glycoprotein-1 on a poorly differentiated myeloid leukemia cell (HL-60) have been identified, and the most attractive candidate for selectin recognition is a sialylalted triLex polylactosamine.38,39 Whether HECA-452 detects the same or a similar glycan on the CLA-antigen on skin-directed lymphocytes is still unknown.
MECA-79 was originally defined to recognize an antigen called
peripheral lymph node adressin (PNAd).30,31
This is
actually a family of glycoproteins, most of which are able to bind
L-selectin. In humans only CD34 and podocalyxin have been identified at
molecular level among the glycoprotein species reacting with
MECA-79.40
Later the recognizing epitope of MECA-79 was
shown to be a sulfate group, most probably on the 6-position of GlcNAc
of a lactosamine backbone.41,42
This antibody does not
recognize 2,3 sialylation or 1,3 fucosylation; however, it is
able to block in vitro and in vivo lymphocyte
homing to murine lymph nodes.30,31
As to the putative pathways on which the glycoforms detected by 2F3 and
HECA-452 would be synthesized by endothelial cells in an
inflammation-dependent manner, we analyzed the expression of 1,3
fucosyltransferase Fuc-TVII enzyme in these
specimens.43,44
The addition of fucose with an 1,3
linkage to the sialylated lactosamine is the last reaction generating
sLex glycans. Previous work has shown that this enzyme is present in
lymph node high endothelium, which is the site of lymphocyte
extravasation into the lymphatic tissue.32
Work carried
out in Fuc-TVII-null mice showed that the absence of endothelial 1,3
fucosylated glycans leads to a marked lymphocytosis in blood and
impaired leukocyte rolling and to decreased extravasation to sites of
inflammation.42
Taken together, these results suggest a
role for Fuc-TVII enzyme in the synthesis of functionally glycosylated
endothelial ligands for L-selectin in mice. To investigate whether the
same enzyme is involved in the synthesis of sLex in human endothelium
at sites of inflammation, we used a rabbit polyclonal anti-murine
Fuc-TVII antibody32
that had been shown to cross-react
with human Fuc-TVII. Using this antibody on consecutive EMBs ranging
from prerejection biopsies and extending to biopsies after rejection
was resolved, we could show that also the expression of Fuc-TVII enzyme
increased at the onset of rejection and decreased as the rejection
episode resolved. Our data support, indirectly, the suggestion that
endothelial Fuc-TVII participates in the synthesis of functional
fucosylated L-selectin ligands. The endothelial specific
6-sulfotransferase(s) involved in the induction of the MECA-79 reacting
epitopes have not yet been identified.
These observations broaden the previous experimental analysis from our laboratory2,13 and others,14 and demonstrate that a similar strong induction of properly decorated endothelial ligands for L-selectin, as previously found in rodent models of inflammation, can be found in man, particularly in acute rejection of human heart allografts. Our findings are in complete agreement with previous work with L-selectin-deficient mice, which demonstrated the importance of L-selectin in targeting the lymphocyte traffic to sites of inflammation.45
Selectin-dependent leukocyte extravasation seems to be a crucial step in the initiation of lymphocytic inflammatory reactions such as acute allograft rejection. The data presented here suggest that not only the inducible expression of endothelial E- and P-selectin, but also the inducible endothelial glycoforms of L-selectin ligands, guide lymphocyte traffic to the sites of inflammation, thus providing a new target for glycan-based immunomodulatory interventions.
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Acknowledgements |
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Footnotes |
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Supported by grants from the Academy of Finland, the Technology Development Center of Finland, the Emil Aaltonen Foundation, the Helsinki University Central Hospital Research Fund, the Duodecim, and the Orion-Farmos Foundations of Helsinki.
Accepted for publication May 11, 1999.
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References |
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(1,3)fucosyltransferase Fuc-TVII in lymphoid aggregate high endothelial venules correlates with expression of L-selectin ligands. J Biol Chem 1996, 271:8250-8259 1,3-fucosyltransferase that is involved in biosynthesis of the sialyl Lewis X carbohydrate determinants in leukocytes. J Biol Chem 1994, 269:14730-14737-1,3-fucosyltransferase capable of synthesizing the sialyl Lewis X determinant. J Biol Chem 1994, 269:16789-16794This article has been cited by other articles:
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