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í Lácha*
ibylová||
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* Department of Nephrology, Transplant Unit, Institute for Clinical and Experimental Medicine, Prague 4, Czech Republic;
Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headington, United Kingdom;
Institute of Anatomy, 1st Faculty of Medicine, Charles University, Prague 2, Czech Republic; and Departments of
Immunology and Gnotobiology, Institute of Microbiology, and
|| Mammalian Development, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague 4, Czech Republic
Correspondence: Petr Mal, Ph.D., Department of Mammalian Development, Institute of Molecular Genetics ASCR, Víde
ská 1083, 142 20 Prague 4, Czech Republic. E-mail: pemal{at}biomed.cas.cz
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(1,3)fucosyltransferase Fuc-TVII, representing a
model for general absence of selectin-ligand expression, and a newly
developed strain with a double mutation in Fuc-TVII and ICAM-1 alleles.
Transplantation of a heart from ICAM-1 -/- or Fuc-TVII/ICAM-1
double-mutated mice into allogeneic recipients resulted in limited
(2–2.5 days) but nevertheless significant prolongation of the graft
survival (P<0.01 and P<0.01 in log-rank test)
compared with the survival of unmodified hearts. When ICAM-1 -/-
hearts were transplanted into Fuc-TVII -/- recipients, the median
survival time was prolonged by 8 days (P<0.01). These data
indicate that endothelial ICAM-1 is involved in adhesion events during
acute cardiac allograft rejection but reveal that the loss of one
type, selectin/leucocyte ligand or selectin/endothelial ligand
interaction, does not markedly affect graft survival, thereby
suggesting a role for other compensatory adhesion molecule/ligand
interactions.
Key Words: selectin ligand • fucosyltransferase • LFA-1 • ICAM-1 • transplantation • Fuc-TVII
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although selectins [6
, 7
],
calcium-dependent adhesion molecules, serve as initiators of leucocyte
rolling along the vessel wall, ß2 and 4 integrins with their
endothelial cell-adhesion counter-receptor molecules, intercellular
cell adhesion molecule-1 (ICAM-1) and vascular cell-adhesion molecule-1
(VCAM-1), mediate high-affinity interactions and cause firm attachment
of rolling cells to the activated endothelium and penetration to the
surrounding tissue. Based on the multiple-steps model of
leucocyte-endothelial migration [1
], selectin-dependent
rolling, mediated by low-affinity/high-velocity interactions of P-, E-,
and L-selectins with their cognate counter-receptors, P-selectin
glycoprotein ligand-1 (PSGL-1), E-selectin ligand-1 (ESL-1), and
vascular endothelial ligands of L-selectin [8
], is a
prerequisite for the function of the ß2 integrins CD11a/CD18
lymphocyte function-associated antigen-1 (LFA-1), CD11b/CD18 (Mac-1),
and CD11c/CD18.
Selectins recognize sialylated, fucosylated carbohydrate determinants
related to tetrasaccharide sialyl Lewis X (sLeX) or its isomer sialyl
Lewis A [9
]. The pivotal role of (1,3)fucosylation
for selectin-ligand function, mediated by mammalian fucosyltransferases
Fuc-TIV [10
11
12
13
] and Fuc-TVII [14
15
16
]
has been well-documented [17
18
19
20
21
22
23
]. Mice defective in the
Fuc-TVII gene lack sLeX expression and exhibit P-, E-, and
L-selectin-ligand deficiency, which is manifested by blood
leucocytosis, defective leucocyte rolling, compromised leucocyte
infiltration to sites of inflammation, and faulty lymphocyte homing to
the lymph nodes [24
].
The significance of ICAM-1 adhesion function for the induction of allograft rejection was studied by Isobe and coworkers [4 ] who showed that monoclonal antibodies (mAb) against ICAM-1 and LFA-1 administered for 6 days after transplantation induced indefinite survival of cardiac allografts. Anti-ICAM-1 therapy has been shown to prolong allograft survival in other models [25 26 27 ], and more recently, ICAM-1 antisense oligodeoxynucleotides have been shown to inhibit renal allograft rejection [5 ].
In contrast, the role of selectins and their ligands during organ rejection has not been studied intensively. Recently, it has been shown that lymphocytes adhere to the endothelium of rejecting rat cardiac transplants but not to the endothelium of syngeneic grafts or normal hearts [28 ]. Lymphocyte adhesion to the endothelium in rejecting cardiac allograft can be decreased significantly by treating lymphocytes with anti-L-selectin antibody or tissue samples with L-selectin immunoglobulin G (IgG) fusion protein, sialidase, anti-sLeX antibodies, or multivalent sLeX synthetic constructs [28 , 29 ]. Therefore, it seems probable that inducible sLeX-carrying endothelial L-selectin ligands participate in acute allograft rejection. This is also supported by data showing that synthetic analogues of sLeX reduce allograft rejection and reperfusion injury in rat lung transplantation [30 ].
We designed this study to explore the role of selectin ligands and ICAM-1 in the onset of organ rejection using models of mice deficient in genes coding for Fuc-TVII (general selectin-ligand deficiency) and/or ICAM-1 molecules.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Male mice, 10–16 weeks old with a weight range of 25–35 g, were used for the experiments and housed under conventional conditions. All animal procedures, including organ procurement, preservation, and transplantation, were performed under aseptic conditions.
Detection of normal and disrupted Fuc-TVII and ICAM-1 alleles
Routine testing of Fuc-TVII -/-, ICAM-1 -/-, and
double-deficient Fuc-TVII/ICAM-1 mice as well as wild-type (WT) control
mice was performed by PCR using tail genomic DNA. Primer pairs for
detection of Fuc-TVII WT locus were the forward TTC TTA TCT GGC ACT GGC
CTT TCA CC or TGA TCA GCA ATT TCC AGG AGC primer and the reverse primer
CAA AGA AGC CAC GAT AAC GAC (amplicon 756 bp and 372 bp, respectively).
For detection of Fuc-TVII -/- locus, we used the forward GGC GGA CCG
CTA TCA GGA CAT AGC GTT or GGA CTG GCT GCT ATT GGG CGA AGT G primer
combined with the reverse TCA AGC CTG GAA CCA GCT TTC AAG GTC TTC
primer (amplicon 315 bp and 690 bp, respectively). PCR was optimized
for amplification using a Stratagene Gradient 96 Robocycler: 94°C, 1
min; 94°C, 20 s; 56°C, 20 s; 72°C, 40 s, 33x;
94°C, 20 s; 56°C, 20 s; 72°C, 2 min, 1x.
Testing of ICAM-1 WT locus was performed as described [31 ] using a forward primer GTT CTT CTG AGC GGC GT and reverse primer AGA ACC ACT GCT AGT CC, identifying a PCR fragment of 1.3 kb. Mutated ICAM-1 allele was detected by 5'-primer CCA AGA TCT TCC AGC TAC CAT CCC and 3'-primer CCG GAC AGG TCG GTC TTG ACA AA, generating a fragment of 1.4 kb. The cycle was the same as amplification of the Fuc-TVII allele with an annealing temperature of 53°C.
Experimental animals and their genetic background
FucT-VII -/-: 100% 129/Sv, H-2b; FucT-VII +/+:
100% 129/Sv, H-2b; ICAM-1 -/-: 98% C57BL/6J and 2%
129/Sv, H-2b; FucT-VII/ICAM-1 -/-: 52% 129/Sv and 48%
C57BL/6J, H-2b; FucT-VII/ICAM-1 +/+: 52% 129/Sv and 48%
C57BL/6J, H-2b; CBA/J: CBA/J, H-2k; C57/BL6:
C57/BL6, H-2b.
Study group
Hearts from 129/Sv Fuc-TVII -/--deficient mice or WT controls
(H-2b) were transplanted to CBA/J (H-2k)
recipients or vice versa.
Hearts of hybrid 129/Sv x C57BL/6J mice, deficient in the genes for ICAM-1 or Fuc-TVII and ICAM-1, and their corresponding WT controls were transplanted to CBA/J recipients. Transplantation of CBA/J hearts to CBA/J recipients (129/Sv hearts into 129/Sv recipients) served as a syngeneic control.
Hearts of hybrid animals with ICAM-1 gene defect and WT controls (C57/BL6) were transplanted into 129/SV Fuc-TVII -/--deficient mice. Transplantation of C57/BL6 hearts into 129/Sv recipients served as controls.
Transplantation
Heterotopic cardiac transplantation was performed essentially as
described by Corry et al. [32
] with minor modifications.
Donor and recipients were anaesthetized by the administration of
phentanyl, midazolam, and droperidol. Donor hearts were perfused with
chilled heparinized saline via the inferior vena cava and were
harvested after the ligation of the vena cava and pulmonary veins.
Harvested hearts were preserved in chilled saline (-4°C), and the
recipient mice were prepared. The aorta and pulmonary artery of each
donor heart were anastomosed to the abdominal aorta and inferior vena
cava of the recipient animal by microsurgical technique: aorta
"end-to-side" to abdominal aorta, a pulmonalis "end-to-side" to
vena cava inferior, continuous suture 10/0. Total duration of heart
operation was up to 55 min; handling time of heart transplantation was
less than 35 min (median, 27 min). Technical failures observed within
the first 60 h were excluded from evaluation. The recipients did
not receive any immunosuppressive agents before or after
transplantation.
Cardiac allograft survival was assessed by daily transabdominal palpation of the allograft pulse that was rated on a scale of 0–3. The hearts were harvested on the day the grafts stopped beating.
Histological examination
Donor hearts were cut into quarters along the crosslines. One
part was fixed with 10%-buffered formalin and embedded in paraffin
according to standard procedures. These specimens were cut serially
into 5 µm-thick sections, stained with hematoxylin and eosin, and
examined by light microscopy. The other parts of the organ were frozen
quickly and used for immunohistochemistry.
Immunohistochemistry
Specimens were embedded with O.C.T. compound (Miles
Laboratories, Elkhart, IN), frozen in liquid nitrogen, and sectioned
into 10 µm slices with use of a cryostat (Reichert-Jung, Wien,
Austria). Sections were washed with ice-cold phosphate-buffered saline
(PBS) followed by a fixation with 2% paraformaldehyde in PBS (pH 7.2).
After washing, sections were treated with cold methanol and incubated
with 0.1% albumin (fraction V, Sigma-Aldrich, Prague, Czech Republic)
for 30 min. Then mouse anti-CD54 (ICAM-1)-biotinylated mAb (PharMingen,
Becton Dickinson Corp., Prague, Czech Republic), diluted as recommended
by the supplier, was used as a first-step antibody for 60 min. After
3x washing with PBS, nonlabeled swine anti-mouse serum was applied.
[It was used as a blocker of the binding of fluorescein isothiocyanate
(FITC)-labeled swine anti-mouse conjugate to anti-CD54 antibody in the
second step.] Subsequently, extensively washed specimens were
incubated with mouse anticollagen type IV mAb (Sigma-Aldrich) and
diluted as recommended by the supplier, also for 60 min.
TRITC-labeled extravidine (Sigma-Aldrich) and FITC-labeled
swine antimouse antibody (SwAM-FITC; TEMDA, Prague, Czech Republic)
were used as a second-step reagent simultaneously for 45 min. The
signal was evaluated using specific filterblocks for FITC and TRITC
using an Optiphot-2 fluorescence microscope (Nikon). Negative controls
were carried out with replacement of first-step antibody with nonimmune
mouse serum or by omitting primary antibody and only incubating with
TRITC-extravidine conjugate.
The ICAM-1 (CD54) was visualized immunohistochemically. The presence of vessels in the graft section was verified using visualization of collagen type IV in basal lamina of capillaries and larger vessels. Expression of L-selectin ligands was detected immunocytochemically using chimaeric antibody L-selectin/human IgM (plasmid was kindly donated by Dr. J. B. Lowe) by a standard immunoperoxidase procedure.
Statistical analysis
The results are expressed as median (min., max.). Statistical
comparison among groups was performed by log-rank test. The
significance levels were adjusted by Holm’s procedure. The difference
was considered to be significant at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(1,3)fucosyltransferase
VII and ICAM-1 molecules {F0 founders, strains of formerly described
(1,3)fusosyltransferase Fuc-TVII -/- [24
], and
ICAM-1 -/- mouse [31
]} led to a generation of
double-heterozygous mice in F1 generation. After crossing F1
littermates, PCR screening of F2 progeny identified several animals
homozygous for null alleles of one gene locus but heterozygous in the
second one. Crossing F2 littermates resulted in double-deficient mice
F3 progeny (Fig. 1
) with expected Mendelian frequency close to 25%. The
corresponding WT control mice were also detected in these crosses (Fig. 1)
. Gene defects in the mice were confirmed by an additional primer
pair specific for a neomycin-resistant cassette (not shown). ICAM-1
deficiency was confirmed by immunohistochemical staining of cardiac
allograft sections with anti-ICAM-1 antibody (Fig. 2
). We found that endothelial cells in two-thirds of vessels located
in the heart allograft of the WT donor express ICAM-1. The capillaries
with ICAM-1-negative endothelial cells and collagen type IV expressed
in basal lamina were located in areas of necrotic cardiomyocytes,
extensively infiltrated with leucocytes. All vessels in the heart graft
of ICAM-1 -/- donor or Fuc-TVII/ICAM-1 double-null mouse were
ICAM-1-negative, although the vessels were present according to
location of collagen type IV in the basal lamina. The leucocytes
infiltrating the heart grafts were ICAM-1-positive in WT host animals,
which can be considered for positive control of the reaction
specificity.
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Double-deficient mice were viable and fertile with grossly normal development. The phenotype of these mutants corresponds to that in single Fuc-TVII -/- mutants with peripheral blood leucocytosis, granulocytosis, and an increased number of megakaryocytes in the spleen.
Graft survival experiments
Fuc-TVII-deficient mice
Our first experiment was designed to evaluate the possible role of
inducible vascular endothelial L-selectin
ligand(s) in allograft rejection. As shown in Table 1
and Figure 3
, cardiac allografts of Fuc-TVII +/+ 129/Sv mice were promptly
rejected in CBA/J recipients [median survival time (MST), 9 days].
The heart grafts of 129/Sv mice, deficient in the Fuc-TVII gene, were
also rejected (MST, 8 days). These data revealed no significant
difference in survival between Fuc-TVII-deficient or WT cardiac
allografts in fully major histocompatibility complex (MHC)-mismatched
recipients.
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ICAM-1 -/- and Fuc-TVII/ICAM-1 double-null mice
To ascertain the function of ICAM-1 and L-selectin-ligand
molecules expressed on activated vascular endothelium during acute
allograft rejection, we transplanted the hearts from the deficient
mouse strains into MHC-incompatible recipients. Cardiac allografts from
hybrid-control WT animals (Fuc-TVII/ICAM-1 +/+) survived in CBA/J
recipients for 8
days (Table 2
and Fig. 4
), whereas the rejection of hearts taken from ICAM-1-deficient mice
was delayed slightly (MST, 10.5 days; P<0.01) in
fully MHC-mismatched CBA/J recipients. Heart allografts from mice
deficient in ICAM-1 and Fuc-TVII genes were rejected in CBA/J
recipients with an MST of 10 days.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To study the precise role of endothelial ICAM-1 expression in the onset
of graft rejection in vivo, ICAM-1-deficient mice were used as organ
donors. ICAM-1 is strongly expressed by activated heart capillary
endothelium during acute rejection of cardiac allografts. Mice
genetically deficient in ICAM-1 do not express endothelial ICAM-1
during allograft rejection, as expected. Deficiency in ICAM-1
expression was sufficient to extend graft survival in CBA/J recipients
by 2.5 days, demonstrating that ICAM-1 is involved in
leucocyte/endothelial cell adhesion during acute allogeneic rejection.
When we transplanted hearts from ICAM-1 -/- donors into P- and
E-selectin-ligand-deficient recipients (Fuc-TVII -/- mice), the graft
survival was even more prolonged, from 8 to16 days. This finding
clearly documents a cumulative effect of mutations, suggesting a
cooperation of selectin ligands with ICAM-1 during rolling/adhesion
events. Contrary to our data, Schowengerdt at al. [34
]
have demonstrated recently that the graft survival of ICAM-1 -/-
hearts transplanted into CBA/J recipients does not differ from the
survival of the control +/+ animals. However, our graft survival data,
indicating a delay in ICAM-1 -/- heart rejection, were independently
supported by Fuc-TVII/ICAM-1 double-deficient donors where the same
delay in cardiac allograft rejection was found. In addition, our
findings correlate with the results of cardiac allograft survival in
fully incompatible mouse-strain transplantation using administration of
ICAM-1 antibody for 6 days after operation, published by Isobe and
coworkers [4
]. It should also be mentioned that blocking
LFA-1 function by anti-CD11a or anti-CD18 mAb had no effect on graft
survival, and the combinatory effect of both of them induced
donor-specific tolerance [4
]. In comparison with these
data, the difference in our graft-survival average value might be a
result of a cumulative effect of a functional blockade for endothelial
as well as ICAM-1-positive leucocyte populations rather than a result
of a difference in mouse strains used for the transplantation. In our
deficient mouse model, we separated an effect of endothelial from
leucocyte ICAM-1 expression found on some lymphocyte subpopulations and
other leucocytes. Another point is that mice deficient in ICAM-1 locus
could partially adapt for the defect during ontogenesis and up-regulate
other pairs of adhesion molecules to compensate for the missing ICAM-1
function. Those include endothelial VCAM-1, ICAM-2, and ICAM-3.
Recently, indeed, it has been demonstrated that lymphocytes can roll
under the shear stress in vitro and in vivo via very late antigen-4
(VLA-4)/VCAM-1 interactions in a selectin-independent manner
[35
]. In addition, the independent pathway of selectins
and 4-integrins for regulation of leucocyte infiltration in lung
inflammation has been documented recently [36
]. Thus,
other pairs of molecules involving selectins and 4-integrins may
substitute a defect of ICAM-1 function. An up-regulation of endothelial
VCAM-1 expression during acute allograft rejection was also found in
histological sections of transplanted organs [37
].
Recently, it has been documented that lymphocytes can roll through
selectin-independent mechanisms, via interactions of 4-integrins
with VCAM-1 [35
] and that selectins and 4-integrins
regulate independent pathways of T-lymphocyte recruitment during
inflammation [36
].
The second part of this study was designed to verify the possible role
of selectin/selectin-ligand interactions in allograft rejection. No
significant difference in graft survival between Fuc-TVII -/- or +/+
strains was observed (8.5 and 8.0 days, respectively). This is an
interesting finding, documenting that neither leucocytosis (threefold
increase) nor peripheral blood lymphocytosis (twofold increase) found
in Fuc-TVII -/- mice [24
] affects leucocyte
infiltration to such a degree as to prolong the allograft survival.
Because the average value for graft survival was not significantly
different in the opposite transplantation model with Fuc-TVII +/+ heart
donors introduced into CBA/J recipients (8.0 and 9.0d, respectively),
we conclude that a reciprocity in the combination of genetic
backgrounds of recipients and donor mice does not change the onset and
extent of allograft rejection. Moreover, this is supported by data for
Fuc-TVII -/- donors versus recipients (8.0 vs. 8.5, respectively).
Graft survival of Fuc-TVII -/- versus +/+ donors was very similar
(8.0 and 9.0, respectively), as well as survival of CBA/J hearts
transplanted into Fuc-TVII -/- or +/+ recipients (8.5 and 8.0 days,
respectively). These data indicate that suppression of selectin-ligand
function in leucocyte or endothelium has no effect on graft rejection,
as confirmed also by an immunohistological examination. In this regard,
we remark that a role for endothelial (1,3)fucosyltransferases in
vascular-inducible L-selectin-ligand expression during acute rejection
has been found (unpublished results).
Finally, we constructed a new strain of double-deficient mice with defects in Fuc-TVII and ICAM-1 genes. These mice, carrying H-2b MHC haplotype, exhibit defects normally found in single Fuc-TVII -/- mice, including granulocytosis and lymphocytosis in peripheral blood and bone marrow populations, indicating that ICAM-1 does not possess a significant additive effect to general selectin-ligand deficiency found in the Fuc-TVII -/- mice. However, transplantation of the donor heart of these double-null mice into fully incompatible recipients of H-2k MHC revealed that the average graft survival reflects a value of that found in ICAM-1 -/- mice (10.5 and 10.0, respectively), with a statistical significance of P < 0.01 compared with survival of control homozygous Fuc-TVII/ICAM-1 +/+ animals. Despite the marginal effect of ICAM-1 deficiency for prolonging graft survival (by 2 days), these data confirm further that ICAM-1 is involved in adhesion events that participate in acute allograft rejection.
The phenotype of Fuc-TVII/ICAM-1 double -/- mice resembles the
defects mediated by selectin-ligand deficiency. A possible
L-selectin-ligand function in the cardiac endothelium of these mice
does not contribute to a significant delay in organ rejection,
confirming the data on single Fuc-TVII -/-. Thus, Fuc-TVII-mediated
selectin-ligand deficiency does not play any functional role in
selectin/selectin-ligand interactions in our model of acute cardiac
allograft rejection. As we separated the effects of leucocyte
selectin-ligand deficiency (in PSGL-1 and ESL-1) in a recipient immune
system from endothelial L-selectin-ligand deficiency in donor cardiac
endothelium in our two different transplant model approaches, the full
effect of selectin/selectin-ligand interactions during organ rejection
needs to be investigated further. To this goal, the Fuc-TVII -/-
donor heart will be allotransplanted into a Fuc-TVII -/- recipient.
Development of the Fuc-TVII -/- mouse strain on a different H-2 MHC
background is in progress. A precise role for the particular
(1,3)fucosyltransferases in endothelial L-selectin-ligand expression
during acute allograft rejection is a major challenge for future
studies.
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ACKNOWLEDGEMENTS |
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ková for excellent technical assistance in
microsurgical operations, Eva Vancová for technical help in the
immunohistochemistry of cryosections, and Drs. V. Lánská
and J. Skibová for statistical analysis. Received May 15, 2000; revised September 10, 2001; accepted September 13, 2001.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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4 integrins regulate independent pathways of T lymphocyte recruitment in the pulmonary immune response J. Immunol. 161,4396-4403This article has been cited by other articles:
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 Y. H. Cai, A. Alvarez, P. Alcaide, P. Duramad, Y.-C. Lim, P. Jarolim, J. B. Lowe, F. W. Luscinskas, and A. H. Lichtman Abrogation of Functional Selectin-Ligand Expression Reduces Migration of Pathogenic CD8+ T Cells into Heart. J. Immunol., June 1, 2006; 176(11): 6568 - 6575. [Abstract] [Full Text] [PDF]
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