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* Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan; and Departments of
Medicine,
Microbiology and Immunology, and
Pathology, Indiana University School of Medicine, Indianapolis, IN 46202
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in response to
col(V). Compared with normal CD4+ T cells, both cell lines
expressed a limited V-
TCR repertoire. Each cell strongly expressed
V- 9 and 16, but differed in expression of other V-s. Adoptive
transfer of each cell line did not induce pathology in lungs of normal
WKY rats. In contrast, adoptive transfer of LT1, but not LT3, caused
marked peribronchiolar and perivascular inflammation in isograft (WKY)
lungs and abrogated col(V)-induced oral tolerance to allograft (F344)
lungs. Collectively, these data show that lung allograft rejection
involves both allo- and autoimmune responses, and graft destruction
that occurs during the rejection response may expose
allograft-infiltrating T cells to potentially antigenic epitopes in
col(V). |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Studies from other investigators have shown that non-MHC Ags, such as myosin and heat shock proteins, are the target of the immune response during cardiac and skin graft rejection, respectively (4, 5, 6, 7, 8). Significantly, anti-cardiac myosin Abs and myosin-specific T cells were shown to exacerbate cardiac allograft rejection (7), and heat shock protein-specific T cells were shown to exacerbate rejection responses in skin allografts (5). Recently, we reported that lung allograft rejection was associated with a delayed-type hypersensitivity (DTH) responses to a native protein, type V collagen (col(V)), and that col(V)-induced oral tolerance prevented the onset of acute rejection and BO (9, 10). Since DTH is believed to reflect cellular immune responses, then DTH responses to col(V) in our studies suggested development of col(V)-specific T cells that are central to the pathogenesis of acute and chronic lung allograft rejection. However, there are no prior data showing that col(V)-specific T cells are present locally during lung allograft rejection, and the potential role of col(V)-specific T cells in the pathogenesis of lung allograft rejection is unknown.
Our laboratory has used the rat model of lung transplantation to investigate the immunopathogenesis of allograft rejection in which F344 (RT1lv1) lung allografts or WKY (RT1l) lung isografts are transplanted orthotopically into WKY recipients (9, 11, 12). Using this model, the purpose of the current study was to determine whether cellular immune responses to col(V) occur in lung allografts during rejection, the phenotype of these T cells, and the role of col(V)-specific T cells in the development of the pathology and immunology of lung allograft rejection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pathogen-free, MHC (RT1)-incompatible male rats were used for the study: Wistar Kyoto (WKY, RT1l), and Fischer 344 (F344, RT1lv1) rats (250–300 g at the time of transplantation). All rats were purchased from Harlan Sprague Dawley (Indianapolis, IN) and housed in the Laboratory Animal Resource Center at the Indiana University School of Medicine (Indianapolis, IN) in accordance with institutional guidelines.
Preparation of collagens
Human col(V), extracted from human placenta and purified by differential NaCl precipitation, was a gift from Dr. J. Seyer (Veterans Affairs Hospital, Hampton, VA) as reported previously (13). Also, col(V) was purchased from Collaborative Biomedical Products (Bedford, MA). Col(V) is highly conserved among species (14), and our previous studies showed that human and bovine col(V) could be used interchangeably (9, 10, 13). Collagen type II (col(II)) was isolated from canine cartilage as previously reported (13) or purchased from Collaborative Biomedical Products. Both preparations were solubilized in 0.005 M acetic acid and dialyzed to yield a final concentration of 0.5 mg/ml. The quantity of collagens were assessed by determination of the hydroxyproline content in the samples (13).
Western blots for col(V) peptides in bronchoalveolar lavage (BAL) fluid
BAL was collected from normal WKY or F344 rats and F344 lung allografts 2 wk after transplantation into WKY recipients. Equal protein concentrations from BAL were loaded onto 7.5% polyacrylamide gels. Positive controls were bovine col(V) (Collaborative Biomedical Products) and col(V) isolated from human placental or lung tissues by Dr. G. Smith (9, 13, 15, 16). All specimens were prepared by diluting 1/1 in loading buffer (10% glycerol, 0.2% SDS, and 0.5% bromphenol blue indicator in Tris-HCl, pH 6.8) and heating to 100°C. The samples were electrophoresed at 80 V for 4 h using a Tall Mighty Small (Hoefer, San Francisco, CA) electrophoresis apparatus, and membranes were washed and blocked. Membranes were probed with anti-col(V) Abs (Biodesign, Kennenbunk, ME) diluted in TBS-Tween 20 to 0.01–1 ng/ml, washed, incubated with a 1/100 dilution of sheep anti-human IgG2 HRP conjugate (The Binding Site, San Diego, CA), washed, and then developed by the chemiluminescence technique (Amersham, Arlington Heights, IL) per the manufacturer’s instructions.
Transplantation model
The orthotopic transplantation of left lung isografts
(WKY
WKY) or allografts (F344WKY) was performed as previously
reported (9, 10, 11, 12). All transplantation procedures were
performed by K. Yasufuku and T. Mizobuchi. The F344WKY transplant
model is associated with the development of mild acute rejection by the
end of the first week and moderate to severe acute rejection by the end
of the second week (9, 11, 17). WKYWKY isografts do not
develop pathologic lesions at any time point posttransplantation.
Survival exceeded 90% in all transplantation groups. No
immunosuppressive therapy was given at any time during the experimental
period.
Induction of oral tolerance by col(V)
As previously reported (9, 10), WKY rats were fed 10 µg of col(V) dissolved in 0.5 ml of saline by a gastric gavage using a 16-gauge ballpoint stainless steel animal feeding needle (Braintree Scientific, Braintree, MA). Animals were fed every other day for eight feedings. Seven days after the last feeding, rats were used as recipients of F344 lung allografts (described above).
Collection of BAL fluid and serum
BAL fluid was obtained from native and transplanted lungs as previously reported (9, 10, 11, 12). Cell-free BAL supernatants obtained from centrifuged specimens were stored at -70°C until use. BAL fluid differential cell counts were performed using light microscopy to count 300 cells/high-power field on cytospin preparations. Serum was obtained by centrifugation of blood obtained by cardiac and venous puncture.
DTH response
DTH responses were performed as reported previously (9, 10). Two weeks after lung transplantation, untreated or col(V)-fed (tolerant) lung allograft recipients received 107 irradiated (3000 rad) donor-derived F344 splenocytes in 30 µl of PBS into the right pinnae by s.c. injection using a 26-gauge needle. The left pinnae received an equal volume of diluent and served as the control site. Naive WKY rats were negative controls. The ear thickness was measured with a micrometer caliper (Mitutoyo, Field Tool Supply, Chicago, IL) in a blinded fashion immediately before and 24 h after injection. In other experiments, the DTH to col(V) was determined in naive WKY rats 24 h after adoptive transfer of 4 x 106 lung T cell (LT) 1 or LT3 cells. Fifteen micrograms of col(V) in 30 µl of diluent was injected into the right ear and 30 L of diluent (control) was injected into the left ear. DTH was determined with a micrometer at 24, 48, and 72 h after injection of col(V). Ag-specific DTH response was calculated according to the following formula: specific ear swelling = (right ear thickness at 24 h - right ear thickness at 0 h) - (left ear thickness at 24 h - left ear thickness at 0 h) x 10-3 mm. All data are reported as the mean of triplicate measurements.
Pathological grading
Pathology in native and isograft lungs was scored by a pathology index describing varying degrees of inflammation based on arbitrary units: grade 0, normal lung tissue; grade 1, minimal inflammation; grade 2, mild inflammation; grade 3, moderate inflammation; and grade 4, severe inflammation. Lung allografts were graded for rejection pathology using standard criteria (18). All pathologic gradings were performed by a pathologist (O.W.C.) in a blinded fashion without prior knowledge of the transplantation group.
Generation of T cell lines and adoptive transfer
Graft-infiltrating lymphocytes were isolated from F344 lung allografts 2 wk after transplantation into WKY recipients (11, 12). Two weeks is the time of onset of severe acute rejection (grade 4) and prior studies have shown that graft-infiltrating lymphocytes are derived from the recipient, and not the donor, rat. After mincing the lung, digestion with collagenase (Roche Biochemical, Indianapolis, IN), DNase (Sigma-Aldrich, St. Louis, MO), and Percoll density gradient centrifugation, lung cells were washed in complete medium (RPMI 1640 (Invitrogen, Grand Island, NY), 10% FCS (HyClone, Logan, UT), 1% penicillin/streptomycin, 1% glutamine, and 0.2% gentamicin (all Invitrogen)). Adherent cells were removed by plating cells for 1 h at 37°C. Nonadherent cells were removed and enriched for lymphocytes by passage over nylon wool. col(V)-specific T cell lines were generated by repeated stimulation of the T cell-enriched lymphocytes (3 x 105) with col(V) (40 µg/ml) and irradiated WKY splenocytes (1.5 x 105; irradiated, 3000 rad) every 7–10 days. Cloning of T cells was performed by limiting dilution, and two col(V)-reactive lines (LT1 and LT3) were isolated.
In some experiments, 4 x 106 LT1 or LT3 cells were adoptively transferred into WKY rats by tail vein injection.
Proliferation assays
Lung lymphocytes (3 x 105/well) obtained from either normal F344 rats or graft-infiltrating lymphocytes from F344 lung allografts were plated in U-bottom 96-well microtiter plates (Costar, Cambridge, MA) with 1.5 x 105 irradiated WKY splenocytes (APC) in 200 µl of complete medium. These cells were cultured with and without col(II) and col(V) (40 µg/ml) and incubated for 4 days at 37°C in 5% CO2. For T cell lines, 2 x 103 allograft T cells were incubated with 1 x 103 APC (F344 or WKY) with or without collagens for 48 h at 37°C in 5% CO2. Eighteen hours before the end of a 4-day coculture, cells were pulsed with [3H]thymidine. Proliferation was determined from the mean ± SEM cpm of [3H]thymidine incorporation in triplicate cultures.
Quantitation of cytokines
Cells were cocultured with stimulators for 3 days in either
complete medium (assays for IL-2, IL-4, IL-10, TNF-
, and IFN-) or
serum-free hybridoma medium (assays for TGF--hybridoma-serum-free
medium; Invitrogen) in the absence or presence of col(V) and
supernatants were assayed for cytokines. TGF- levels in culture
supernatants were quantitated by ELISA using a TGF-1 immunoassay
system (Promega, Madison, WI) per the manufacturer’s protocol. IL-2,
IL-4, IL-10, TNF-, and IFN- levels were quantitated by ELISA
using Cytoscreen immunoassay kits (BioSource International, Camarillo,
CA) per the manufacturer’s protocol.
Flow cytometry
Phenotypes of cell lines were determined using FITC-labeled anti-rat CD4, CD8, CD5, CD25, and OX40 Abs from BD PharMingen (San Diego, CA). All appropriate control Abs were obtained from BD PharMingen. Cells were analyzed on a FACSCalibur flow cytometer (BD Biosciences, Mountain View, CA).
RT-PCR
Expression of the TCRs V- domains from the cell lines and
normal T cells was performed by RT-PCR using rat V--specific primers
(19). Total RNA extraction was performed using an RNeasy
Mini kit (Qiagen, Valencia, CA) according to the manufacturer’s
instructions. Approximately 15 µg of total RNA was reverse
transcribed into first-strand cDNA by using a cDNA Cycle kit
(Invitrogen) according to the manufacturer’s instructions. The cDNA
was used for enzymatic amplification with specific TCR V- element
primers and a common constant region C- primer. The PCR mixture
consisted of 5 µl of cDNA, 45 µl of Platinum PCR SuperMix
(Invitrogen), and a 200 nM final concentration of the respective TCR
C- and V- primers. Amplifications were performed with an iCycler
Thermal Cycler (Bio-Rad, Hercules, CA) by preheating at 95°C (2 min),
then denaturation at 95°C (40 s), annealing at 55°C (2 min), and
extension at 72°C (1 min) over 5 cycles. This was followed by
denaturation at 95°C (1 min), annealing at 55°C (20 s), and
extension at 72°C over 30 cycles with a prolonged 10 min extension
during the last cycle. Primers used are shown in Table I
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1,
V7, V8.1, and V8.2 primers were used for PCR and RT-PCR. For
the PCR, dNTPs, Taq DNA polymerase, primers, and buffer
described above were mixed with 1 µg of RNA as template. RT-PCR was
performed using the conditions described above. Results showed that
amplified products were present only after RT-PCR and not PCR,
indicating that the rearranged V- genes post-RT-PCR were derived
from RNA and not DNA. Statistics
All data are expressed as the mean ± SEM. Differences between groups were determined by ANOVA. Results were considered statistically different if p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In theory, in order for col(V) to become an Ag, graft-infiltrating
immune cells would need to be exposed to col(V) during the rejection
response. col(V) is located in the perivascular and peribronchiolar
tissues (20, 21) which are sites of rejection activity and
which undergo remodeling during rejection. The remodeling process could
result in the release of col(V) fragments into the local environment.
Therefore, we determined whether lung allograft rejection was
associated with local release of col(V) fragments. To conduct these
studies, Western blots for col(V) were performed on BAL fluid obtained
from F344 lung allografts undergoing severe acute rejection, WKY
isograft lungs, as well as normal WKY rats. Fig. 1 shows that col(V) peptides were not
detected in BAL fluid in the normal lung. In contrast, col(V) fragments
(116 kDa) were detected in BAL fluid of allografts undergoing rejection
and in isograft BAL. col(II), found in cartilage, but not the lung and
a control for these studies, was not detected by Western blotting (data
not shown).
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shows
that both cell lines were CD4+ (> 97% pure) and
expressed negligible levels of CD5, and CD25, markers of autoreactive T
cells in some studies (22) and activated and/or regulatory
T cells (23, 24), respectively. OX40 another marker
of activated T cells (25), was not expressed at
significant levels (Table II). Fas (CD95) was expressed on 19.86% of
LT1 cells and 10.82% of LT3 cells.
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A shows that the cell
lines isolated from lung allografts during rejection proliferate in
response to col(V) in a dose-dependent manner in vitro. In contrast to
col(V), which is present in the lung, col(II) did not induce
proliferation in these cells (data not shown). We next determined
whether col(V) induced comparable proliferation in the cell lines and
the Ag specificity of these cells. Fig. 2B shows that both
LT1 and LT3 cell lines do not proliferate in response to autologous
(WKY) APC, but that col(V) presented by autologous APC induces vigorous
proliferation in both cell lines. Significantly, the proliferative
response to col(V) is Ag specific since neither cell proliferated in
response to allogeneic (F344) APC, either alone or in the presence of
col(V) (Fig. 2C).
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expression of the TCR was examined by RT-PCR to determine the
clonality of the cell lines. Compared with CD4 cells from normal WKY
rats, Fig. 3 shows that both cell lines
displayed limited variability in TCR V- expression. Although both
cell lines express V-5, 9, 16, and 8.2, only LT1 expresses V-4
and 8.1. In contrast, compared with LT1, only LT3 expresses V-7.
Germline DNA was not found as a contaminant in any specimens as
determined using PCR and the sizes shown are very similar to that
reported for CD4+ T cells in rats with the same
haplotype (19).
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To further evaluate the potential function of LT1 and LT3, the Th1
(IL-2, TNF-, IFN-) and Th2 (IL-4 and IL-10) cytokine profiles
were determined for these cells. Table III shows that neither cell produced
IL-10, IL-4, or IL-2 constitutively. Culturing the cells in the
presence of either col(V) or autologous APC did not induce production
of IL-10, IL-4, IL-2, or IFN-. Both cells produced low levels of
TNF- that was enhanced upon coculture with APC. In contrast, col(V)
presented by APC induced the production of low levels of IL-2, IL-10,
and TNF- and the vigorous production of IFN-. Presentation of
col(V) by APC did not induce production of IL-4.
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col(V) is present in the normal lung and could be a target of
col(V)-specific T cells. To determine whether LT1 or LT3 would induce
disease in normal lungs, each cell type (4 x
106) was adoptively transferred into normal WKY
rats followed by an assessment of lung histology 1 wk later. Neither
cell type induced any pathologic lesions in the lungs of recipient
healthy normal rats (data not shown). Since col(V) may be a sequestered
Ag in the lung and not exposed unless there is local inflammation, we
repeated these studies in WKY rats that received isograft lung
transplants 24 h after adoptive transfer of the cell lines.
Isograft lungs are exposed to ischemia and reperfusion, which could
lead to mild inflammation locally. Fig. 4
shows that under normal conditions macrophages comprise nearly 97% of
cells in BAL with similar amounts in native and isograft lungs in WKY
rats, and that few cells are polymorphonuclear leukocytes (PMN).
Adoptive transfer of LT3 cells before transplantation induced a slight,
but measurable increase in the quantity of PMN in both native and
isograft lungs compared with normal rats. Adoptive transfer of LT1
cells resulted in a greater influx of PMN in native lungs compared with
rats that received LT3 cells (p < 0.05). The
transfer of LT1 cells resulted in a marked increase in the percentage
of PMN in isograft lungs, comprising nearly 45% of total BAL cells
(p < 0.05).
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A shows that adoptive
transfer of LT1 induced discoloration and induration of the entire
isograft lung and the apex of the native lung. Tissue sections of the
isograft lungs reveal extensive edema, peribronchiolar and perivascular
inflammation (Fig. 5C), with less severe inflammation in the
native lungs (Fig. 5D). In contrast, Fig. 5E
shows that adoptive transfer of LT3 did not induce alterations in the
gross anatomy of isograft or native lungs or histology (Fig. 5, F and G). The severity of disease induced by
adoptive transfer of LT1 and LT3 cells was quantitated by a pathology
index shown in Fig. 6. The pathology
indices of the native and isograft lungs from rats that received LT1
cells were significantly greater than that observed from rats that
received LT3 cells (p < 0.001 for native lungs
and p < 0.05 for isograft lungs).
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shows that adoptive transfer of LT1,
but not LT3, induced strong DTH responses to col(V), and a significant
DTH response persisted for at least 72 h postadoptive
transfer.
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A shows that allografts in
untreated recipients develop severe acute rejection 2 wk after
transplantation (grade 4), whereas col(V)-induced oral tolerance
results in only mild rejection in the allograft (grade 2, Fig. 8B) (9). Fig. 8C shows that adoptive
transfer of LT3 to a tolerant recipient did not affect rejection
pathology (grade 2). In contrast, Fig. 8D shows that
adoptive transfer of LT1 cells abrogated col(V)-induced oral tolerance,
which resulted in severe acute rejection (grade 4).
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shows that before adoptive transfer,
tolerant rats have reduced DTH responses to donor Ags as compared with
untreated allograft recipients. However, adoptive transfer of LT1 cells
to tolerant lung allograft recipients resulted in recovery of DTH
responses to donor Ags (Fig. 9). Adoptive transfer of LT3 to tolerant
recipients’ cells had no effect on DTH responses to donor Ags
(Fig. 9).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The basis for alloimmunity is the recognition of polymorphisms present in donor (allogeneic) MHC molecules. The importance of these polymorphisms is demonstrated by studies showing that minimizing polymorphisms between donor and recipient MHC molecules results in diminished rejection responses and improved outcomes for the allograft recipient (3, 30). However, data in the current study and our prior reports demonstrate that col(V), a molecule that is highly conserved among individuals and species, is a target of the rejection response in the lung. Therefore, these data demonstrate immune responses to a "self-"Ag, as well as alloimmunity, are involved in the pathogenesis of lung allograft rejection.
Although the role of self or autoantigens in alloimmunity has been
controversial, recent studies confirm a role for these Ags in the
rejection of allografts other than the lung (4, 5, 6, 7, 8, 31).
Fedoseyeva et al. (7) reported that cellular and humoral
autoimmunity to cardiac myosin contributes to cardiac allograft
rejection. Although the role of another self-Ag is more controversial
(reviewed in Ref. 31), Duquesnoy et al. (6)
reported that immune responses to heat shock protein 65 also
participated in rejection of cardiac allografts. Additionally, immune
responses to the -chains of type IV collagen have been reported to
contribute to the rejection of renal allografts in patients with a
congenital disease known as Alport’s syndrome (32, 33, 34).
The importance of the immune response to these collagens in renal
allograft rejection in these patients is exemplified in a recent study
that recognized -chains 3, 4, and 5 of type IV collagen as
alloantigens (34).
Data shown in Fig. 1
could explain how col(V) becomes an Ag during the
rejection response. col(V) is considered a minor collagen in the lung
and is believed to be complexed within type I collagen, the major
collagen in the lung (20, 21). These collagens are located
in the perivascular and peribronchiolar tissues. During rejection and
inflammation, these tissues undergo extensive remodeling, mediated in
part by activity of metalloproteinases (MMP) capable of cleaving
collagen molecules. Indeed, a study from Trello et al.
(35) showed that lung allograft rejection is associated
with up-regulated activity of MMP-2 and MMP-9, both of which are
capable of cleaving col(V) (36). Using the same transplant
model reported in the current study, we have confirmed the activity of
MMP-2 and MMP-9 in F344 lung allografts during severe acute rejection
(D. S. Wilkes, unpublished observations). Data in the current
study also showed that adoptive transfer of LT1 cells into rats that
received isograft lungs, but not normal rats, induced pulmonary
disease. These data may be explained by the fact that the
transplantation procedure itself is associated with
ischemia-reperfusion injury causing a mild form of perivascular and
peribronchiolar edema, resulting in access of these tissues to
infiltrating lymphocytes. Indeed, Yano et al. (37)
reported that ischemia-reperfusion injury in lung allografts is
associated with MMP-9 expression, a process that could expose
col(V)-rich sites to infiltrating T cells. Therefore, we hypothesize
that remodeling of the allograft may contribute to the rejection
response by creating col(V) peptides that induce alloreactivity,
ultimately playing a role in allograft destruction. This hypothesis is
supported by our ongoing studies in human lung allograft recipients
showing that the presence of col(V) fragments in allograft BAL fluid
and immunoreactivity to col(V) may portend a poor prognosis due to
progressive BO (D. S. Wilkes and W. Burlingham, manuscript in
preparation). Similar to a theory proposed by Fedoseyeva et al.
(7) in studies of cardiac allograft rejection, we propose
that strategies that prevent remodeling and release of antigenic
self-peptides/proteins may result in decreased morbidity and mortality
in lung allograft recipients.
In the data presented, two col(V)-specific T cell lines were isolated,
both were CD4+: LT1, which was pathogenic, and
LT3, which did not induce disease when adoptively transferred into the
host. Data in Fig. 3 show that compared with normal
CD4+ T cells these two cells have very limited
variability in V- expression. The major differences between LT1 and
LT3 are in expression of V-4, 7, and 8.1. Although V- 8.2
expression has identified autoreactive T cells in experimental
autoimmune encephalitis, a rat model similar to multiple sclerosis
(38, 39, 40), the expression of this V- in the current
study was present on both cell lines. These data suggest that, unlike
other diseases of autoreactivity, the expression of V8.2 is not
associated with col(V) reactivity or lung allograft rejection. The
other V sequences expressed in either cell line have not been
attributed to the induction of disease in other studies of allo- or
autoimmunity (41).
Data showing that LT1 and LT3 have differential effects when adoptively
transferred and differ in V- expression suggest multiple mechanisms
for their function. One possibility is that the cells recognize
different epitopes on col(V). However, differing affinities of the TCR
for col(V) could account for these differences. In addition, variable
expression of costimulatory molecules required for T cell activation or
differential expression of CD4 could explain some of these findings.
These mechanisms and the epitopes of col(V) recognized by LT1 and LT3
will be investigated in future studies.
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Footnotes |
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2 M.A.H. and T.M. contributed equally to this work and are considered co-first authors.
3 Address correspondence and reprint requests to Dr. David S. Wilkes, Division of Pulmonary and Critical Care Medicine, Indiana University School of Medicine, 1001 West Tenth Street, OPW 42 5, Indianapolis, IN 46202. E-mail address: dwilkes{at}iupui.edu
4 Abbreviations used in this paper: BO, bronchiolitis obliterans; col(V), type V collagen; DTH, delayed-type hypersensitivity; col(II), type II collagen; BAL, bronchoalveolar lavage; PMN, polymorphonuclear leukocyte; MMP, metalloproteinase; LT, lung T cell.
Received for publication February 7, 2002. Accepted for publication May 20, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, T helper 1/T helper 2 cytokines, IgG subclasses, and pathology in a rat model of lung transplantation. J. Immunol. 159:4084.[Abstract]
, 2, 3) collagens of cartilage. J. Biol. Chem. 260:10761.14 NK T cells. J. Immunol. 166:662.3(IV) collagen alloantibodies in Alport syndrome. Kidney Int. 45:721.[Medline]
3(IV) collagen alloantibodies in Alport syndrome. Kidney Int. 47:1199.[Medline]
3, 4, and 5 chains of type IV collagen as alloantigens for Alport posttransplant anti-glomerular basement membrane antibodies. Transplantation 69:679.[Medline]
5.2 and V6.1 CDR2 peptides. J. Immunol. 152:2520.[Abstract]
8.2 TCR spectratype in the central nervous system of rats with chronic relapsing EAE. J. Immunol. 161:6993.This article has been cited by other articles:
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  T. Iwata, A. Philipovskiy, A. J. Fisher, R. G. Presson Jr., M. Chiyo, J. Lee, E. Mickler, G. N. Smith, I. Petrache, D. B. Brand, et al. Anti-Type V Collagen Humoral Immunity in Lung Transplant Primary Graft Dysfunction J. Immunol., October 15, 2008; 181(8): 5738 - 5747. [Abstract] [Full Text] [PDF]
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 J. L. Bobadilla, R. B. Love, E. Jankowska-Gan, Q. Xu, L. D. Haynes, R. K. Braun, M. S. Hayney, A. Munoz del Rio, K. Meyer, D. S. Greenspan, et al. Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation Am. J. Respir. Crit. Care Med., March 15, 2008; 177(6): 660 - 668. [Abstract] [Full Text] [PDF]
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 B. Mahesh, H.-S. Leong, A. McCormack, P. Sarathchandra, A. Holder, and M. L. Rose Autoantibodies to Vimentin Cause Accelerated Rejection of Cardiac Allografts Am. J. Pathol., April 1, 2007; 170(4): 1415 - 1427. [Abstract] [Full Text] [PDF]
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S. A. Daud, R. D. Yusen, B. F. Meyers, M. M. Chakinala, M. J. Walter, A. A. Aloush, G. A. Patterson, E. P. Trulock, and R. R. Hachem Impact of Immediate Primary Lung Allograft Dysfunction on Bronchiolitis Obliterans Syndrome Am. J. Respir. Crit. Care Med., March 1, 2007; 175(5): 507 - 513. [Abstract] [Full Text] [PDF]
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A. Bharat, R. C. Fields, E. P. Trulock, G. A. Patterson, and T. Mohanakumar Induction of IL-10 Suppressors in Lung Transplant Patients by CD4+25+ Regulatory T Cells through CTLA-4 Signaling J. Immunol., October 15, 2006; 177(8): 5631 - 5638. [Abstract] [Full Text] [PDF]
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D. S. Wilkes, T. M. Egan, and H. Y. Reynolds Lung Transplantation: Opportunities for Research and Clinical Advancement Am. J. Respir. Crit. Care Med., October 15, 2005; 172(8): 944 - 955. [Abstract] [Full Text] [PDF]
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 C. Ponticelli Renal transplantation 2004: where do we stand today? Nephrol. Dial. Transplant., December 1, 2004; 19(12): 2937 - 2947. [Abstract] [Full Text] [PDF]
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 K. A. Swanson, Y. Zheng, K. M. Heidler, T. Mizobuchi, and D. S. Wilkes CDllc+ Cells Modulate Pulmonary Immune Responses by Production of Indoleamine 2,3-Dioxygenase Am. J. Respir. Cell Mol. Biol., March 1, 2004; 30(3): 311 - 318. [Abstract] [Full Text] [PDF]
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), APC alone (
), T cells
plus APC (
), and T cells plus APC plus col(V) (
).
), 
