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T cell activation is a proximal event in the initiation of chronic rejection
that may ultimately lead to obliterative bronchiolitis (OB) after lung
transplantation. In addition to primary signals generated by the T cell
receptor, T cell activation relies on costimulatory signals, of which the
most important are mediated via interaction between CD28 and its
ligands B7-1 and B7-2. In nontreated rat tracheal allografts, B7-2, but
not B7-1, expression peaked 10 d after transplantation, unlike in syngeneic grafts, where no B7-2 upregulation was observed. Selective
blockade of the CD28/B7-1 T cell costimulatory pathway by a mutant
form of CTLA4Ig (cytotoxic T lymphocyte antigen 4 immunoglobulin),
CTLA4IgY100F, did not affect epithelial injury or degree of luminal occlusion in rat tracheal allografts. Treatment with CTLA4Ig fusion protein, which blocks both CD28/B7-1 and CD28/B7-2 interaction, significantly delayed the development of epithelial injury and airway
occlusion. Immunohistochemical analyses of allografts showed that selective inhibition of the CD28/B7-1 pathway did not affect cytokine expression. In contrast, treatment with CTLA4Ig was associated with a
significant decrease in the intragraft production of tumor necrosis factor 
, interleukin 2, and interferon 
, as well as slightly increased intragraft expression of interleukin 10. In conclusion, CTLA4Ig-mediated costimulatory blockade delays epithelial injury and attenuates obliterative changes and is associated with marked suppression of helper T
cell type 1 (Th1)-dominated cytokine response. These observations
emphasize the role of the CD28/B7-2 costimulatory pathway in regulating proinflammatory and Th1 cytokine responses and thereby in
the development of epithelial and graft injury gradually leading to
obliteration of the airway lumen.
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Keywords: lung transplantation; obliterative bronchiolitis; T cell costimulation
Obliterative bronchiolitis (OB) as a manifestation of chronic rejection constitutes a major problem after lung and heart- lung transplantation (1). The heterotopic rat tracheal allograft model is well-established for the investigation of experimental OB after transplantation (2). In this model, nonimmunosuppressed allografts develop a fibroproliferative lesion closely resembling histological changes of OB in humans. However, the regulatory and effector mechanisms underlying the disease process remain incompletely known. It is postulated that macrophage and T cell activation plays a critical role in the initiation of the delayed-type hypersensitivity reaction leading to cytokine and growth factor production, culminating in epithelial damage, smooth muscle cell (SMC) proliferation, and gradual occlusion of the airway lumen (8).
In addition to signals generated by the T cell receptor (TCR) on recognition of a peptide presented by antigen-presenting cells (APCs), T cell activation depends on costimulatory signals. The most important costimulatory pathway is mediated via interaction between CD28 and its ligands B7-1 (CD80) and B7-2 (CD86) expressed on APCs (9, 10). Blockade of this interaction results in inhibition of T cell proliferation and cytokine production. In addition, blocking CD28/B7-mediated T cell costimulation by CTLA4Ig (anti-cytotoxic T lymphocyte-associated protein 4 immunoglobulin) inhibits the development of OB (11) as well as other forms of chronic allograft rejection (12).
This study was undertaken to investigate the effect of early blockade of CD28/B7 in the pathogenesis of OB. To differentiate between CD28/B7-1 and CD28/B7-2 interaction, we used human and murine CTLA4Igs that block both CD28/B7-1 and CD28/B7-2 costimulation as well as a mutant form of CTLA4Ig, CTLA4IgY100F, that blocks only CD28/B7-1 interaction (15). In addition, we studied the effects of CTLA4Ig on the intragraft cytokine profile.
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Rats
Specific pathogen-free inbred male DA (AG-B4, RT1a) and WF (AG-B2, RT1u) rats weighing 200-300 g and 2-3 mo of age (Laboratory Animal Center, University of Helsinki, Helsinki, Finland) were used. Tracheal grafts were transplanted from DA donors to DA recipients (syngeneic) or from DA to WF recipients (allografts) as described previously (4). Rats received humane care in compliance with the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH Pub. No. 80-23, revised 1978). Proposed animal experiments received approval from the regional government of southern Finland.
Treatment Protocols
Both human and murine CTLA4Ig, its mutant counterpart CTLA4I gY100F, and control IgG were generously provided by R. Peach (Bristol-Myers Squibb, Seattle, WA). Two groups (n = 10/group) were given human CTLA4Ig (hCTLA4Ig), murine CTLA4Ig (mCTLA4Ig), hCTLA4IgY100F, or mCTLA4IgY100F (0.5 mg, intraperitoneal) 2 d after transplantation. Controls (n = 10/group) received normal hIgG or mIgG. The grafts were removed 30 d after transplantation for histological assessment. A detailed immunohistochemical analysis was performed on Day 10 to examine how CD28/B7 blockade modulates production of mediators of inflammation in tracheal grafts.
Histological Evaluation and Morphometry
Each grafted trachea was excised, embedded in Tissue-Tek (Miles,
Elkhart, IN), snap frozen in liquid nitrogen, and stored at 
70° C until
used. For histological evaluation, frozen sections were stained with
Mayer's hematoxylin-eosin. Epithelial necrosis was defined as the
percentage of the circumference of the trachea not lined by epithelium. luminal occlusion was evaluated by determining the reduction in
luminal area, using public domain NIH Image program version 1.59 (National Technical Information Service, Springfield, VA).
Immunostaining
Immunohistochemical analyses were performed by the avidin-biotin
complex (ABC) method (Vectastain Elite ABC kit; Vector Laboratories, Burlingame, CA) (4). The following antibodies were used: mouse monoclonal antibodies against rat B7-1 (22660; PharMingen, San Diego, CA), B7-2 (22670, PharMingen), interleukin 4 (IL-4) (MRC OX-81;
Serotec, Oxford, UK), and IL-10 (24061, PharMingen); rabbit polyclonal antibodies against interleukin 1
(IL-1) (80-3688-01; Genzyme
Diagnostics, Cambridge, MA), IL-2 (sc-7896; Santa Cruz Biotechnology, Santa Cruz, CA), and tumor necrosis factor (TNF-) (IP-310;
Genzyme Diagnostics); and a goat polyclonal antibody against interferon (IFN-) (sc-9344; Santa Cruz Biotechnology). Specificity controls were performed with the same immunoglobulin concentrations
of species- and isotype-matched antibodies. None of the control stainings showed any immunoreactivity.
The results are expressed as number of positive cells per cross-section for B7-1, B7-2, IL-2, IL-4, and IL-10 or semiquantitatively from 0 to 3 for IL-1, TNF-, and IFN- when staining was intense and multifocal, disallowing counting of separate cells (0, no visible staining; 1, few cells with faint staining; 2, moderate intensity with multifocal
staining; and 3, intense diffuse staining of the cells analyzed).
Statistical Analyses
All data are expressed as means ± SEM. In all analyses, the nonparametric multiple comparison Kruskal-Wallis test was used (Statview 512+ program; Brain Power, Calabasas, CA). The resulting rank sums were used for the Dunn test at significance levels of 5% and 1% to assess the level of statistical significance (Medstat; Astra Group, Copenhagen, Denmark). p < 0.05 was regarded as statistically significant.
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Expression of B7-1 and B7-2 in Tracheal Allografts
In normal trachea as well as syngeneic and allogeneic grafts, B7-1 expression was detected in a few scattered graft-infiltrating mononuclear cells (Figures 1A and 1C). In normal trachea, B7-2 expression was constitutive and localized to mononuclear cells underlying the epithelium. Syngeneic transplantation did not influence B7-2 expression. In allografts, B7-2 expression peaked at 10 d and was localized mainly to mononuclear cells of the allograft airway wall (Figures 1B and 1C, p = NS).
|
,
Syngeneic graft; 
, allogeneic
graft.
Effect of CD28/B7 Blockade on Tracheal Allograft Histology
In the heterotopic tracheal transplantation model, syngeneic grafts undergo slight epithelial damage due to ischemia but recover quickly thereafter. At 30 d after transplantation, the syngeneic graft is lined with functioning respiratory epithelium and there is no evidence of luminal occlusion by the myofibroproliferative lesion (4). On the other hand, untreated allografts quickly develop severe epithelial necrosis and a myofibroproliferative lesion gradually occluding the tracheal lumen by 30 d (4).
Allografts treated with mIgG showed severe luminal occlusion (75 ± 9%). Treatment with mCTLA4IgY100F and mCTLA4Ig had a slightly beneficial but nonsignificant effect on tracheal occlusion (56 ± 11 and 52 ± 12%, respectively; Figures 2 and 4).
|
, Murine IgG; 
, murine CTLA4IgY100F;
, murine CTLA4Ig.
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At 30 d, hIgG-treated allografts showed severe luminal occlusion (72 ± 8%). hCTLA4IgY100F treatment did not affect tracheal occlusion (69 ± 5%), compared with hIgG-treated allografts (p = NS). In contrast, administration of human CTLA4Ig halved tracheal obliteration in comparison with hIgG treatment (33 ± 10%, p < 0.05). As only hCTLA4Ig showed efficacy, we excluded the murine forms of CTLA4Ig and CTLA4IgY100F from further analyses on Day 10.
At 10 d after transplantation, severe epithelial necrosis was recorded in hIgG-treated allografts. Treatment with hCTLA4 IgY100F failed to preserve the epithelium, whereas hCTLA4Ig-treated allografts showed significantly reduced epithelial necrosis in comparison with hIgG-treated allografts (p < 0.05; Figure 3). No differences in luminal occlusion between the groups could be identified at 10 d (Figures 3 and 4; p = NS).
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Effect of CD28/B7 Blockade on Tracheal Allograft Cytokine Expression
Tracheal allograft cytokine expression was determined at 10 d,
the time of peak inflammatory response (Figure 5, and Figure E1 in the online data supplement). Whereas mutant form
hCTLA4IgY100F treatment had no influence on intragraft cytokine expression, hCTLA4Ig treatment was associated with significant suppression of helper T cell type 1 (Th1)-like immune
responses as expression of both IL-2 and IFN- was markedly
reduced by hCTLA4Ig treatment (p < 0.05). Also, expression of
TNF- was significantly lower in hCTLA4Ig-treated allografts
(p < 0.05). Furthermore, there was a trend toward increased expression of the Th2-like cytokine IL-10 (p = 0.06).
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In this paper, we report that B7-2 expression, but not B7-1 expression, peaks in nontreated allografts 10 d after transplantation. We also show that early inhibition of CD28/B7-2, but not
CD28/B7-1, interaction plays a crucial role in the development
of experimental OB by downregulating intragraft proinflammatory cytokine TNF- expression and causing suppression of
Th1-dominated immune response and a trend toward increased
Th2-type immune response, resulting in reduced epithelial injury and obliterative lesions in rat tracheal allografts.
In the heterotopic rat tracheal transplantation model, syngeneic grafts develop slight epithelial damage due to ischemia- reperfusion injury mediated by neutrophils, free radicals, and complement activation. However, after establishing blood supply from the vasculature of the greater omentum, syngeneic grafts quickly recover, and by 30 d after transplantation, the trachea are lined with mucus-secreting epithelium and no luminal occlusion can be observed. In allografts, ischemia- reperfusion injury is followed by acute rejection mediated mainly by CD4+ and CD8+ lymphocytes as well as macrophages, leading to rapid loss of epithelium. Graft injury along with alloimmune activation then lead to increased production of growth factors, such as platelet-derived growth factor (PDGF), that induce migration and proliferation of smooth muscle cells, finally leading to obliteration of the tracheal occlusion (4, 16, 17). Therefore, activation of T cells and macrophages plays a vital role in the pathogenesis of experimental OB in this model. In support of this, we have previously shown that inhibition of proximal alloimmune responses by high-dose cyclosporine treatment prevented epithelial necrosis and luminal occlusion (4). On the other hand, immunosuppressive drugs such as mycophenolate mofetil and 15-deoxyspergualin, which act distally in immune activation, show no significant effect on the development of OB (4). Although our experimental rat tracheal transplantation model mimics the histopathological features of OB seen in humans, there are some limitations to this model that deserve to be addressed. First, the pace of the fibrotic response in tracheal implants is faster than that seen in clinical transplantation, where OB occurs usually months after transplantation. Second, the immune response to donor antigens is being assessed in large airways of rats, which differ significantly from bronchioles in the human lung allograft. The large airways may contain more donor-derived antigen-presenting cells such as dendritic cells and macrophages than small airways of a human lung allograft. Also, the blood supply is different as the blood supply of a tracheal allograft comes from systemic arterioles, which contain more highly oxygenated blood than the bronchial circulation of human lung allograft, which is largely fed by the retrograde flow through bronchopulmonary anastomoses.
In our study, hCTLA4Ig treatment led to decreased epithelial damage by 10 d but not by 30 d after transplantation. This indicates that hCTLA4Ig treatment inhibited and/or delayed the onset of acute alloimmune response but did not completely block it. However, the delay in the initiation of graft injury and Th1-dominated immune response effectively slowed the development of the obliterative lesion, as could be seen 30 d after transplantation. Blockade of CD28/B7 costimulation forms an efficient means of preventing acute cardiac and skin allograft rejection and can induce tolerance in these models (13, 15, 18). CTLA4Ig treatment can successfully inhibit the progression of chronic rejection in heart and tracheal allografts (11, 14). Timing of CTLA4Ig treatment is crucial. Initiation of CTLA4Ig treatment before transplantation proved inefficient (18, 19), whereas a single injection of CTLA4Ig 2 d after transplantation significantly prolonged kidney allograft survival (20) and proved efficient in this study as well. Also, expression patterns of B7-1 and B7-2 differ in that B7-2 is expressed immediately after transplantation, whereas the expression of B7-1 is delayed and can be observed from the third postoperative day on (21). B7-1 inhibition showed efficacy in the prevention of rat cardiac allograft arteriosclerosis when initiated 30 d after transplantation (22) but did not show efficacy in our study or in other studies when given immediately postoperatively (15, 22). The results suggest that interaction between CD28 and B7-2, but not B7-1, is crucial for the initiation of the alloimmune response, but CD28/B7-1 interaction may be required for sustaining the alloimmune response later during the development of chronic lesions (22, 23).
In this study, hCTLA4Ig treatment resulted in marked suppression of Th1-like immune response and a trend toward increased Th2-type cytokine response. Successful treatment of murine kidney allograft rejection by a single injection of CTLA4Ig
was associated with increased expression of Th2 cytokines and
downregulation of Th1 cytokines 1 wk after transplantation
(19). A significant reduction in IL-2 and IFN- mRNA as well
as upregulation of IL-10 mRNA expression were observed in
CTLA4Ig-treated rat cardiac allograft recipients (24), and
Russell and coworkers linked attenuation of chronic rat heart
allograft rejection by CTLA4Ig to decreased expression of
IFN- (14). As the mutant form of hCTLA4Ig had no effect
on the intragraft cytokine profile in this study, CD28/B7-2 interaction may be required for the efficient development of a Th1-dominated immune response in vivo in the alloimmune
setting. In contrast, in models of airway hyperresponsiveness,
CD28/B7-2 blockade seems to inhibit primarily Th2 responses
(25, 26), and during experimental mouse leishmaniasis CTLA4Ig
treatment resulted in protective upregulation of Th1 cytokines
(27). Therefore, CTLA4Ig treatment apparently does not inherently drive cytokine expression in either direction, but
rather mediates its effects by inhibiting the dominant type of
Th response. Another interesting finding in this study was the
reduced expression of proinflammatory cytokine TNF- in
the hCTLA4Ig-treated allografts. This finding implies that inhibition of T cell costimulation results in reduced TNF- secretion by activated T cells and/or reduced macrophage activity,
possibly via reduced expression of IFN- and other macrophage-activating cytokines. In addition to playing a central
role in the alloimmune response by producing proinflammatory cytokines, macrophages secrete growth factors, such as
PDGF, that increase migration and proliferation of smooth
muscle cells, which can occlude the airway lumen. Supporting this, CTLA4Ig treatment resulted in reduced expression of
TNF- and PDGF in kidney allografts (28).
The role of the CD28/B7 costimulatory pathway in the pathogenesis of inflammatory lung diseases has been studied extensively. B7-2 seems to be expressed markedly more than B7-1 in lung tissue as seen in mice with hypersensitivity pneumonitis (29) as well as in our study. Therefore, B7-2 is likely to be more important than B7-1 in inflammatory responses of the lung, but B7-1 may play a complementary role in these immune responses, for mice having germ line deletions of either B7-1 or B7-2 showed reduced ovalbumin-induced airway hyperresponsiveness (30). The role of B7-2 is further highlighted by the finding that, in the pathogenesis of ovalbumin-induced airway hyperresponsiveness, selective inhibition of CD28/B7-2, but not of CD28/B7-1, interaction by monoclonal antibodies resulted in similar attenuation of lung inflammation as does CTLA4Ig treatment (25, 26). However, the majority of studies investigating the role of costimulatory blockade in lung inflammation has centered on models of airway hyperresponsiveness that are dominated by a Th2-like immune response. In these models, inhibition of the CD28/B7 interaction tends to decrease Th2-type and increase Th1-type cytokine expression (25, 31, 32). In a model of mouse hypersensitivity pneumonitis in which mice are inoculated with Saccharopolyspora rectivirgula and subsequently develop a Th1-dominated immune response, CTLA4Ig treatment reduced both Th1- and Th2-type cytokine expression and lung inflammation (33).
In this study, the human form of CTLA4Ig was more effective than its murine counterpart. The finding is somewhat contradictory to previous experimental studies that have suggested murine CTLA4Ig to be superior to the human form because of its potential to suppress T cell responses in vitro and in vivo more effectively (34, 35). However, these studies were performed in mice (36, 37), whereas in the majority of rat studies the human form of CTLA4Ig has been applied (28, 38).
In conclusion, hCTLA4Ig-mediated CD28/B7 costimulatory blockade inhibits the alloimmune response, resulting in
decreased intragraft expression of proinflammatory cytokine
TNF- and suppression of the Th1-dominated immune response, and ultimately reduces epithelial necrosis and tracheal
luminal occlusion. Blocking the CD28/B7-1 interaction with
hCTLA4IgY100F, a mutant form of hCTLA4Ig, did not affect
the development of OB, nor did it influence intragraft cytokine expression. The results emphasize the role of the CD28/ B7-2 costimulatory pathway in the initiation of the alloimmune response and suggest that CTLA4Ig may be of use in
the prevention of chronic lung allograft rejection in humans.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Jussi M. Tikkanen, M.D., Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki, Haartmaninkatu 3, 00029 Helsinki, Finland. E-mail: jussi. tikkanen{at}helsinki.fi
(Received in original form July 18, 2001 and accepted in revised form November 19, 2001).
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org
Acknowledgments:
Supported by grants from the Helsinki University Central Hospital Research
Funds, the University of Helsinki, the Juselius Foundation, the Finnish Foundation
for Cardiovascular Research, the Aarne Koskelo Foundation, the Jalmari and
Rauha Ahokas Foundation, the Finnish Medical Society Duodecim, the Farmos
Research Foundation, and the Ida Montin Foundation (Helsinki, Finland).
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