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,
Departments of
*
Urology and
Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195;
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(KC) was
observed first and reached peak levels by 6 h after transplant and
was followed by the monocyte/macrophage chemoattractant protein-1 (JE)
and then macrophage inflammatory proteins 1
and 1. Administration
of rabbit KC antiserum to allograft recipients within 30 min of cardiac
transplantation attenuated downstream events including intra-allograft
expression of the T cell chemoattractants IFN-
-inducible protein-10
and monokine induced by IFN-, cellular infiltration into the
allograft, and graft rejection. Similarly, depletion of recipient
neutrophils at the time of transplantation significantly extended
allograft survival from day 8 to 10 in control-treated recipients up to
day 21 after transplant. These results indicate the induction of highly
organized cascades of neutrophil and macrophage chemoattractants in
cardiac grafts and support the proposal that early inflammatory events
are required for optimal recruitment of T cells into allografts during
the progression of acute rejection of cardiac
allografts. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Another important component of inflammation is the production of
cytokines with chemoattractant properties for leukocyte populations,
chemokines (11, 12). Chemokines are grouped into families
(CXC, CC, C, and CX3C) based on cysteine motifs.
The CXC family includes the neutrophil chemoattractants IL-8 and
growth-related oncogene , of which KC is the murine homologue, and
two potent chemoattractants for Ag-activated T cells, IFN--inducible
protein-10 (IP-10)3
and monokine induced by IFN- (Mig). The CC family includes the
monocyte/macrophage chemoattractant protein-1 (MCP-1), of which JE is
the murine homologue, as well as macrophage inflammatory proteins
(MIP)-1 and 1. Studies from this and several other laboratories
have indicated the presence of chemokine mRNA and/or protein during
acute rejection of allografts in experimental and clinical
transplantation (13, 14, 15, 16, 17). IP-10 and Mig expression was
observed in heterotopically transplanted cardiac allografts but not
isografts at day 3 after transplant, whereas expression of MIP-1,
MIP-1, and KC was absent in iso- and allografts (14, 18). The production of IP-10 and Mig may be an important step in
the acute rejection process due to their strong chemoattractive
properties for Ag-primed T cells (19).
The induction and role of specific chemokines in the rejection of solid
organ allografts remains unclear. In the current study, we have tested
the expression of four chemokines 1.5–48 h after transplant in murine
cardiac iso- and allografts. The results indicate the induction of
organized cascades of chemokine RNA expression initiated by KC and
followed by JE, MIP-1, and MIP-1 at early times after transplant
in both iso- and allografts. Administration of a single dose of rabbit
antiserum to KC results in a substantial increase in allogeneic heart
graft survival. The prolonged survival is associated with the decreased
expression of Mig and IP-10, as well as decreased T cell infiltration
into the allograft. These results indicate the importance of early
inflammatory events on the subsequent production of T cell
chemoattractants and T cell recruitment into the allograft during the
acute rejection process.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A/J (H-2a) and C57BL/6 (H-2b) mice were obtained through Dr. C. Reeder at the National Cancer Institute (Frederick, MD). Adult males of 8–12 wk of age were used throughout this study.
Abs and antiserum
Rabbit immune serum to a KC-specific peptide (sequence QTMAGIHLKNIQS) was made at BioSynthesis (Louisville, TX). This antiserum reacts with KC and not with other CXC chemokines including IP-10 and Mig in Western blot analyses and inhibits recombinant KC-mediated chemotaxis of thioglycolate-induced peritoneal neutrophils in in vitro chemotaxis assays (Ref. 20 and data not shown). Normal rabbit serum (NRS) was used as control Ig for in vivo Ab treatment experiments. Mice were depleted of neutrophils by giving 100-µg aliquots of the rat anti-Ly6G mAb, RB6.8C5 (21), on two consecutive days. This treatment resulted in <5% neutrophils in the peritoneal wash of mice 4 h after thioglycolate injection as assessed by staining the peritoneal cells with Wright’s stain. Previous studies have shown that treatment with either the KC antiserum or RB6.8C5 does not affect the viability of circulating or lymphoid T cell populations (20). For use in immunocytochemistry, GK1.5, rat anti-mouse CD4 mAb, was obtained from BD PharMingen (San Diego, CA); 53-6.7, rat anti-mouse CD8 mAb, and biotinylated goat anti-rat polyclonal Ab were purchased from DAKO (Carpinteria, CA); and control rat IgG was purchased from R&D Systems (Minneapolis, MN).
Heterotopic cardiac transplant
Cardiac transplants were performed according to the method of Corry and coworkers (22). Briefly, donor and recipient mice were anesthetized with phenobarbital. Donor hearts were harvested and placed in chilled lactated Ringer’s solution while the recipient mice were prepared. The donor heart was anastomosed to the recipient abdominal aorta and vena cava using microsurgical techniques. Upon completion of the anastomosis and organ perfusion, the transplanted hearts resumed spontaneous contraction. The strength and quality of cardiac impulses were graded each day, as described previously (14, 18). Rejection of cardiac grafts was considered complete by the cessation of impulse and was confirmed visually for each graft by laparotomy. In C57BL/6 recipients, complete rejection of A/J cardiac grafts occurs between 8 and 10 days after transplantation. Cardiac isografts in the C57BL/6 recipients functioned for >300 days. Significance in allograft survival between recipient treatment groups was analyzed by log rank test, and p < 0.01 was considered a significant difference between groups.
Northern blot analysis
Whole-cell RNA was isolated from transplanted and native heart
tissue using TRIzol (Life Technologies, Grand Island, NY). Briefly,
transplanted and naive hearts were excised from recipients, snap
frozen, and homogenized in TRIzol. After extraction, precipitation, and
resuspension in diethylpyrocarbonate-treated
dH2O, 10-µg aliquots of RNA were
electrophoresed in 1% agarose formaldehyde-denaturing gels and
analyzed by Northern blot analysis, as described previously
(14). Blots were hybridized with
32P-labeled oligonucleotide probes specific for
KC, MIP-1, MIP-1, JE, IP-10, and Mig. After hybridization and
exposure with one cytokine oligonucleotide probe, the filter was
stripped of the probe by washing the blot three times in 0.4% SDS at
90°C and then hybridized with the next test cytokine probe. After
hybridization with the test cytokine probes was completed, the blot was
stripped and probed with a rat GAPDH cDNA (23).
Densitometry using Storage Phosphor Screen analyzer (Molecular
Dynamics, Sunnyvale, CA) was used to comparatively measure the cytokine
signal and the GAPDH signal for each sample of the blot. The cytokine
signals for each sample of the blot were then normalized by expressing
the density of the cytokine signal as a ratio to the signal of the
GAPDH signal for each RNA sample. The mean ratio for each group (i.e.,
time point or treatment) was determined, and differences between means
were tested using Welch’s t test. A p <
0.05 was considered a significant difference.
Immunohistology
Heart grafts were retrieved at day 7 after transplant, embedded in OCT compound (Sakura Finetek, Torrence, CA), and frozen at -80°C. Sections were cut at 8 µm and mounted onto slides. For immunohistochemistry, sections were fixed in acetone for 10 min and air dried. Slides were immersed in PBS for 10 min and then in 0.03% H2O2 for 10 min to eliminate endogenous peroxidase activity. The slides were then stained for 1 h with 5 µg/ml anti-CD4 mAb (GK1.5) or anti-CD8 mAb (53-6.7) in 0.05 Tris-HCl with 1% BSA. Control slides were incubated with rat IgG as the primary Ab. After three washes in PBS for 5 min each, slides were incubated for 20 min with biotinylated goat anti-rat IgG diluted 1/300 in PBS. After three washes in PBS, slides were incubated with streptavidin-HRP (DAKO) for 20 min and washed another three times. To prepare the substrate-chromagen solution, a 10-mg tablet of 3,3'-diaminobenzidine (Sigma, St. Louis, MO) was dissolved in 15 ml of PBS plus 12 µl of 30% H2O2. The solution was applied to the slides, which were incubated for 3–7 min and then rinsed in dH2O to stop the reaction. The slides were counterstained with hematoxylin for 3 min, rinsed with tap water, and immersed in 37 nM NH4OH for 10 s. Finally, the slides were dehydrated, viewed under light microscopy, and the images were captured using ImagePro Plus (Media Cybernetics, Silver Spring, MD). Numbers of cells staining positive were counted in eight random fields from three different tissue sections from three different grafts, and significance between mean numbers of positive cells per field in different treatment groups was tested using Mann-Whitney U test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and MIP-1. KC and
JE expression was first apparent at 3 h after transplant and
peaked at 6 h after transplant in both iso- and allografts (Fig. 1
). These levels dropped quickly by
9 h after ransplant, and by 48 h after transplant, levels of
KC and JE expression in iso- and allografts had receded to background
levels.
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in both syngeneic and allogeneic heart grafts
also began to appear at low levels at 3 h after transplant. In
contrast to KC and JE, expression levels of MIP-1 dipped slightly
after 6 h after transplant and rose to a second peak at 24 h
after transplant before beginning to fall to background levels 48
h after transplant. Expression of MIP-1 did not begin to become
apparent until 12–18 h after transplant, reached peak levels at 24-
48 h after transplant, and then decreased.
Because KC was the first chemokine we observed expressed in the cardiac
grafts, we tested the effect of KC antagonism on the survival of the
A/J cardiac allografts in C57BL/6 recipients. Groups of allograft
recipients were given 200 µl NRS or rabbit KC antiserum i.v. within
30 min after graft reperfusion. Heart graft beating in recipients was
monitored daily by palpation and cessation of beating was confirmed by
laparotomy. With one exception, heart allografts in recipients treated
with NRS ceased beating between days 7 and 10 after transplant (Fig. 2). In contrast, significant prolongation
of allograft survival up to day 23 after transplant was observed in
recipients treated with the KC antiserum. This enhanced survival was
accompanied by a visible decrease in cellular infiltration of the heart
allografts from the KC antiserum-treated recipients when compared with
allografts from NRS-treated recipients at day 7 after transplant (Fig. 3, A vs B). The
decrease in cellular infiltration was particularly evident around
vessels and within the graft interstitium (Fig. 3, C vs
D). Furthermore, vessels in allografts from NRS-treated
recipients had signs of endothelial degeneration at day 7 after
transplant that were absent in allografts from the KC antiserum-treated
recipients. To compare T cell infiltration into allografts from control
and KC antiserum-treated recipients, graft tissue sections were also
prepared and stained with anti-CD8 or anti-CD4 mAb. KC
antiserum treatment resulted in a clear decrease in
CD8+ and CD4+ T cell
infiltration into the allograft interstitium (Figs. 4, A vs B, and
5). There was little to no T cell
infiltration evident in sections prepared from isografts at day 7 after
transplant (data not shown).
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).
However, depletion of recipient neutrophils at the time of
transplantation extended the survival of the allografts up to day 21
after transplantation. In conjunction with the extended survival in
recipients treated with the KC antiserum, these results indicate the
importance of neutrophils in acute rejection of vascularized heart
allografts.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-1, and chemokines and the up-regulation of adhesion
molecules (4, 5, 6, 7, 24, 25). Although chemokines play a
critical role in leukocyte recruitment to peripheral tissues, few
studies have tested the induction and role of chemokines during acute
rejection of solid organ allografts. The results of the current report
indicate coordinated cascades of chemokine gene expression in
transplanted cardiac grafts within hours after graft revascularization.
Northern blot analysis of RNA isolated from cardiac grafts 1.5–48 h
after revascularization indicated no difference between isografts and
allografts with respect to patterns and levels of chemokine expression.
The equivalent expression in allografts and isografts suggests that the
early cascades occur without the influence of adaptive immune
mechanisms.
The chemokines expressed in cardiac grafts during the early time
periods following transplant are those directing the recruitment of
neutrophils and macrophages during wound healing. Whether the
expression of these early chemokines is induced directly by the
ischemia and trauma of the transplant surgery or induced indirectly by
other cytokines produced during the initial inflammation is unclear at
this time. Several investigators have reported the rapid after
transplant induction of TNF- in allo- and isografts (26, 27). Because TNF- also induces expression and production of
IL-8 and MIP-1 (28, 29), this cytokine may initiate the
early chemokine cascades observed in the current studies.
The results of the current report clearly indicate that induction of
early inflammatory events in the cardiac grafts influences the
progression of downstream events involving adaptive immune responses to
the allograft. Recent results from this laboratory have demonstrated
that Mig and IP-10 expression is observed as early as day 2 after
transplant in cardiac allografts but not in isografts
(18), 
1 day after intragraft expression of KC has
subsided. Treatment of recipients with KC antiserum at the time of
transplantation decreased intraallograft expression of the T cell
chemoattractants IP-10 and Mig. Ab depletion studies and the use of
recipients deficient in CD4+ vs
CD8+ T cells have indicated that day 2 expression
of IP-10 and Mig is mediated by IFN--producing
CD8+ T cells (18). On the basis of
these results, we have proposed that circulating
CD8+ T cells interact with inflammatory sites in
the vascular endothelium and those T cells with allogeneic class I MHC
specificity are stimulated to produce IFN- that in turn stimulates
endothelial cell production of Mig and IP-10. The importance of Mig
production in the rejection of the heart allografts has been shown in
our laboratory by the ability of Mig-specific Abs to inhibit T cell
infiltration into the cardiac allograft and prolong survival from day
8–9 to day 18–20 after
transplant.4 In light
of these results, the effects of KC antagonism on T cell graft
infiltration and survival observed in the current report may be
indirectly mediated through decreases in Mig. The early chemokine
cascades in cardiac grafts may be coordinated so that optimal induction
of each cascade is dependent on induction of the preceding chemokine
cascade.
The mechanism by which treatment with the KC antiserum attenuates the
expression of IP-10 and Mig and T cell infiltration into the graft
remains unclear at this time. The chemoattractive properties of KC for
neutrophils is suggestive of a potential role of these cells in
initiating downstream events in the graft rejection process.
Alternatively, recipient treatment with KC antiserum may inhibit a
critical neutrophil-mediated activity without affecting neutrophil
infiltration into the allograft. Further evidence for a neutrophil role
in acute rejection of the heart allografts is indicated by the ability
of recipient neutrophil depletion to extend heart allograft survival.
Although Ab-mediated neutrophil depletion results in 50% mortality
of the heart allograft recipients from decreased resistance to
infections, rejection of allografts in the surviving recipients is
delayed until 18–21 days after transplant, which is similar to that
observed in the KC antiserum-treated recipients. Such observations
support a role for neutrophils in the establishment of inflammatory
foci in the allograft that facilitate T cell recruitment and graft
infiltration. Several laboratories have documented the critical role of
neutrophils in ischemia/reperufsion injury (30, 31, 32).
Antagonism of neutrophil adhesion to the endothelium effectively
attenuates this injury in many models. Recent results from this
laboratory have indicated marked inhibition of neutrophil infiltration
into renal tissue and decreased tissue pathology by treating mice with
KC-specific antiserum following reperfusion of kidneys subjected to
1 h of warm ischemia (M. Miura, manuscript in preparation). In
addition to their role in ischemia/reperfusion injury, activation of
neutrophils with solid-phase IL-8 stimulates neutrophils to produce or
release many different chemoattractants for T cells (33, 34). Such events could certainly play a role in recruiting
and/or focusing T cells to the sites of inflammation in the vascular
endothelium of cardiac allografts during progression of acute allograft
rejection.
In summary, the results in the current report have indicated the induction of a programmed cascade of chemokines in both isografts and allografts at early times following the transplantation surgery. Treatment of recipients with Abs to one of the first components in these cascades attenuates downstream events including the expression of chemokines with chemoattractive properties for Ag-primed T cells and cellular infiltration into the graft. These data are the first to expose the induction of such cascades in transplanted organ allografts. Furthermore, these data indicate the profound effects of innate immune components on alloantigen-specific rejection responses and suggest that strategies aimed at antagonizing early inflammatory events in heart allografts will have substantial benefit in attenuating acute rejection of cardiac allografts.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Robert L. Fairchild, NB3-79, Department of Immunology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195-0001. E-mail address: fairchr{at}ccf.org
3 Abbreviations used in this paper: IP-10, IFN--inducible protein-10; MCP-1, monocyte chemotactic protein-1; Mig, monokine induced by IFN-; MIP, macrophage inflammatory protein; NRS, normal rabbit serum.
4 M. Miura. Monokine induced by IFN- is a dominant factor directing T cells into murine cardiac allografts during acute rejection. Submitted for publication.
Received for publication August 16, 2000. Accepted for publication June 20, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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or IL-4 and is not required for allograft rejection. Am. J. Pathol. 147:166.[Abstract]
induced chemokines in allogeneic heart grafts is mediated by CD8+ T cells. Transplantation 69:1147.[Medline]
mediated recruitment of neutrophils is required for elicitation of contact hypersensitivity. Eur. J. Immunol. 29:3485.[Medline]
, MCP-1, IP-10, and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing. Am. J. Pathol. 153:1849. genes in rejecting skin allografts. Transplantation 67:672.[Medline]
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