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Departments of
*
Urology and
Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195;
Department of Urology, Hokkaido University School of Medicine, Sapporo, Japan;
§
Department of Urology, Tokyo Women’s Medical College, Tokyo, Japan; and
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Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44195
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, macrophage-inflammatory
protein-1ß, GRO- (KC), JE, and IFN-
-inducible protein (IP-10)
were expressed at equivalent levels in allo- and isografts for 2–4
days posttransplant and then returned to low or undetectable levels;
and 2) IP-10 and monokine induced by IFN- (Mig) were expressed in
the allografts 3 days before rejection was completed, suggesting a
possible role in recruiting primed T cells into the allograft. Three
days before completion of rejection, intraallograft IP-10 protein was
restricted to the epidermis, whereas Mig was located in the lower
dermis and associated with the intense infiltration of mononuclear
cells. Treatment of B10.D2 recipients with rabbit antiserum to Mig, but
not to IP-10, delayed rejection of the allografts 3–4 days. The
results suggest that Mig mediates optimal recruitment of T cells into
MHC-matched/multiple minor histocompatibility Ag-disparate allografts
during rejection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, of which KC is the murine homologue, and two chemokines that
are potent chemoattractants for activated T cells, IFN--inducible
protein (IP-10)3 and
monokine induced by IFN- (Mig) (7, 8, 9, 10). The C-C
chemokines have chemoattractant properties for lymphocytes,
monocytes/macrophages, eosinophils, and NK cells. Representative ß
chemokines include RANTES, macrophage-inflammatory protein (MIP)-1,
MIP-1ß, and monocyte chemoattractant protein-1, the murine homologue
of which is JE (11, 12, 13, 14). In addition to mediating
chemotaxis of target leukocytes, specific chemokines may amplify tissue
inflammation by stimulating increased integrin expression and cell
adhesion, neutrophil degranulation, and monocyte superoxide production
(15, 16, 17, 18, 19).
The presence of chemokine transcripts and/or protein in allografts
during rejection has been reported by several laboratories
(20, 21, 22, 23, 24, 25). Previous results from this laboratory indicated
two general patterns of intraallograft chemokine gene expression during
acute rejection of murine allogeneic skin grafts with single or
multiple disparities at MHC loci (26). Expression of JE,
KC, MIP-1, and MIP-1ß was induced early (e.g., day 3–4
posttransplant) and at levels 2–5-fold higher than those observed in
isografts. Expression of two other chemokine genes, IP-10 and RANTES,
was observed only in allografts and not until 3–4 days before
rejection of the grafts. One of the objectives of the current study was
to test the temporal expression of these chemokines during rejection of
skin allografts matched at the MHC, but disparate at multiple minor
histocompatibility Ag (mHAg) loci. The influence of alloantigen-primed
CD4+ vs CD8+ T cell
activity on the intraallograft expression of chemokines has not yet
been tested. Rejection of MHC-matched/multiple mHAg-disparate skin
grafts is mediated by CD4+ T cells, although
CD8+ T cells mediate rejection of the grafts in
recipients depleted of CD4+ T cells (27, 28). This allowed us to test the intraallograft expression of
these chemokines when acute rejection was mediated by either
CD4+ or CD8+ T cells. The
third objective of this study was to examine the role of chemokines
expressed late in the graft rejection process in the recruitment of T
cells to the graft. We have tested the ability of rabbit antisera
generated to IP-10 and to Mig to inhibit leukocyte infiltration and
rejection of the mHAg-mismatched skin grafts.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c (H-2d) mice were obtained through Dr. Clarence Reeder (National Cancer Institute, Frederick, MD). B10.D2 (H-2d) mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Adult females of 6–8 wk of age were used throughout this study.
Antibodies
mAb from the culture supernatant of the IgG-producing hybridomas GK1.5 (anti-mouse CD4) and YTS 169.4.2.1 (anti-mouse CD8) (29) were purified from culture supernatants by protein G chromatography. FITC-conjugated Abs specific for mouse CD11a and CD44 and PE-conjugated Abs specific for mouse CD4 and CD8 were purchased from PharMingen (San Diego, CA). Rabbit antisera to an IP-10-specific peptide (sequence: CIHIDDGPVRMRAIGK) and to a Mig-specific peptide (sequence: CISTSRGTIHYKSLKDLKQFAPS) were generated by Biosynthesis (Lewisville, TX). Previous studies have shown that each antiserum reacts with the specific recombinant chemokine in Western blot analyses (30).
Skin grafting
Skin grafting was performed using a modification of the protocol
of Billingham and Medawar (31). Briefly, trunk skin was
prepared from donor ventral skin, and 12-mm-diameter circular full
thickness grafts were punched from the skin. Graft beds were prepared
by excising 14-mm-diameter circles of skin from the lateral dorsal
thoracic wall of recipients. BALB/c recipient mice were grafted with
the B10.D2 allograft on one side of the lateral thoracic wall and, as a
control, a syngeneic isograft on the other side, separated by a 10-mm
skin bridge. The grafts were covered with Vaseline gauze and an
adhesive bandage for 7 days. On various days after transplantation, the
graft tissue was harvested to isolate RNA for Northern blot or
histological analyses. To compare the time of rejection between groups,
the graft was left on five to eight recipients in each group until
rejection was complete. Each graft was examined daily beginning at day
7 posttransplant and was considered rejected when 
80% or more of
the graft tissue was destroyed and transformed to scab as assessed by
visual examination.
Ab treatment of graft recipients
Recipient CD4+ and/or CD8+ T cells were depleted by i.p. injection of 100 µg of rat IgG (control), YTS 169.4.2.1 (anti-mouse CD8), or GK1.5 (anti-mouse CD4 mAb) before skin grafting (days -3, -2, and 0) and weekly after transplantation (days 7, 14, and 21). Ab staining and flow cytometry analysis of lymph node and spleen cells from control and mAb-treated mice indicated depletion of 94–96% of the target T cell population (data not shown). To test the role of Mig vs IP-10 in the rejection of B10.D2 allogeneic skin grafts, BALB/c recipients received 0.5-ml aliquots of NRS, Mig antiserum, or IP-10 antiserum i.p. beginning at day 7 posttransplant every other day until rejection of the allograft was completed.
Northern blot analysis
Whole cell RNA was isolated from transplanted skin tissue using
the protocol of Chirgwin and coworkers (32). Briefly,
allogeneic and syngeneic skin graft tissue was excised from the graft
bed, avoiding the surrounding recipient tissue, and homogenized in 4 M
guanidine isothiocyanate using a Polytron homogenizer (Brickmann
Instruments, Westbury, NY). The RNA was pelleted by overnight
centrifugation of the tissue homogenate through a 5.7 M
CsCl2 gradient. After resuspension in
diethylpyrocarbonate-treated dH2O, 10-µg
aliquots of RNA were electrophoresed in 1% agarose/2.2 M
formaldehyde-denaturing gels and analyzed by Northern blot analysis, as
described previously (26). Northern blots were probed by
hybridization with 32P-labeled oligonucleotide
probes specific for murine IP-10, JE, KC, Mig, MIP-1, MIP-1ß, and
RANTES. The quantity of RNA in each lane was standardized by washing
the blot three times in Tris-EDTA at 90°C to strip off the probe and
reprobing the blot with an oligonucleotide probe specific for rat GAPDH
(33). As described previously (26),
densitometry was used to measure the cytokine signal and the GAPDH
signal for each sample of the blot. The chemokine signals for each
sample are expressed in the figures as the density of cytokine signal
to that of the GAPDH signal. All experiments were repeated at least
three times, with similar results observed each time. The results from
a single representative experiment are shown.
Histological analyses
For histological analyses, the grafts with a small cuff of adjacent host skin and underlying host fascia and panniculus carnosus muscle were removed and kept into 4% paraformaldehyde for 30 min. The specimens were imbedded in OCT compound (Sakura Finetek U.S.A., Torrance, CA) and frozen at -80°C. Full-length cross sections of the frozen tissue blocks were cut at 8 µm, mounted onto slides, and stained with rabbit antisera to IP-10 or to Mig by a procedure involving the following sequential steps: 1) for blocking nonspecific binding of the first Ab, sections were incubated with 0.3% Triton X-100 and 3% goat serum in PBS (blocking buffer) for 1 h at room temperature; 2) incubation with NRS or rabbit anti-chemokine immune serum diluted 1/20 with blocking buffer overnight at 4°C; 3) after four washes in PBS, sections were incubated with FITC or Texas Red-conjugated AffiniPure goat anti-rabbit IgG (Jackson ImmunoResearch, West Grove, PA) diluted 1/100 in blocking buffer for 1 h at room temperature; and 4) mounted in Vectashield mounting media (Vector Laboratories, Burlingame, CA). The slides were viewed under a fluorescent microscope, and the images were captured using Adobe Photoshop 4.0 (Mountain View, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous studies have indicated that CD4+ T
cells are the primary effector cells rejecting MHC-matched/multiple
mHAg-disparate skin grafts, and that rejection mediated by
CD8+ T cells in CD4-depleted recipients is
delayed 7–10 days (27, 28). To evaluate the ability of
our anti-CD4 and anti-CD8 mAb to reproduce these results, we
first compared the time of B10.D2 (H-2d)
allograft rejection mediated by CD4+ vs
CD8+ T cells from BALB/c
(H-2d) recipients. Groups of BALB/c mice were
treated with control IgG, anti-CD4, and/or anti-CD8 mAb before
receiving the B10.D2 allogeneic and an isogeneic skin graft and at days
7, 14, and 21 posttransplant. Ab staining and flow cytometry analyses
of lymph node cells from Ab-treated recipients at the time of graft
rejection indicated >94% depletion of the target T cell population.
The isografts were maintained indefinitely on recipients in all
treatment groups. Control rat IgG-treated BALB/c mice mounted a rapid
and consistent rejection response to the B10.D2 allografts with a mean
graft survival of 11.8 days (Table I
).
Grafts from anti-CD8 mAb-treated recipients were rejected at the
same time as the control Ab-treated recipients, suggesting that
CD8+ T cells were not critical to the rejection
of the grafts. In contrast, survival of the B10.D2 allografts on
recipients treated with anti-CD4 mAb (GK1.5) at days -3, -2, 0,
+7, and +14 was extended to day 21 posttransplant. As further
indication of the efficacy of mAb treat-ment on allograft recipients,
graft survival on recipients treated with both anti-CD4 and
anti-CD8 mAb at days -3, -2, 0, +7, +14, and +21 was extended to
49 days posttransplant.
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The intraallograft expression of chemokines during rejection of
MHC-matched allogeneic skin grafts has been tested (26).
To test this expression during rejection of MHC-matched/multiple
mHAg-disparate grafts, the intraallograft induction of chemokine mRNA
expression during rejection of B10.D2 skin allografts by BALB/c
recipients was examined by Northern blot analysis of RNA isolated from
grafts retrieved from control IgG-treated recipients at various times
posttransplant. Several patterns of intragraft chemokine mRNA
expression were observed during the rejection of the B10.D2 allografts
(Fig. 1). First, the expression of
MIP-1, MIP-1ß, KC, and JE appeared early in both allo- and
isografts, attaining peak levels at day 2–4 posttransplant. Although
the levels of mRNA were observed slightly earlier in the isografts than
in the allografts (e.g., day 2 vs 4 posttransplant), the peak levels
were equivalent in the iso- and allografts. The levels in the iso- and
allografts quickly declined to low or undetectable levels by day 7
posttransplant. These low or undetectable levels were maintained until
rejection of the allograft was completed. Second, expression of IP-10
mRNA also appeared early in both iso- and allografts, attaining peak
levels by day 2–4 posttransplant and declining to undetectable levels
by day 7 posttransplant. At day 9 posttransplant, however, IP-10 mRNA
appeared at very high levels in the allografts. Expression of Mig mRNA
was undetectable at the early times posttransplant, but was expressed
at high levels in the allograft beginning at day 9 posttransplant
(e.g., 2 or 3 days before completion of rejection). Intragraft
expression of RANTES mRNA was also undetectable until day 9
posttransplant, when low levels were detected in the allograft. The
temporal intragraft expression patterns of these chemokines during
rejection of the B10.D2 allografts by BALB/c recipients were more
apparent when the signal intensity for each chemokine was plotted as a
ratio of the signal intensity for GAPDH (Fig. 2).
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To test the intraallograft expression of chemokine mRNA when
rejection of B10.D2 grafts was mediated by BALB/c
CD4+ T cells, allografts were retrieved from
recipient mice treated with anti-CD8 mAb and RNA was prepared and
analyzed by Northern blot. With the exception of a decrease in MIP-1ß
mRNA levels, the levels of chemokine mRNA expression were identical to
those observed in allografts on control, rat Ig-treated recipients
(Fig. 2
).
The intraallograft expression of chemokine mRNA during
CD8+ T cell-mediated rejection of B10.D2
allografts was also tested. BALB/c recipients of syngeneic B10.D2
allogeneic skin grafts were treated with anti-CD4 mAb, as detailed
in Table I. The grafts were retrieved on various days posttransplant,
and RNA was prepared and tested for chemokine RNA levels. Again, the
early chemokine pattern was observed at equivalent levels in iso- and
allografts and was similar to the results observed in grafts on control
Ig- and anti-CD8 mAb-treated recipients (Fig. 2). As shown in Fig. 3, intraallograft expression of Mig and
IP-10 mRNA was undetectable at day 9 in anti-CD4 mAb-treated
recipients, but was expressed at high levels at day 18 posttransplant
(e.g., 3 days before the completion of rejection). In contrast to
B10.D2 allografts on control Ig- or anti-CD4 mAb-treated BALB/c
recipients, intraallograft expression of RANTES mRNA was detectable at
high levels during rejection of allografts on anti-CD4 mAb-treated
recipients. This expression was first observed at day 18
posttransplant, similar to the time when IP-10 and Mig mRNA were
detectable in the grafts.
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The late intraallograft expression of Mig and IP-10 mRNA was
further examined by testing the presence and location of the chemokine
proteins in B10.D2 allografts during rejection by BALB/c recipients.
Rabbit antisera generated to a Mig peptide or to a IP-10 peptide were
used in immunohistology studies to identify the tissue location of
these chemokines at day 10 posttransplant. Staining of allograft tissue
sections with hematoxylin and eosin revealed an intense mononuclear
cell infiltration in the lower dermis (Fig. 4a). In sections stained with
the rabbit antiserum to Mig, reactive protein was clearly present in
the allograft in the lower dermis and was associated with the
mononuclear cell infiltration (Fig. 4b). In sections stained
with the rabbit antiserum to IP-10, reactive protein was also present
in the allograft. In contrast to Mig, however, IP-10 protein was
restricted to the epidermis of the graft (Fig. 4c).
Consistent with the absence of Mig and IP-10 mRNA expression in
isografts, both proteins were undetectable in tissue sections prepared
from isografts at day 10 posttransplant (data not shown).
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The late expression of IP-10 and/or Mig may be indicative that
these chemokines play a role in the recruitment of T cells to the
B10.D2 allograft site during acute allograft rejection. To begin to
test this, BALB/c mice were engrafted with B10.D2 allografts and
isografts, and beginning at day 7 posttransplantation, the recipients
were injected every other day with 0.5 ml of NRS, Mig antiserum, or
IP-10 antiserum. Similar to the rejection of B10.D1 skin allografts by
nontreated BALB/c recipients, recipients treated with NRS rejected the
allografts at day 12 (Table II).
Recipient treatment with the rabbit antiserum to IP-10 did not prolong
the survival of the allografts. Injection of the Mig antiserum,
however, resulted in a significant prolongation
(p < 0.05) of allograft survival from day 12
to day 15 posttransplant.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and MIP-1ß were induced as early
as day 2–3 posttransplant in both iso- and allografts. As observed in
the current report, these genes were also induced at early times
posttransplant in MHC-matched/multiple mHAg-disparate skin allografts.
These early chemokines are primarily chemoattractant for innate immune
components, including neutrophils, macrophages, and NK cells (5, 6). It is likely that the ischemia and surgical trauma of the
transplant procedure induce the chemokines observed at early times
posttransplant and that their target leukocytes function in the healing
of the surgical wound. Consistent with this proposal, the induction of
these early chemokines has also been observed during wound healing in
rodent and human models (34, 35). Whereas the expression
of the early chemokine genes quickly subsided (e.g., by day 3–4
posttransplant) in isografts and in B10.D2 allografts on MHC-matched
BALB/c recipients, expression in MHC-disparate grafts continued at high
levels. These results indicate the ability of recipients of MHC-disparate, but not of MHC-matched/multiple mHAg-disparate allografts to detect and to react to the allograft at early times posttransplant. Recent results have indicated a role for NK cells in mediating the increased early RNA expression and protein production of chemokines in MHC-mismatched skin grafts (36). This early response is observed in MHC-disparate grafts on T cell-deficient recipients and is abrogated in athymic and euthymic allograft recipients treated with NK cell-depleting Abs. Furthermore, the elevated early chemokine response is not observed in (A/J x C57BL/6)F1 allografts transplanted to C57BL/6 recipients, in which NK cells would be inactivated by expression of recipient class I MHC molecules (37). Class I MHC identity on the MHC-matched/multiple mHAg-disparate B10.D2 skin allograft donor and the BALB/c graft recipient (i.e., Kd and Dd) would also be expected to inactivate recipient NK cell activity.
We have recently reported that intraallograft expression of RANTES is mediated by CD8+ T cells during skin allograft rejection (38). We were therefore not surprised to see the absence of RANTES expression in multiple mHAg-disparate allografts on recipients depleted of CD8+ T cells. In control Ig-treated recipients, however, the intraallograft expression of RANTES was also at very low levels or was absent altogether. This most likely indicates the absence of CD8+ T cell activity in the B10.D2 allograft. In support of this, we observed a very low infiltration by CD8+ T cells (<10% of the graft-infiltrating T cells) into allografts on the control Ig-treated recipients.
In vitro stimulation of a number of different cell types with IFN-
stimulates expression and production of both Mig and IP-10 (9, 10, 39). It was therefore unexpected to observe the presence of
the IP-10 and Mig proteins in completely different locations in the
B10.D2 allograft tissue during rejection. These are the first results
indicating the locations of these potent chemoattractants for activated
T cells in allografts during acute rejection. To our knowledge, these
results are also unique in indicating different tissue locations for
these IFN--induced chemokines during an inflammatory process. The
different tissue location of Mig and IP-10 is not a characteristic
unique to the rejection of MHC-matched/multiple mHAg skin grafts, as
these tissue-staining locations are also observed during the rejection
of completely MHC-disparate BALB/c (H-2d) grafts
on C57BL/6 (H-2b) recipients (S. Koga,
unpublished observations). IP-10, but not Mig, expression is also
observed in both iso- and B10.D2 allografts during the early (e.g., day
2–4) period posttransplant. The absence of IP-10 protein in locations
in which Mig is produced may reflect the differential ability of
stromal cells in the graft dermis to produce Mig vs IP-10. An
alternative possibility is that the activity of cells in the intense
leukocyte infiltration of the graft inhibits the production of IP-10,
but not Mig. A third possibility is the differential production of
cytokines in each of the different allograft tissue locations. In
addition to IFN-, IP-10 is induced by IFN-/ß and Mig can be
induced by TNF- (39). IFN-/ß is produced during
allogeneic skin rejection and may induce the IP-10 observed in the
epidermis during rejection of the skin grafts and account for the lack
of Mig production at this tissue location. TNF- is also expressed in
allogeneic skin grafts at both early and late periods of rejection
(40). The expression of IP-10 and Mig is not observed,
however, during the rejection of skin and heart allografts by
IFN--deficient mice, suggesting, at least, a requirement for
recipient IFN--producing cells for the induction of these chemokines
in the allograft (41, 42).
Results from several laboratories have demonstrated the ability of chemokine-specific Abs or receptor antagonists to inhibit leukocyte infiltration and tissue pathology in animal models (43, 44, 45, 46, 47, 48). Despite the potent chemoattractant properties of IP-10 and Mig for activated T cells, few studies have targeted these chemokines for inhibition during T cell-mediated inflammation (30). The results presented in the current study represent one of the few studies testing the ability of chemokine-specific Abs to prolong the survival of allografts. The administration of rabbit antiserum to Mig but not to IP-10 resulted in modest but significant prolongation of MHC-matched/multiple mHAg-disparate skin allograft survival, and was associated with a decrease in graft-infiltrating T cells into the graft. In contrast to the distinct tissue locations of IP-10 and Mig during the rejection of skin allografts, Mig and IP-10 protein are present in the same location, in the myocardium, during rejection of heterotopically transplanted MHC-mismatched A/J cardiac grafts by C57BL/6 recipients (42). Furthermore, recipient treatment with either the Mig or the IP-10 antisera prolongs the survival of the allografts. These results suggest that the function of IP-10 and Mig, as well as other chemokines, in recruiting target leukocyte populations to inflammatory sites is likely to be dependent on its tissue location.
There are several potential reasons for the inability of the Mig
antiserum to prolong survival of the B10.D2 allografts longer than 3–4
days. The amount of antiserum given may not have been sufficient to
completely inhibit Mig-mediated T cell infiltration into the allograft.
Expression of Mig in BALB/c skin allografts on C57BL/6 recipients is
4–5-fold greater than in B6.H-2bm12 grafts, and
whereas the survival of BALB/c grafts is only extended 3–4 days by the
Mig antiserum, the survival of the B6.H-2bm12
grafts is extended 40 days or more. These results suggest that
increased immunogenetic disparity and stronger T cell responses result
in greater production of intraallograft Mig during rejection.
Alternatively, other factors in addition to Mig may be important in
recruiting alloantigen-primed T cells into allografts with complete MHC
or multiple mHAg disparities. As discussed above, intraallograft Mig is
not observed during rejection of grafts on IFN--deficient
recipients, and several laboratories have demonstrated the ability of
these animals to reject allografts (49, 50). This may be
indicative that other factors, including other chemokines, mediate
recruitment of alloantigen-primed T cells into allografts. Thus, a
cocktail of reagents directed to multiple recruiting factors may be
required to efficiently inhibit T cell infiltration into
allografts.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Robert L. Fairchild, Departments of Immunology and Urology, NB3-79, Cleveland Clinic Foundation, Cleveland, OH 44195-0001.
3 Abbreviations used in this paper: IP-10, IFN--inducible protein; mHAg, minor histocompatibility Ag; Mig, monokine induced by IFN-; MIP, macrophage-inflammatory protein; NRS, normal rabbit serum.
Received for publication August 17, 1999. Accepted for publication March 16, 2000.
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C. He, S. Schenk, Q. Zhang, A. Valujskikh, J. Bayer, R. L. Fairchild, and P. S. Heeger Effects of T Cell Frequency and Graft Size on Transplant Outcome in Mice J. Immunol., January 1, 2004; 172(1): 240 - 247. [Abstract] [Full Text] [PDF]
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M. Miura, K. Morita, H. Kobayashi, T. A. Hamilton, M. D. Burdick, R. M. Strieter, and R. L. Fairchild Monokine Induced by IFN-{gamma} Is a Dominant Factor Directing T Cells into Murine Cardiac Allografts During Acute Rejection J. Immunol., September 15, 2001; 167(6): 3494 - 3504. [Abstract] [Full Text] [PDF]
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