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-Induced Chemokine Mig1
,
Departments of
*
Urology and
Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195;
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106; and
§
Department of Urology, Tokyo Women’s Medical School, Tokyo, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-inducible protein-10 and monokine induced by IFN-
(Mig) are expressed in allogeneic skin grafts during the late stages of
acute rejection. Survival of class II MHC-disparate
B6.H-2bm12 allografts is prolonged from day 14 to day 55
posttransplant when C57BL/6 recipients are given a short course
treatment with an antiserum to Mig. This treatment also inhibits T cell
and macrophage infiltration into the allografts. B6.H-2bm12
allografts are also not rejected by IFN--/- C57BL/6
recipients. Injection of Mig directly into B6.H-2bm12
grafts on IFN--deficient recipients restores T cell infiltration and
rejection. Therefore, the inability of IFN--deficient recipients to
reject the class II MHC-disparate allografts is due to the lack of
intraallograft Mig production and alloantigen-primed T cell recruitment
to the graft. These results indicate for the first time the potential
utility of chemokine neutralization strategies in preventing T cell
infiltration into allografts and abrogating acute
rejection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Chemokines are a superfamily of structurally related cytokines having chemoattractant properties for leukocytes (9, 10). Studies using chemokine-specific Abs or receptor-binding antagonists to inhibit leukocyte infiltration and ameliorate tissue pathology in animal models have directly demonstrated the important role of chemokines in inflammation (11, 12, 13, 14, 15). Studies from this and several other laboratories have demonstrated the presence of chemokine mRNA and/or protein in allografts during rejection, suggesting a role for chemokines during rejection of the grafts (16, 17, 18, 19, 20). The function of chemokines in recruiting T cells into allografts, however, has not been directly tested.
Following infiltration of transplanted allografts, specific T cells are
activated to produce the proinflammatory cytokines and/or express the
cytolytic activities mediating destruction of the graft tissue.
IFN-, which stimulates increased expression of class I and II MHC
molecules on many cell types, is often produced and detected in
allografts during rejection (21, 22, 23). Rejection of class
II MHC-disparate B6.H-2bm12 grafts is inhibited
when recipient C57BL/6 mice are treated with an anti-IFN- Ab
(24). One interpretation of these results has been that
the Ab treatment inhibits IFN--mediated up-regulation of class II
MHC expression and there is a lack of target molecules in the graft to
activate the effector CD4+ T cells to mediate
rejection of the allograft. IFN- up-regulates or down-regulates many
functions during the course of immune responses. Of particular interest
to this laboratory is the ability of IFN- to stimulate many
different types of cells to produce two 
(CXC) chemokines, monokine
induced by IFN-
(Mig)3
(3), and IFN--inducible protein-10 (IP-10) (25, 26). These chemokines have potent chemoattractant properties for
activated T cells, raising the possibility that IP-10 and/or Mig might
be critical factors directing alloantigen-primed T cell infiltration
into allografts during rejection. In this study, we demonstrate for the
first time the inhibition of T cell infiltration into class II
MHC-disparate allografts and prevention of acute rejection by treatment
of the recipient with Abs to a single chemokine, Mig. We also
demonstrate that the inability of
IFN--/--deficient recipients to reject class
II MHC-disparate skin grafts is circumvented by delivering recombinant
Mig into the graft. In light of these results, the multiple functions
of IFN- in the graft rejection process are discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Adult female mice of 6–10 wk of age were used throughout this
study. BALB/c (H-2d), A/J
(H-2a), and C57BL/6 (H-2b)
mice were obtained through Dr. Clarence Reeder (National Cancer
Institute, Frederick, MD). B6.C-H-2bm1,
B6.C-H-2bm12, and C57BL/6 mice with a targeted
deletion in the IFN- (IFN--/-) gene were
purchased from The Jackson Laboratory (Bar Harbor, ME).
Abs and cytokines
mAb from the culture supernatant of the IgG-producing hybridomas
GK1.5 (rat anti-mouse CD4) and 30-H12 (anti-Thy-1.2) were
purified by protein G chromatography. The following mAb and antisera
were used for immunohistology: GK1.5; 53-6.7 (rat anti-mouse
CD8) was purchased from PharMingen (San Diego, CA); MOMA-2 (rat
anti-macrophage) was purchased from BioSource International
(Camarillo, CA); and Texas Red-conjugated donkey Ab specific for rat
IgG was purchased from Jackson ImmunoResearch (West Grove, PA). Rabbit
antiserum to a Mig-specific peptide (sequence: CISTSRGTIHYKSLKDLKQFAPS)
was generated by Biosynthesis (Lewisville, TX). This antiserum detected
recombinant mouse Mig and not recombinant mouse KC (Gro) in Western
blot analyses. Recombinant mouse Mig was purchased from R&D Systems
(Minneapolis, MN).
Transplantation
Full thickness trunk skin grafting was performed using a
modification of the protocol of Billingham and Medawar
(27). Briefly, trunk skin was prepared from donor ventral
skin, and 12-mm-diameter circles of full thickness skin were punched.
Graft beds were prepared by excising 14-mm-diameter circles of skin
from the lateral dorsal thoracic wall of recipients. Recipient C57BL/6
mice were grafted with a syngeneic graft on one side of the lateral
dorsal thoracic wall and an allogeneic graft 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. To determine the time of
graft survival in the various recipient groups, the graft was left on
five recipients in each group until rejection was complete. Each graft
was examined daily beginning at day 7 posttransplant and was considered
rejected when 
60% or more of the graft tissue was destroyed and
transformed to scab as assessed by visual examination.
Northern blot analysis
Whole cell RNA was isolated from transplanted skin tissue using the protocol of Chirgwin and coworkers (28). Briefly, 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 (Brinkmann Instruments, Westbury, NY). The RNA was pelleted by overnight centrifugation of the tissue homogenate through a 5.7 M CsCl2 gradient. Following resuspension in diethyl pyrocarbonate-treated dH2O, 10-µg aliquots of RNA were subjected to electrophoresis in 1% agarose/2.2 M formaldehyde-denaturing gels and analyzed by Northern blot analysis, as previously described (19, 20). Northern blots were probed by hybridization with 32P-labeled oligonucleotide probes specific for IP-10 and Mig. The quantity of RNA in each analysis was standardized by washing the blot three times in Tris-EDTA at 90°C to strip off the cytokine probe and reprobing the blot with an oligonucleotide probe specific for rat GAPDH. All experiments were repeated three times, with similar results observed each time, and the results from a single representative experiment are shown.
Immunohistology
For immunohistology, 6-µm frozen sections of allogeneic and isogeneic skin grafts were cut, fixed in acetone for 10 min, and air dried. Slides were stained overnight with GK1.5 or 53-6.7, diluted to 5 µg/ml, or MOMA-2, diluted to 50 µg/ml. Control slides were incubated with rat or goat IgG as the primary Ab. After three washes in PBS for 5 min each, slides were incubated with FITC-conjugated donkey anti-goat IgG and/or Texas Red-conjugated donkey anti-rat IgG, diluted to 7.5 µg/ml. After staining, slides were washed in PBS, and a drop of Vectashield (Vector Laboratories, Burlingame, CA) was used to reduce fluorescence photobleaching. The slides were viewed under a fluorescent microscope, and the images were captured using Adobe Photoshop 4.0 (Mountain View, CA). In all experiments, from five to seven different cut tissue sections were examined, and a representative histological result is shown.
Antiserum treatment
To test the role of Mig in allogeneic skin graft rejection, graft recipients received 0.5-ml aliquots of rabbit anti-Mig antiserum, or as a control normal rabbit serum (NRS), i.p. every other day from day 7 to day 21 posttransplantation.
Mixed lymphocyte reactivity
T cells from naive and skin allograft recipients were tested for alloantigen reactivity by performing mixed lymphocyte reactions. Responder T cell suspensions were prepared from lymph nodes draining the allograft site (brachial and axillary nodes). The cells were suspended at 2.5 x 106/ml in complete medium, RPMI (Life Technologies, Gaithersburg, MD) supplemented with 10% FCS (Sigma, St. Louis, MO), 2 mM L-glutamine, 5 x 10-5 M 2-ME, 10 mM HEPES, and 20 µg/ml gentamicin, and 100-µl aliquots were delivered in triplicate to the wells of a 96-well round-bottom tissue culture plate. Stimulator cells were prepared from spleens of syngeneic, allograft donor, and third-party allogeneic mice. The spleen cell suspensions were treated with Tris-NH4Cl for 5 min and washed three times. The cells were given 2500 R gamma-irradiation and resuspended in culture media at 5 x 106/ml, and 100-µl aliquots were delivered to each well in the culture plates. After 48 h, cultures were pulsed with 1 µCi [3H]thymidine, and 20 h later the cultures were harvested onto fiber filter mats and the amount of 3H incorporation was determined by liquid scintillation counting.
Cytotoxicity assays
Cytotoxic activity of LNC from naive and skin allograft recipients was tested using the JAM assay described by Matzinger (29). Briefly, LNC suspensions to be tested as effector cells were cultured at 107 cells/ml with 5 x 106 irradiated (3000 rad) stimulator cells/ml in complete medium for 3 days in 24-well plates. Stimulator and target cells for the assay were syngeneic and allogeneic LPS blasts. To prepare LPS blasts, spleen cells were depleted of T cells by treating with anti-Thy-1.2 mAb and complement and culturing the treated cells at 1 x 106/ml with 1 µg/ml LPS (Sigma) for 40 h. During the last 4 h of culture, the cells were labeled with 5 µCi/ml [3H]thymidine. After labeling, the LPS blasts were washed, and quadruplicate cocultures of 104 LPS blasts with 100 to 12.5 x 105 of the effector LNC were established in a final volume of 200 µl/well in 96-well round-bottom plates. The cultures were incubated for 3 h at 37°C and then harvested onto fiber filter mats. The amount of [3H]thymidine incorporation was determined by liquid scintillation counting. Results are expressed as percent specific lysis (i.e., percentage of specific DNA loss) calculated as: % specific lysis = 100 x [(cpmspont - cpmexp)]/cpmspont, where spontaneous killing (spont) = retained DNA in the absence of cytotoxic cells and experimental killing (exp) = retained DNA in the presence of cytotoxic cells.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To begin to test the potential role of IP-10 and Mig in recruiting
T cells into allografts during acute rejection, the expression of Mig
and IP-10 mRNA in syngeneic and allogeneic skin grafts was tested by
Northern blot hybridization. C57BL/6 (H-2b) mice
received a full thickness trunk skin graft from a syngeneic donor and
from an allogeneic donor with a full or partial MHC disparity. On
various days posttransplant, the iso- and allografts were retrieved for
RNA isolation and analysis by Northern blot hybridization. Allografts
with a complete MHC disparity, BALB/c (H-2d),
were rejected by C57BL/6 recipients between days 12 and 13
posttransplant. Expression of Mig and IP-10 was undetectable or at low
levels in BALB/c allografts 6 to 7 days before rejection (i.e., day 6
posttransplant), but was detected at high levels thereafter (Fig. 1
a). Mig and IP-10 RNA
expression was not detected in isografts at any time examined.
Allografts with a single class I (B6.H-2bm1) MHC
disparity were rejected by C57BL/6 recipients between days 16 and 17
posttransplant, and allografts with a single class II
(B6.H-2bm12) MHC disparity were rejected between
days 14 and 15 posttransplant. Expression of IP-10 and Mig in
B6.H-2bm1 and B6.H-2bm12
allografts was also not observed until late in the rejection process
(Fig. 1, b and c). Low levels of both IP-10 and
Mig RNA were observed in B6.H-2bm12 allografts 5
days before rejection, 3- to 5-fold less than the levels observed in
B6.H-2bm1 allografts at comparable times before
completion of graft rejection. In contrast to expression in the
completely allogeneic (BALB/c) graft, expression of Mig and IP-10 in
B6.H-2bm1 and B6.H-2bm12
allografts quickly decreased from the peak levels observed (i.e., 5
days before rejection) and was virtually undetectable the day before
completion of rejection.
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A rabbit antiserum generated to a Mig peptide was tested for the
ability to prolong allograft survival. Full thickness skin grafts from
BALB/c, B6.H-2bm1, and B6.H-2bm12 donors were
transplanted to C57BL/6 recipients. Beginning at day 7 posttransplant,
groups of recipients were given 0.5 ml of NRS or the Mig antiserum
every other day until day 21 posttransplant. Survival of skin grafts
was assessed by visual examination with 60% or more of tissue
destruction interpreted as the completion of rejection. Treatment with
NRS did not affect the time of rejection of the allogeneic skin grafts
when compared with nontreated recipients. Treatment of recipients of
BALB/c or B6.H-2bm1 allografts with the Mig
antiserum delayed graft rejection 2–4 days (Fig. 2, a and b). In
contrast, treatment with Mig antiserum prolonged the survival of the
B6.H-2bm12 allografts to day 53–56
posttransplant (Fig. 2c). Isografts on recipients treated
with either NRS or Mig antiserum were maintained indefinitely (data not
shown).
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). In contrast,
allografts from recipients treated with Mig antiserum had few
detectable mononuclear cells at this time point. By day 53
posttransplant, however, allografts retrieved from Mig
antiserum-treated recipients were heavily infiltrated with large
mononuclear cells.
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). Consistent with the previous
analysis, few graft-infiltrating CD4+ T cells and
macrophages were detected in allografts retrieved from Mig
antiserum-treated recipients at day 14 posttransplant. At the time of
rejection (e.g., day 53 posttransplant), allografts from Mig
antiserum-treated recipients had evidence of both macrophages and
CD4+ T cells, with the macrophages more
predominant than CD4+ T cells. The number of
CD4+ T cells and macrophages were counted in five
to seven microscope fields of the stained graft tissue sections from
NRS- and Mig antiserum-treated recipients (Table I). Consistent with the previous results,
Mig antiserum inhibited CD4+ T cell and
macrophage infiltration into the allograft at day 14 posttransplant.
Furthermore, the number of allograft-infiltrating macrophages was
significantly increased in allografts from recipients treated with Mig
antiserum when compared with allografts from NRS-treated recipients at
the time of allograft rejection (i.e., day 14 vs day 53 posttransplant,
respectively).
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). Lymph node T cells obtained at
day 14 posttransplant from graft recipients treated with NRS vs Mig
antiserum had equivalent proliferative responses to
B6.H-2bm12 stimulator cells. Furthermore, the
presence of B6.H-2bm12-reactive T cells in the
Mig antiserum-treated graft recipients remained detectable at later
times posttransplant. In conjunction with the histological analyses,
these results indicated that the prolonged survival of
B6.H-2bm12 allografts on Mig antiserum-treated
recipients was not mediated through diminished T cell priming or
alloreactivity, but was mediated by inhibition of T cell recruitment
into the graft tissue.
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-/- recipients to
reject B6.H-2bm12 allografts is due to lack of intragraft
Mig production
The ability of the Mig antiserum to inhibit the rejection of skin
allografts suggested a critical role of IFN- in stimulating
intraallograft production of Mig and the subsequent recruitment of
alloantigen-primed T cells into the graft. To test this,
B6.H-2bm12 skin grafts were transplanted to
IFN--deficient C57BL/6. In contrast to
B6.H-2bm12 allografts on C57BL/6 wild-type
recipients, the allografts survived indefinitely on C57BL/6
IFN--/- recipients (Fig. 6). Examination of the allografts
indicated a complete absence of Mig mRNA expression and a low level of
mononuclear cell graft infiltration at day 12 posttransplant (data not
shown).
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-/- recipients of
B6.H-2bm12 allografts was tested 11 days after
skin transplantation. First, lymph node T cells from wild-type C57BL/6
and C57BL/6 IFN--/- recipients of the
allografts were compared for proliferative reactivity to
B6.H-2bm12 and third-party allogenic (A/J)
stimulator cells in 72-h MLC (Fig. 7).
Lymph node T cells from C57BL/6 IFN--/-
recipients of B6.H-2bm12 allografts had slightly
greater proliferative responses than responses of cells from C57BL/6
IFN-+/+ recipients of the
B6.H-2bm12 allografts. Second, lymph node T cells
from wild-type C57BL/6 and C57BL/6 IFN--/-
recipients of B6.H-2bm12 allografts were cultured
for 3 days with B6.H-2bm12 spleen cells and were
then tested for cytotoxic activity to LPS blasts prepared from
B6.H-2bm12 spleen cells. T cells from C57BL/6
IFN--/- allograft recipients, but not from
naive C57BL/6 IFN--/- mice, expressed primed
CTL responses following short-term culture with the
B6.H-2bm12 stimulator cells (Fig. 8). Similar to the proliferative
responses, the cytotoxic activities of LNC from the C57BL/6
IFN--/- recipients were slightly but
consistently higher than the cytotoxic activity of LNC from wild-type
recipients.
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-deficient C57BL/6 recipients, the T cells
appeared unable to infiltrate the allograft. Injection of recombinant
Mig directly (i.e., intradermally) into the allografts restored the
ability of the C57BL/6 IFN--/- recipients to
reject the allografts (Fig. 6
). Injection of saline into the allografts
did not induce graft rejection. Rejection of Mig-injected
B6.H-2bm12 allografts on C57BL/6
IFN--/- recipients was associated with an
intense leukocytic infiltration of the allografts and necrosis of the
tissue (Fig. 9c). Injection of
saline into the allograft did not result in rejection, but did induce a
mild cellular infiltration (Figs. 6 and 9a). Injection of
Mig into C57BL/6 isografts on C57BL/6
IFN--/- recipients did not induce cellular
infiltration into the allografts or rejection of the isograft (Fig. 9b).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The results in the current study are the first to demonstrate that treating a recipient with an anti-chemokine reagent can inhibit allograft rejection. We chose to test the effect of Abs to Mig based on preliminary immunohistological studies indicating association of Mig, and not IP-10, with allograft-infiltrating cells during the late stages of rejection (unpublished results). Neutralization of Mig resulted in long-term survival of B6.H-2bm12 skin grafts on C57BL/6 recipients with a complete absence of infiltrating T cells at the time the allografts were rejected in NRS-treated recipients. At the time of rejection in Mig antiserum-treated recipients (e.g., day 53 posttransplant), B6.H-2bm12 allografts were heavily infiltrated with macrophages. This infiltration was associated with a high level of MCP-1 expression in the allograft, whereas allografts from NRS-treated recipients have low levels of MCP-1 expression at the time of rejection at day 12–13 posttransplant (data not shown). These results suggest that the cellular and cytokine dynamics of the graft rejection response change when an integral component of the response is either neutralized or deleted.
In contrast to the B6.H-2bm12 allografts, the survival of allografts from BALB/c or from B6.H-2bm1 donors transplanted to C57BL/6 recipients was only prolonged 3 to 4 days by treatment with the Mig antiserum. This difference suggests that the infiltration of B6.H-2bm12 grafts by alloantigen-primed, effector CD4+ T cells is strictly dependent upon Mig, whereas the infiltration of BALB/c and B6.H-2bm1 allografts by alloantigen-primed (CD4+ and/or CD8+) T cells is not strictly dependent upon Mig. Other (late) chemokines such as IP-10 and RANTES are also expressed at low levels in the B6.H-2bm12 allografts, but are expressed at high levels in fully allogeneic and class I MHC-disparate grafts. This raises the possibility that other chemokines may be involved in recruiting alloantigen-primed CD4+ and/or CD8+ T cells into grafts during the rejection of fully allogeneic and class I MHC-disparate grafts. Alternatively, Mig was expressed at low levels in the B6.H-2bm12 allografts and at much higher levels in the BALB/c and B6.H-2bm1 allografts. Thus, the difference in the efficacy of the Mig antiserum treatment in preventing B6.H-2bm12 allograft rejection may simply be due to the amount of Mig protein neutralized by the administered antiserum.
The current results indicate the strict requirement for Mig in the
rejection of B6.H-2bm12 allografts. Studies by
Rosenberg and coworkers (24) had previously indicated the
ability of anti-IFN- mAb to prevent C57BL/6 recipient rejection
of B6.H-2bm12 allogeneic skin grafts. Another
group of investigators recently reported the inability of
IFN--/--deficient recipients to reject
B6.H-2bm12 skin grafts (31). Each of
these groups postulated that IFN--dependent up-regulation of class
II MHC was required to increase graft immunogenicity for
CD4+ T cell-mediated rejection. The results of
the current study suggest an alternate interpretation of these results.
IFN- is also required to induce production of Mig, and
intraallograft Mig is not observed in skin or heart grafts transplanted
to IFN--/- recipients. As shown in this
study, C57BL/6 IFN--/- recipients do not
reject class II MHC-disparate B6.H-2bm12
allografts despite the presence of alloantigen-primed T cells in the
lymph nodes draining the graft site. Direct delivery of Mig protein
into B6.H-2bm12 skin grafts on the
IFN--/- recipients, however, induces T cell
infiltration of the allograft and rejection. Thus, Ab-mediated
neutralization of IFN- in wild-type recipients may inhibit the
production of intraallograft Mig and the subsequent infiltration of
alloantigen-primed CD4+ T cells into
B6.H-2bm12 allografts. The recruitment of
alloantigen-primed T cell into the graft induced by intradermal
injection of Mig is not due to a nonspecific inflammatory response
(e.g., mediated by the injection), as delivery of saline does not
result in rejection of the allografts. Recent studies have also shown
that injection of recombinant RANTES into the allograft does not
mediate rejection of the skin grafts (S. Koga, unpublished results).
This may indicate that other chemokines cannot substitute for Mig in
mediating the rejection of these allografts and the critical role of
IFN--induced Mig in the rejection of
B6.H-2bm12 allografts by C57BL/6 recipients. It
is also worth noting that injection of Mig into isografts on C57BL/6
IFN--/- recipients of
B6.H-2bm12 allografts did not induce T cell
recruitment into the isograft. We postulate that Mig-dependent
infiltration fails to occur in the isografts because expression of the
Mig-binding receptor, CXCR3, on alloantigen-primed T cells requires the
stimulation provided by alloantigen recognition.
The ability of intradermally delivered Mig to mediate
alloantigen-primed T cell recruitment and allograft rejection
independently of IFN- indicates that IFN--mediated up-regulation
of class II MHC determinants is not required for
CD4+ T cell-mediated rejection of
B6.H-2bm12 allografts. One interpretation of
these results is that the level of class II MHC expression in
B6.H-2bm12 allografts on
IFN--/- C57BL/6 recipients may be sufficient
for rejection of the grafts if recipient T cells can be recruited to
the graft site. Alternatively, T cells recruited to the graft site by
Mig may induce up-regulated expression of class II MHC independently of
IFN-. Class II MHC expression is increased on a cell-specific basis
during cell-cell interactions as well as by many other cytokines in
addition to IFN- (21). We have recently observed the
up-regulated expression of class II MHC on
B6.H-2bm12 B cells following culture with T cells
from IFN--/- recipients of
B6.H-2bm12 grafts (R. Fairchild, unpublished
results). Once Mig has induced recruitment of alloantigen-primed
CD4+ T cells into
B6.H-2bm12 grafts on
IFN--/- recipients, class II MHC may be
up-regulated on allogeneic cells by other (i.e., IFN--independent)
mechanisms. Rather than increasing the immunogenicity of the allograft
through up-regulated class II MHC expression, these results suggest
that a more critical function of IFN- during allograft rejection may
be the induction of T cell-recruiting factors such as Mig.
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Acknowledgments |
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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. E-mail address:
3 Abbreviations used in this paper: Mig, monokine induced by IFN-; IP-10, IFN--inducible protein-10; LNC, lymph node cell; NRS, normal rabbit serum.
Received for publication April 7, 1999. Accepted for publication August 16, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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interferon-inducible cytokine (IP-10). J. Exp. Med. 166:1084. is necessary for initiating the acute rejection of major histocompatibility complex class II-disparate skin allografts. Transplantation 67:1362.[Medline]
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G. C. Hildebrandt, L. A. Corrion, K. M. Olkiewicz, B. Lu, K. Lowler, U. A. Duffner, B. B. Moore, W. A. Kuziel, C. Liu, and K. R. Cooke Blockade of CXCR3 Receptor:Ligand Interactions Reduces Leukocyte Recruitment to the Lung and the Severity of Experimental Idiopathic Pneumonia Syndrome J. Immunol., August 1, 2004; 173(3): 2050 - 2059. [Abstract] [Full Text] [PDF]
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D. Whiting, G. Hsieh, J. J. Yun, A. Banerji, W. Yao, M. C. Fishbein, J. Belperio, R. M. Strieter, B. Bonavida, and A. Ardehali Chemokine Monokine Induced by IFN-{gamma}/CXC Chemokine Ligand 9 Stimulates T Lymphocyte Proliferation and Effector Cytokine Production J. Immunol., June 15, 2004; 172(12): 7417 - 7424. [Abstract] [Full Text] [PDF]
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P. B. Sugerman, S. B. Faber, L. M. Willis, A. Petrovic, G. F. Murphy, J. Pappo, D. Silberstein, and M. R. M. van den Brink Kinetics of Gene Expression in Murine Cutaneous Graft-versus-Host Disease Am. J. Pathol., June 1, 2004; 164(6): 2189 - 2202. [Abstract] [Full Text] [PDF]
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 B. L. Colvin, A. E. Morelli, A. J. Logar, A. H. Lau, and A. W. Thomson Comparative evaluation of CC chemokine-induced migration of murine CD8{alpha}+ and CD8{alpha}- dendritic cells and their in vivo trafficking J. Leukoc. Biol., February 1, 2004; 75(2): 275 - 285. [Abstract] [Full Text] [PDF]
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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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J. A. Belperio, M. P. Keane, M. D. Burdick, J. P. Lynch III, D. A. Zisman, Y. Y. Xue, K. Li, A. Ardehali, D. J. Ross, and R. M. Strieter Role of CXCL9/CXCR3 Chemokine Biology during Pathogenesis of Acute Lung Allograft Rejection J. Immunol., November 1, 2003; 171(9): 4844 - 4852. [Abstract] [Full Text] [PDF]
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R. L. Rabin, M. A. Alston, J. C. Sircus, B. Knollmann-Ritschel, C. Moratz, D. Ngo, and J. M. Farber CXCR3 Is Induced Early on the Pathway of CD4+ T Cell Differentiation and Bridges Central and Peripheral Functions J. Immunol., September 15, 2003; 171(6): 2812 - 2824. [Abstract] [Full Text] [PDF]
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Q.-W. Zhang, D. D. Kish, and R. L. Fairchild Absence of Allograft ICAM-1 Attenuates Alloantigen-Specific T Cell Priming, But Not Primed T Cell Trafficking into the Graft, to Mediate Acute Rejection J. Immunol., June 1, 2003; 170(11): 5530 - 5537. [Abstract] [Full Text] [PDF]
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M. Jiankuo, W. Xingbing, H. Baojun, W. Xiongwin, L. Zhuoya, X. Ping, X. Yong, L. Anting, H. Chunsong, G. Feili, et al. Peptide Nucleic Acid Antisense Prolongs Skin Allograft Survival by Means of Blockade of CXCR3 Expression Directing T Cells into Graft J. Immunol., February 1, 2003; 170(3): 1556 - 1565. [Abstract] [Full Text] [PDF]
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G. T. Brice, N. L. Graber, D. J. Carucci, and D. L. Doolan Optimal induction of antigen-specific CD8+ T cell responses requires bystander cell participation J. Leukoc. Biol., December 1, 2002; 72(6): 1164 - 1171. [Abstract] [Full Text] [PDF]
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J. J. Yun, M. P. Fischbein, D. Whiting, Y. Irie, M. C. Fishbein, M. D. Burdick, J. Belperio, R. M. Strieter, H. Laks, J. A. Berliner, et al. The Role of MIG/CXCL9 in Cardiac Allograft Vasculopathy Am. J. Pathol., October 1, 2002; 161(4): 1307 - 1313. [Abstract] [Full Text] [PDF]
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 N. G. Inston and P. Cockwell The evolving role of chemokines and their receptors in acute allograft rejection Nephrol. Dial. Transplant., August 1, 2002; 17(8): 1374 - 1379. [Full Text] [PDF]
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M. K. Park, D. Amichay, P. Love, E. Wick, F. Liao, A. Grinberg, R. L. Rabin, H. H. Zhang, S. Gebeyehu, T. M. Wright, et al. The CXC Chemokine Murine Monokine Induced by IFN-{gamma} (CXC Chemokine Ligand 9) Is Made by APCs, Targets Lymphocytes Including Activated B Cells, and Supports Antibody Responses to a Bacterial Pathogen In Vivo J. Immunol., August 1, 2002; 169(3): 1433 - 1443. [Abstract] [Full Text] [PDF]
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J. A. Belperio, M. P. Keane, M. D. Burdick, J. P. Lynch III, Y. Y. Xue, K. Li, D. J. Ross, and R. M. Strieter Critical Role for CXCR3 Chemokine Biology in the Pathogenesis of Bronchiolitis Obliterans Syndrome J. Immunol., July 15, 2002; 169(2): 1037 - 1049. [Abstract] [Full Text] [PDF]
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 Y.-G. Yang, J. Qi, M.-G. Wang, and M. Sykes Donor-derived interferon gamma separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells Blood, May 13, 2002; 99(11): 4207 - 4215. [Abstract] [Full Text] [PDF]
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J. H. Dufour, M. Dziejman, M. T. Liu, J. H. Leung, T. E. Lane, and A. D. Luster IFN-{gamma}-Inducible Protein 10 (IP-10; CXCL10)-Deficient Mice Reveal a Role for IP-10 in Effector T Cell Generation and Trafficking J. Immunol., April 1, 2002; 168(7): 3195 - 3204. [Abstract] [Full Text] [PDF]
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Z. Zhang, L. Kaptanoglu, W. Haddad, D. Ivancic, Z. Alnadjim, S. Hurst, D. Tishler, A. D. Luster, T. A. Barrett, and J. Fryer Donor T Cell Activation Initiates Small Bowel Allograft Rejection Through an IFN-{gamma}-Inducible Protein-10-Dependent Mechanism J. Immunol., April 1, 2002; 168(7): 3205 - 3212. [Abstract] [Full Text] [PDF]
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A. Fox-Marsh and L. C. Harrison Emerging evidence that molecules expressed by mammalian tissue grafts are recognized by the innate immune system J. Leukoc. Biol., March 1, 2002; 71(3): 401 - 409. [Abstract] [Full Text] [PDF]
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 R. Ganss, E. Ryschich, E. Klar, B. Arnold, and G. J. Hammerling Combination of T-Cell Therapy and Trigger of Inflammation Induces Remodeling of the Vasculature and Tumor Eradication Cancer Res., March 1, 2002; 62(5): 1462 - 1470. [Abstract] [Full Text] [PDF]
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M. Miura, X. Fu, Q.-W. Zhang, D. G. Remick, and R. L. Fairchild Neutralization of Gro{alpha} and Macrophage Inflammatory Protein-2 Attenuates Renal Ischemia/Reperfusion Injury Am. J. Pathol., December 1, 2001; 159(6): 2137 - 2145. [Abstract] [Full Text] [PDF]
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Z. Guo, J. Wang, L. Meng, Q. Wu, O. Kim, J. Hart, G. He, P. Zhou, J. R. Thistlethwaite Jr., M.-L. Alegre, et al. Cutting Edge: Membrane Lymphotoxin Regulates CD8+ T Cell-Mediated Intestinal Allograft Rejection J. Immunol., November 1, 2001; 167(9): 4796 - 4800. [Abstract] [Full Text] [PDF]
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A. C. Wiseman, B. A. Pietra, B. P. Kelly, G. R. Rayat, M. Rizeq, and R. G. Gill Donor IFN-{gamma} Receptors Are Critical for Acute CD4+ T Cell-Mediated Cardiac Allograft Rejection J. Immunol., November 1, 2001; 167(9): 5457 - 5463. [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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P. F. Halloran, L. W. Miller, J. Urmson, V. Ramassar, L.-F. Zhu, N. M. Kneteman, K. Solez, and M. Afrouzian IFN-{{gamma}} Alters the Pathology of Graft Rejection: Protection from Early Necrosis J. Immunol., June 15, 2001; 166(12): 7072 - 7081. [Abstract] [Full Text] [PDF]
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C. Nakajima, Y. Uekusa, M. Iwasaki, N. Yamaguchi, T. Mukai, P. Gao, M. Tomura, S. Ono, T. Tsujimura, H. Fujiwara, et al. A Role of Interferon-{{gamma}} (IFN-{{gamma}}) in Tumor Immunity: T Cells with the Capacity to Reject Tumor Cells Are Generated But Fail to Migrate to Tumor Sitesin IFN-{{gamma}}-deficient Mice Cancer Res., April 1, 2001; 61(8): 3399 - 3405. [Abstract] [Full Text]
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D. K. Bishop, S. C. Wood, E. J. Eichwald, and C. G. Orosz Immunobiology of Allograft Rejection in the Absence of IFN-{{gamma}}: CD8+ Effector Cells Develop Independently of CD4+ Cells and CD40-CD40 Ligand Interactions J. Immunol., March 1, 2001; 166(5): 3248 - 3255. [Abstract] [Full Text] [PDF]
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A. Fox, J. Mountford, A. Braakhuis, and L. C. Harrison Innate and Adaptive Immune Responses to Nonvascular Xenografts: Evidence That Macrophages Are Direct Effectors of Xenograft Rejection J. Immunol., February 1, 2001; 166(3): 2133 - 2140. [Abstract] [Full Text] [PDF]
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P. F. Halloran, M. Afrouzian, V. Ramassar, J. Urmson, L.-F. Zhu, L. M. H. Helms, K. Solez, and N. M. Kneteman Interferon-{{gamma}} Acts Directly on Rejecting Renal Allografts to Prevent Graft Necrosis Am. J. Pathol., January 1, 2001; 158(1): 215 - 226. [Abstract] [Full Text] [PDF]
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 Y. Sekine, K. Yasufuku, K. M. Heidler, O. W. Cummings, N. Van Rooijen, T. Fujisawa, J. Brown, and D. S. Wilkes Monocyte Chemoattractant Protein-1 and RANTES Are Chemotactic for Graft Infiltrating Lymphocytes during Acute Lung Allograft Rejection Am. J. Respir. Cell Mol. Biol., December 1, 2000; 23(6): 719 - 726. [Abstract] [Full Text]
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 A. A. Ashkar, J. P. Di Santo, and B. A. Croy Interferon {gamma} Contributes to Initiation of Uterine Vascular Modification, Decidual Integrity, and Uterine Natural Killer Cell Maturation during Normal Murine Pregnancy J. Exp. Med., July 17, 2000; 192(2): 259 - 270. [Abstract] [Full Text] [PDF]
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A. S. Diamond and R. G. Gill An Essential Contribution by IFN-{gamma} to CD8+ T Cell-Mediated Rejection of Pancreatic Islet Allografts J. Immunol., July 1, 2000; 165(1): 247 - 255. [Abstract] [Full Text] [PDF]
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D. P. Widney, Y.-R. Xia, A. J. Lusis, and J. B. Smith The Murine Chemokine CXCL11 (IFN-Inducible T Cell {alpha} Chemoattractant) Is an IFN-{gamma}- and Lipopolysaccharide- Inducible Glucocorticoid-Attenuated Response Gene Expressed in Lung and Other Tissues During Endotoxemia J. Immunol., June 15, 2000; 164(12): 6322 - 6331. [Abstract] [Full Text] [PDF]
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Y. Watarai, S. Koga, D. R. Paolone, T. M. Engeman, C. Tannenbaum, T. A. Hamilton, and R. L. Fairchild Intraallograft Chemokine RNA and Protein During Rejection of MHC-Matched/Multiple Minor Histocompatibility-Disparate Skin Grafts J. Immunol., June 1, 2000; 164(11): 6027 - 6033. [Abstract] [Full Text] [PDF]
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) and C57BL/6
IFN-
) and C57BL/6
IFN-
) mice were cultured with B6.
H-2bm12 LPS blasts as unprimed T cell controls. After 3
days, the T cells were tested for cytotoxicity during culture with
[3H]thymidine-labeled B6. H-2bm12 LPS blasts
at the effector cell to target LPS blast ratios shown. After 3 h,
the cultures were harvested onto fiber filter mats, and the amount of
3H incorporation was tested by liquid scintillation.
Percent specific cytolysis was calculated as described in
Materials and Methods. Effector cell cytolysis of
3H-labeled syngeneic LPS blasts was between 0 and 10% for
all groups.