Impact of a Case Series of Corneal Transplant Rejection
on the Kinetics of Cytokine Concentrations
in Human Tears after Keratoplasty
Aki Fuchigami, Jane
Huang, Kyoko Nakajima, Masahiko Kozawa, Kazuhiko Yoshinaga, Eiichi Uchio
Aki Fuchigami, Jane Huang, Masahiko Kozawa, Eiichi
Uchio, Department of Ophthalmology, Faculty of Medicine,
Fukuoka University, Nanakuma, Jonan-ku, Fukuoka city, Japan
Kyoko Nakajima,
Department of
Joint Laboratory for Frontier Medical Science, Faculty of Medicine, Fukuoka
University, Nanakuma, Jonan-ku, Fukuoka city, Japan
Kazuhiko Yoshinaga,
Department of
Research Laboratory for Social Medicine, Faculty of Medicine, Fukuoka
University, Nanakuma, Jonan-ku, Fukuoka city, Japan
Correspondence to:
Aki Fuchigami, Department of Ophthalmology, Fukuoka University School of Medicine,
7-45-1 Nanakuma, Jonan-ku, Fukuoka city 814-0180, Japan
Email:
autumn_men94@yahoo.co.jp
Telephone: +81-92-801 -1011
Fax: +81-92-865-4445
Received: July 14, 2015
Revised: August 31, 2015
Accepted: September 1, 2015
Published online: September 6, 2015
ABSTRACT
AIM: Our purpose was to monitor cytokine levels in tears after
keratoplasty, and to establish correlations with corneal rejection.
Methods: This prospective study included 18
healthy subjects (control group) and 30 patients (31 eyes; treated group) who
underwent penetrating keratoplasty (PKP; N=25) and lamellar keratoplasty
(LKP, N=6). They were followed for at least six months to detect
transplant rejection and evaluate tear fluid composition in cytokines
[interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF), interferon
(IFN)-γ, and IL-17A].
Results: Transplant rejection occurred in four
eyes after PKP, in the first month (N=1), third month (N=2), and
sixth month (N=1). The most abundant cytokines in all groups were IL-6
and IL-17A, whereas IFN-γ was >10-fold higher in the nonrejection group than
in the control and rejection groups. Kinetics analysis showed that IL-6
response was limited to a transient increase during the first 24 h, whereas the
other cytokines accumulated throughout the follow-up period, starting after Day
7. The concentrations of IL-2, IL-4, IL-10, TNF, IFN-γ, and IL-17A spiked 24 h
at least before rejection (P<0.05), and were significantly higher
than those of the nonrejection group (P<0.01), except for IFN-γ.
Conclusion: This study should be some of a useful
step that corneal transplant rejection is preceded by a massive increase in
proinflammatory cytokines that may constitute quantitative predictors of
rejection.
© 2015 ACT. All rights reserved.
Key words: Interferon gamma;
Human tears; Corneal graft rejection; Penetrating keratoplasty; Lamellar
keratoplasty
Fuchigami A, Huang J, Nakajima K, Kozawa M, Yoshinaga K,
Uchio E. Impact of a Case Series of Corneal Transplant Rejection on the Kinetics
of Cytokine Concentrations in Human Tears after Keratoplasty. International Journal of Ophthalmic Research 2015; 1(2): 59-65
Available from: URL: http://www.ghrnet.org/index.php/ijor/article/view/1288
INTRODUCTION
Corneal graft rejection is one of the most significant complications of
corneal transplantation[1-5]. Despite the immunologically privileged
nature of the cornea, immune-mediated graft rejection remains the major cause
of unsuccessful human corneal allograft transplantation[6,7]. The
precise mechanisms leading to graft rejection remains poorly understood.
Therefore, there is currently no quantitative method to predict surgical
outcome or to detect early signs of rejection[8,9].
During corneal
transplant rejection, the inflammatory responses are dominated by T helper cell
type1 (Th1)-type cytokines, such as interleukin-2 (IL-2),
interferon gamma (IFN-γ), or tumor necrosis factor alpha (TNF-α), and
strategies are proposed to restore balance through an upregulation of Th2-type
responses from cytokines, such as interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6
(IL-6), or interleukin-10 (IL-10)[10]. Therefore, the Th1/Th2
factors susceptible of inducing corneal graft rejection after penetrating
keratoplasty (PKP) are indirectly investigated by the determination of cytokine
levels in aqueous humor or tears[11,12]. The expression of cytokines
and chemokines has been monitored after corneal transplant at the mRNA and
protein levels in animal models and at the protein level in the aqueous humor
of human subjects[5,11-17]. The importance and the role of various
cytokines in different inflammatory diseases are well documented, but the
levels and exact contributions of cytokines in human tears in the
postkeratoplasty period are not clarified[13,14]. A recent study
reported the impact of corneal transplant rejection on the kinetic of cytokine
concentrations in the tears of patients after PKP[8]. However, this
study did not include a control group of healthy subjects to compare baseline
cytokine levels before surgery and identify factors predisposing patients to a
poor outcome.
The aim of this study was to examine the signs of corneal graft
rejection using the safety method of collecting tears in a filter paper. We
investigated longitudinal cytokines in human tear fluid with or without
rejection and their correlation with the occurrence of rejection. It has been
previously reported that tear levels of several cytokines showed increase or
decrease before rejection[6]. We report the following seven
different cytokines: IL-2, IL-4, IL-6, IL-10, TNF, IFN-γ, and IL-17A in the
human tears of patients with keratoplasty to evaluate their possible roles in
predicting corneal rejection.
METHODS
and Methods
Study subjects
This prospective study was conducted on 30 consecutive patients who
underwent keratoplasty between August 2011 and September 2012 at the Fukuoka
University Hospital. All subjects were followed for at least six months. This
study also included a group of healthy control subjects, including preoperative
patients who underwent cataract or vitrectomy but without ocular or systemic
infection or allergy. The control subjects did not take any medication that
would interfere with tear secretion. None of the subjects suffered from any
disease of known immunological origin. All procedures were performed in
adherence to the Declaration of Helsinki for research involving human subjects.
This study was approved by the local ethics committee and written informed
consent was obtained from all participants before sample collection and
surgery.
Subjects
Characteristics
This study included a control group (8 males, 10 females) with mean age
of 39.4±10.3 years and a treated group (17 males, 14 females) with mean age of
64.2±14.6 years. The characteristics of each patient who underwent keratoplasty
are presented in Table 1. Among the 30 treated patients, six patients had
lamellar keratoplasty (LKP) and 25 patients had penetrating keratoplasty (PKP).
Rejection occurred in four PKP eyes, with one case in the first month, two
cases in the third month, and one case in the sixth month. At six months after
keratoplasty, 16% of the PKP eyes had corneal graft rejection. Therefore, the
treated group was separated into a nonrejection group and a rejection group for
the cytokine analysis.
Keroplasty
Procedure
All surgeries were conducted by the same surgeon. The donor material
was preserved in Optisol-GS (Bausch & Lomb, NY) before the surgery. Routine
medication (local corticosteroids and antibiotics) was provided for six months
after keratoplasty. Patients only received systemic anti-inflammatory therapy
(oral corticosteroid or oral immunosuppressant) when an increased risk for
immune reactions was identified.
Diagnosis of
Corneal Transplant Rejection
Corneal endothelial rejection was diagnosed by the onset of an acute
inflammatory episode, combined with endothelial precipitates and/or stromal
edema, which was depicted by increased central corneal thickness.
Collection of
Tear Samples
The anterior ocular status of each subject was
carefully assessed before tear collection. Tear samples were collected at least
15 min after the eye drop instillation. We used antibiotic and steroid drops,
having dwindled it in the order of betamethasone sodium phosphate, dexamethasone
sodium phosphate, and fluorometholone for every 3 months. Corneal endothelial
rejection was diagnosed by the onset of an acute inflammatory episode combined
with endothelial precipitates and/or stromal edema with increased central
corneal thickness. Tear fluid was extracted by the Schirmer method, as
previously described[18]. Tears were sampled on preoperative day 0
and postoperative day 1, day 7, month 1, month 3, and month 6. All samples were
rapidly frozen at −20℃ and maintained at −80℃ until cytokine
analysis. Tear fluid extraction was performed with 0.5 M NaCl and 0.5% Tween 20
in 0.01 M phosphate buffer (pH 7.2).
Measurements of
Cytokine Concentrations
The cytokine composition of the tears was analyzed using the BDTM
(Becton, Dickinson and Company, Franklin Lakes, NJ) Cytometric Bead Array
system and a flow cytometer (BDTM FACS Canto II), according to the
manufacturer’s instructions. Data were acquired and analyzed using the FCAP
ArrayTM software (version 1.0.1, BD Biosciences). Standard curves
were generated using the reference cytokine concentrations supplied by the
manufacturer. The following seven inflammatory cytokines were analyzed: IL-2,
IL-4, IL-6, IL-10, TNF, IFN-γ, and IL-17A.
Statistical
Analysis
All data were expressed as mean±standard deviations
(SD). The treated group was separated into a nonrejection group and a rejection
group for the cytokine analysis. The cytokine concentrations in tear samples of
the control, treated, nonrejection, and rejection groups were compared by
Wilcoxon’s rank-sum test or Mann-Whitney’s test, as deemed appropriate.
Statistical significance was set at p < 0.05.
RESULTS
Impact of Transplant Rejection on the Preoperative
Cytokine Profile
The baseline cytokine concentration profiles of tears
were determined for the control group and before keratoplasty for the
nonrejection and rejection groups (Figure 1). In the control group, all
cytokine concentrations were low (<5 pg/mL), except for IL-6 (26.16 pg/mL)
and IL-17A (21.97 pg/mL). LKP, PKP without rejection and PKP with rejection
were compared. There was no significantly difference between LKP and PKP
without rejection in concentrations of IL-2, IL-4, IL-6, IL-10, TNF, IFN-γ, and
IL-17A (P=0.63, 0.43, 0.63, 0.42, 0.63, 0.43, and 0.63, respectively).
The preoperative concentrations of IL-2, IL-6, IL-10, TNF, and IL-17A in the
rejection group were significantly higher than those in the control group (P=0.0023,
0.0025, 0.0025, 0.0015, and 0.0025, respectively). In contrast, IL-4 and IFN-γ
concentrations were significantly lower in the rejection group than those in
the control group (P=0.0025 and 0.0025, respectively). The preoperative
concentrations of IL-2, IL-4, IL-10, TNF, and IL-17A in the rejection group
were significantly higher those than in the nonrejection group (P=0.0014,
0.0014, 0.0016, 0.0011, and 0.0015, respectively). In contrast, IL-6 and IFN-γ
concentrations were significantly lower in the rejection group than those in
the nonrejection group (P=0.0016 and 0.0016, respectively). The most
remarkable difference between the two treated groups was a five-fold higher
IL-10 concentration in the rejection group than that in the nonrejection group.
Kinetics of
Cytokine Responses after Keratoplasty
Time-course analysis was conducted to compare the
cytokine responses of the nonrejection group and rejection group on
keratoplasty (Figure 2). In the nonrejection group, the concentrations of
proinflammatory cytokines (IL-2, IL-4, IL-10, TNF, and IL-17A) gradually
increased from day 7 until the end of the follow-up (6 months), whereas IL-6
concentration was only elevated during the first week. In contrast,
anti-inflammatory IFN-γ responded to the surgery by an initial decrease in
concentration during the first 24 h at least. Subsequently, the levels gradual
returned to normal over the first month and then drastically decreased during
the remaining five months. The initial increase in IL-6 was the only
significant direct response to surgery in both groups (P<0.01).
Transplant rejection did not significantly affect the kinetics, except for IFN-γ
(P=0.03). In the rejection group, IFN-γ concentration was initially very
low, and remained significantly lower than that in the nonrejection group
during at least the first 30 days postoperation.
Impact of
Rejection Delay on Cytokine Kinetics
The patients who developed transplant rejection 1, 3 or 6 months after
PKP were compared in terms of cytokine responses during the six months
follow-up period (Figure 3). For the patient diagnosed with transplant
rejection after 1 month, the cytokine levels remained very low during the
entire follow-up period. In contrast, the patient diagnosed with transplant
rejection at the three-month follow-up examination showed a transient elevation
of proinflammatory cytokines (IL-2, IL-4, IL-10, TNF, IFN-γ) that was detected
at the one-month follow-up. In contrast, the patient diagnosed with transplant
rejection at the six-month follow-up exam, showed a delayed peak accumulation of
the same proinflammatory cytokines (IL-2, IL-4, IL-10, TNF, IFN-γ) and a peak
for IL-17A at the three-month follow-up visit. In contrast, the timing of
transplant rejection did not affect the IL-6 response, which showed a
consistent peak concentration on day 1 postoperation.
The cytokines
associated with corneal transplant rejection were further assessed by comparing
the concentrations measured in these three patients on day −2, −1, and 0
(onset) of rejection (Figure 4). The large differences detected on Day −1 are
consistent with the gradual accumulation of these cytokines during the
six-month period and delay before rejection onset. The IL-2, IL-4, IL-10, TNF,
IFN-γ, and IL-17A levels increased significantly from Day −2 to Day −1 (P =
0.028, 0.030, 0.028, 0.028, 0.028, and 0.028, respectively) and decreased
significantly from Day −1 to Day 0 (P=0.028, 0.029, 0.028, 0.030, 0.030,
and 0.028, respectively). In contrast, IL-6 levels kept decreasing after
postoperative day 1 and remained very low on Day −1 and Day 0 (P=0.028,
and 0.028, respectively). These data suggest that a combination of cytokines is
involved in corneal transplant rejection after PKP and the cytokine responses
consistently occur within 24 h at least before the onset of rejection.
As the balance of pro- and anti-inflammatory cytokines determines the
inflammatory status of the eye, we calculated the ratio of the average of each
cytokine concentration to that of IL-10. The IL-4/IL-10 and IFN-γ/IL-10 ratios
of these four patients, measured on Day −1 of rejection onset, were
significantly lower than those of the non-rejection group throughout the
follow-up period (P<0.01). We determined the most pertinent ratios.
The ratio of IL-10/TNF-α expression, a measure of cytokine polarization, may be
a better indicator of regulatory function than IL-10 expression alone[19].
We calculated the ratio of IL-10/TNF; however, there was no significant
difference between the rejection and non-rejection groups. We measured these
ratios to determine any significant difference, which was observed in previous
reports[8]. Plasma levels of IFN-γ, IL-4, and their ratios did not
correlate with the rejection or immunosuppressive therapy, Th1/Th2 cytokine
monitoring during the first week post-transplant does not predict early
rejection[20]. We consider that tear levels of IFN-γ, IL-4 reflect
the latest change of rejection rather than the plasma levels. The tendency
observed in the graph was the same as that in the group without rejection if
these ratios are similar on days 29, 89, and 119 of the follow-up, because
these days correspond to Day −1 of rejection onset for the four PKP patients.
DISCUSSION
In the corneal tissue, IL-6 plays
critical roles, including the maintenance of clear corneal button and
stimulation of collagen synthesis and wound healing[21]. These
functions are consistent with the rapid and robust increase in IL-6
concentration we detected during the first 24 h at least after keratoplasty,
the most intensive phase of wound healing. These data are consistent with the
acute increase in IL-6 level reported in the tears of patients after PKP[8].
As the healing process continued, we observed a gradual decrease in IL-6 back
to preoperative levels within one month after surgery. Then IL-6 concentrations
remained low during the remaining five months, even in the rejection patients.
In contrast, previous studies reported an increase in IL-6 concentration in
aqueous humor at the time of corneal transplant rejection[5,14].
These data suggest different kinetics of cytokine levels in the tears and
aqueous humor and that IL-6 plays different roles in these two distinct
environments.
Other cytokines, i.e., IL-1β,
IL-8, and TNF-α, are involved in the neovascularization process[22].
Therefore, the enhanced expression of TNF-α may promote the tissue infiltration
observed after high-risk corneal transplant in patients performed with inflamed
vascular beds[23]. In the cornea, TNF-α expression was found
elevated at the mRNA[13] and protein[24] levels in the
anterior chamber and serum of hosts with rejected corneal allografts. Likewise,
we found a significant increase of TNF levels in the tears of patients sampled
24 h at least before the onset of corneal rejection. It has been suggested that
TNF-α increases the susceptibility of corneal endothelial and epithelial cells
to apoptosis[8]. Therefore, these data are consistent with the role
for TNF in corneal transplant rejection.
IL-17A is a proinflammatory
cytokine that has recently received attention for its role in the pathogenesis
of several autoimmune diseases. IL-17A has also been implicated in cardiac and
renal allograft rejections[25-28]. These reports propose that a
depletion of IL-17A enhances corneal allograft survival. However, Cunnusamy et
al. suggested that IL-17A is essential for the maintenance of corneal immune
privilege and establishes a new paradigm, whereby interactions between IL-17A
and CD4+CD25+ Tregs is necessary for the survival of
corneal allografts[29]. In our study, IL-17A levels decreased before
rejection onset, suggesting a loss of the protective effect of the cytokine.
The most remarkable cytokine
responses were observed from the anti-inflammatory cytokines. First, the
nonrejection groups had >10-fold higher IFN-γ concentrations than those in
the control and rejection groups. The injection of IFN-γ was able to heal
corneal transplant rejection in patients after PKP[30]. Therefore,
the preoperative analysis of tear samples showing high IFN-γ levels would
support a favorable PKP outcome. Second, IFN-γ and IL-10 concentrations
increased >10-fold 24 h before rejection and then decreased back to baseline
level at rejection onset. The reduced level of IL-10 in tears of patients with
endothelial rejection could be an important promoter of transplant rejection.
In animal models, IL-10 had the potential to delay or reduce corneal transplant
rejection[31-33]. IL-10 has been shown to decrease the expression of
MHC class II in monocytes/macrophages, and therefore interfering with their
antigen-presenting function. In addition, IL-10 modulates monocytes by
suppressing the production of their proinflammatory cytokines, such as TNF-α,
IL-1β and IL-8[34]. In our study, the fact that IL-10 concentration
suddenly decreased at the onset of corneal rejection suggests a loss of
protection by this cytokine. Therefore, corneal transplant rejection may be
initiated by a sudden increase in proinflammatory/anti-inflammatory cytokine
ratio.
The main limitations of this
study are the short follow-up period and the irregular sampling intervals.
First, longer follow-up periods are necessary to confirm the differences in
cytokine levels between the rejection and nonrejection group. Second, the
irregular sampling intervals (days to months) may have missed important
fluctuations in cytokine levels. The number of patients of this study was
small. Further investigations are needed.
Therefore, monitoring
cytokines in tear fluid is a simple and noninvasive method to identify
high-risk patients for corneal transplant rejection before PKP (IFN-γ) and to
monitor the first signs of rejection after PKP.
ACKNOWLEDGMENTS
We thank Dr. Sophie for editing
this manuscript.
CONFLICT
OF INTERESTS
The authors have no conflicts of
interest to declare.
REFERENCES
1
King WJ, Comer RM, Huddle T, Larkin
DFP, George AJT. Cytokine and chemokine expression kinetics after corneal
transplantation. Transplantation 2000; 70:1225-1233.
2
Pleyer U, Dannowski H, Volk H-D, Ritter
T. Corneal allograft rejection: current understanding. Ophthalmologica 2001;
215: 254-262.
3
Claesson M, Armitage WJ, Fagerholm P,
Stenevi U. Visual outocome in corneal grafts: a preliminary analysis of the
Swedish Corneal Transplant Register. Br J Ophthalmol 2002; 86: 174-180.
4
Xie L, Shi W, Guo P. Roles of tumor
necrosis factor-related apoptosis inducing ligand in corneal transplantation.
Transplantation 2003; 76: 1556-1559.
5
Funding M, Vorum H, Nexo E, Moestrup
SK, Ehlers N, Moller HJ. Soluble CD163 and interleukin-6 are increased in
aqueous humour from patients with endothelial rejection of corneal grafts. Acta
Ophthalmol Scand 2005; 83: 234-239.
6
Niederkorn JY, Mayhew E, Mellon J,
Hedge S. Role of tumor necrosis factor receptor expression in anterior
chamber-associated immune deviation (ACAID) and corneal allograft survival.
Invest Ophthalmol Vis Sci 2004; 45: 2674-2681.
7
Ritter T, Yang J, Dannowski H, Vogt K,
Volk HD, Pleyer U. Effects of interleukin-12p40 gene transfer on rat corneal
allograft survival. Transplant Immunol 2007; 18: 101-107.
8
Fodor M, Gogolak P, Rajnavolgyi E,
Berta A, Kardos L, Modis L, Facsk A. Long-term kinetics of cytokine responses
in human tears after penetrating keratoplasty. J Interferon Cytokine Res 2009;
29: 375-379.
9
Maier P, Heizmann U, Bohringer D, Kern
Y, Reinhard T. Predicting the risk for corneal graft rejection by aqueous humor
analysis. Mol Vis 2011; 17: 1016-1023.
10
Niederkorn JY. Immunology and
immunomodulation of corneal transplantation. Int Rev Immunol 2002; 21:173-196.
11
Reinhard T, Bocking A, Pomjanski N,
Sundmacher R. Immune cells in the anterior chamber of patients with immune
reactions after penetrating keratoplasty. Cornea 2002; 21: 56-61.
12
Ventura ACS, Engelmann K, Dahinden C,
Bohnke M. Endotoxins modulate the autocrine function of organ cultured donor
corneas and increase the incidence of endothelial cell death. Br J Ophthalmol
1997; 81:1093-1098.
13
Torres PE, De Vos AF, van der Gaag R,
Martins B, Kijlstra A. Cytokine mRNA expression during experimental corneal
allograft rejection. Exp Eye Res 1996; 63: 453-461.
14
van Gelderen BE, van der Lelij A, Peek
R, Broersma L, Treffers WF, Ruijter JM, van der Gaag R. Cytokines in aqueous
humor and serum before and after corneal transplantation and during rejection.
Ophthalmic Res 2000; 32: 157-164.
15
Sano Y, Osawa H, Sotozono C, Kinoshita
S. Cytokine expression during orthotopic corneal allograft rejection in mice.
Invest Ophthalmol Vis Sci 1998; 39:1953-1957.
16
Yamagami S, Kawashima H, Endo H, Tsuru
T, Shibuta H, Kagawa Y, Hori J, Yamagami H, Isobe M. Cytokine profiles of
aqueous humor and graft in orthotopic mouse corneal transplantation.
Transplantation 1998; 66:1504-1510.
17
Zhu S, Dekaris I, Duncker G, Dana R.
Early expression of proinflammatory cytokines interleukin-1 and tumor necrosis
factor-γ after corneal transplantation. J Interferon Cytokine Res 1999;
19:661-669.
18
Shoji J, Kitazawa M, Inada N, Sawa M,
Ono T, Kawamura M, Kato H. Efficacy of tear eosinophil cationic protein level
measurement using filter paper for diagnosing allergic conjunctival disorders.
Jpn J Ophthalmol 2003; 47:64-68.
19
Cherukuri A, Rothstein DM, Clark B,
Carter CR, Davison A, Hernandez-Fuentes M, Hewitt E, Salama AD, Baker RJ.
Immunologic human renal allograft injury associates with an altered IL-10/TNF-α
expression ratio in regulatory B cells. J Am Soc Nephrol 2014; 25:1575-1585.
20
E Granot, A Tarcsafalvi, S Emre, P
Sheiner, S Guy, ME Schwartz, P Boros, CM Miller. Th1/Th2 cytokines and ICAM-1
levels post-liver transplant do not predict early rejection. Mediators Inflamm
2000; 9: 35-38.
21
Ventura ACS, Engelmann K, Dahinden C,
Bohnke M. Endotoxins modulate the autocrine function of organ cultured donor
corneas and increase the incidence of endothelial cell death. Br J Ophthalmol
1997; 81:1093-1092.
22
Torres PF, Kijlstra A. The role of
cytokines in corneal immunopathology. Ocular Immunol Inflammn 2001; 9: 9-24.
23
Yamagami S, Hamrah P, Zhang Q, Liu Y,
Huq S, Dana MR. Early ocular chemokine gene expression and leukocyte
infiltration after high-risk corneal transplantation. Mol Vis 2005; 11:632-640.
24
Pleyer U, Milani JK, Ruckert D, Rieck
P, Mondino BJ. Determinations of serum tumor necrosis factor alpha in corneal
allografts. Ocul Immunol Inflamm 1997; 5:149-155.
25
Li L, Huang L, Vergis AL, Ye H, Bajwa
A, Narayan V, Strieter RM, Rosin DL, Okusa MD. IL-17 produced by neutrophils
regulates IFN-gamma-mediated neutrophil migration in mouse kidney
ischemia-reperfusion injury. J Clin Invest 2010; 120: 331-342.
26
Liao YH, Xia N, Zhou SF, Tang TT, Yan
XX, Lv BJ, Nie SF, Wang J, Iwakura Y, Xiao H, Yuan J, Jevallee H, Wei F, Shi
GP, Cheng X. Interleukin-17A contributes to myocardial ischemia/reperfusion
injury by regulating cardiomyocyte apoptosis and neutrophil infiltration. J Am
Coll Cardiol 2012; 59: 420-429.
27
Loong CC, Hsieh HG, Lui WY, Chen A, Lin
CY. Evidence for the early involvement of interleukin 17 in human and
experimental renal allograft rejection. J Pathol 2002; 197: 322-332.
28
Yuan X, Paez-Cortez J, Schmitt-Knosalla
I, D’Addio F, Mfarrej B, Donnarumma M, Habicht A, Clarkson MR, Iacomini J,
Glimcher LH, Sayegh MH, Ansari MJ. A novel role of CD4 Th17 cells in mediating
cardiac allograft rejection and vasculopathy. J Exp Med 2008; 205: 3133-3144.
29
Klebe S, Sykes PJ, Coster DJ, Krishnan
R, Williams KA. Prolongation of sheep corneal allograft survival by ex vivo
transfer of the gene encoding interleukin-10. Transplantation 2001;
71:1214-1220.
30
Gong N, Pleyer U, Volk HD, Ritter T.
Effects of local and systemic viral interleukin-10 gene transfer on corneal
allograft survival. Gene Ther 2007; 14:484-490.
31
Chen B, Kapturczak MH, Joseph R, George
JF, Campbell-Thompson M, Wasserfall CH, Atkinson MA, Tisher CC, Flotte TR,
Agarwal A, Chen S. Adeno-assoiated viral vector-mediated interleukin-10 prolongs
allograft survival in a rat kidney transplantation model. Am J Transplant 2007;
7:1112-1120.
32
Dallman MJ. Cytokines as mediators of
organ graft rejection and tolerance. Curr Opin Immunol 1993; 5:788-793.
33
Cunnusamy K, Chen PW, Niederkorn JY.
IL-17A-dependent CD4+CD25+ regulatory T cells promote immune privilege of
corneal allografts. J Immunol. 2011; 186:6737-6745.
34
Skurkovich S, Kasparov A, Narbut N,
Skurkovich B. Treatment of corneal transplant rejection in humans with
anti-interferon-gamma antibodies. Am J Ophthalmol 2002; 133:829-830.
Peer reviewers: Lan
Gong, Professor, Department of Ophthalmology, Eye & ENT Hospital of Fudan
University, 83 Fenyang Road, Shanghai, China; Karl Anders Knutsson, Department
of Ophthalmology, San Raffaele Hospital, Università Vita-Salute San Raffaele,
Milan, Italy; Mohammad Soleimani MD, Department of ocular trauma and emergency,
Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Postal
code: 1336616351, Iran.
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