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,
Departments of
* Dermatology and
Ophthalmology, Harvard Medical School, Boston, MA 02114; and
Department of Medicine, Pulmonary Division, Brigham and Women’s Hospital, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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2-treated
peritoneal exudate cells i.v. These mice were then immunized with OVA
plus alum strategy that generates Th2-mediated OVA-specific pulmonary
pathology. When pretreated mice were challenged intratracheally with
OVA, their bronchoalveolar lavage fluids contained far fewer
eosinophils and significantly less IL-4, IL-5, and IL-13 compared with
that of positive, nonpretreated controls. Similarly, lung-draining
lymph node cells of pretreated mice secreted significantly less IL-4,
IL-5, and IL-13 when challenged in vitro with OVA. Moreover, sera from
pretreated mice contained much lower titers of OVA-specific IgE Abs. We
conclude that Ags injected into the anterior chamber of the eye impair
both Th1 and Th2 responses. These results reduce the likelihood that
ACAID regulates Th1 responses via a Th2-like mechanism. Thus, immune
privilege of the eye regulates inflammation secondary to both Th1- and
Th2-type immune responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Moreover, D’Orazio and Niederkorn
(8) showed that ACAID could not be induced in mice
deficient in IL-10. Because Th2 cells can secrete IL-10 and because
IL-10 is regarded as an immune inhibitory cytokine, the failure of
ACAID to develop in IL-10-deficient mice is consistent with the view
that ACAID is dependent upon Th2 responses. Moreover, since Th2-type
immune responses have been often characterized as anti-inflammatory
(10) and since it has been proposed that immune
privilege in the eye exists to suppress inflammation, it is reasonable
to propose that ACAID could be mediated by Th2 cells because ACAID is
linked to the phenomenon of immunologic privilege in the eye and in the
brain (11). Although several experimental diseases of the eye are known to be mediated by Th1 effector cells (experimental autoimmune uveitis (12), herpes simplex keratitis (13)), evidence reported during the past decade has also implicated Th2 cells in the pathogenesis of ocular inflammatory disease. Foster and colleagues (14) reported that inflammation of the cornea in the setting of experimental herpes virus infection of the ocular surface can be mediated by HSV-specific Th2 cells. More recently, Pearlman et al. (15) have characterized a Th2-mediated inflammation of the cornea secondary to ocular infection with Onchocercal volvulus. Thus, since Th2 cells are capable of promoting inflammation of the ocular surface that leads to blindness, it is of interest to know whether functionally similar cells have the ability to mediate ACAID, a process that is believed to inhibit the blinding consequences of inflammation. To this point, it has recently been demonstrated that ACAID can readily be induced in mice in which the IL-4 gene had been disrupted, a genetic lesion that prevents these mice from acquiring Th2-type responses to exogenous Ags (8, 9).
In the present study, we examined the potential role of Th2 cells in
ACAID by determining whether induction of ACAID with OVA promoted or
interfered with the development of a well-characterized model of
OVA-induced experimental allergic lung disease in mice, a Th2-mediated
disease (16, 17, 18). Our results indicate that mice
pretreated with an anterior chamber injection of OVA or with an i.v.
injection of OVA-pulsed ACAID-inducing APCs exposed in vitro to
TGF-2 (19, 20) acquired OVA-specific ACAID and failed
to develop the typical signs of OVA-dependent experimental allergic
lung disease. These findings exclude the possibility that ACAID is
mediated by Th2 regulatory cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c mice were bred in our animal facility or were purchased from Taconic Farms (Germantown, NY) and were used at 8–12 wk of age. All animals were treated according to the Association for Research in Vision and Ophthalmology Statement on the Use of Animals in Ophthalmic and Vision Research. All protocols were preapproved by the Animal Care and Use Committee of the Schepens Eye Research Institute in accordance with National Institutes of Health guidelines.
Administration of Ag by various routes and immunization regimens
For induction of experimental allergic lung disease, the procedure of sensitization and challenge was modified from the method of Kung et al. (16). Briefly, mice were immunized i.p. with 10 µg of OVA (Sigma-Aldrich, St. Louis, MO) mixed with 2.25 mg of aluminum hydroxide (Imject Alum; Pierce, South Iselin, NJ) (alum) in 100 µl of PBS. The animals received a booster i.p. injection of this alum-OVA mixture 7 days later. Five days after the second i.p. injection, mice were intubated and challenged intratracheally (i.t.) with 50 µg of OVA dissolved in 50 µl of PBS.
For intraocular injection, each mouse received a 3-µl inoculation of OVA (50 µg) dissolved in HBSS into the anterior chamber (AC) of the right eye 7 days before sensitization. In some experiments, 50 µg of keyhole limpet hemocyanin (KLH; Calbiochem, Darmstadt, Germany) dissolved in PBS was inoculated into the AC.
For conventional sensitization, mice received a s.c. injection of 100 µg of OVA emulsified in CFA (Life Technologies, Grand Island, NY).
Generation of ACAID-inducing APCs
Serum-free medium was used for generation of ACAID-inducing
APCs. This medium was composed of RPMI 1640 medium, 10 mM HEPES, 0.1 mM
nonessential amino acids, 1 mM sodium pyruvate, 100 U/ml penicillin,
100 µg/ml streptomycin (all from BioWhittaker, Walkersville, MD), and
1 x 10-5 M 2-ME (Sigma-Aldrich)
supplemented with 0.1% BSA (Sigma-Aldrich),
ITS+ culture supplement (1 µg/ml
iron-free transferrin, 10 ng/ml linoleic acid, 0.3 ng/ml
Na2Se, and 0.2 µg/ml
Fe(NO3)3 (Collaborative
Biomedical Products, Bedford, MA). Peritoneal exudate cells (PEC) were
obtained from normal BALB/c mice that received 3 ml of thioglycolate
(Sigma-Aldrich) i.p. 3 days earlier. As described previously, PEC were
washed, resuspended, placed in 24-well culture plates (1 x
106/well), and treated with 5 ng/ml porcine
TGF-2 (R&D Systems, Minneapolis, MN) and 5 mg/ml OVA in serum-free
medium at 37°C in an atmosphere of 5% CO2.
After overnight culture, plates were washed three times with culture
medium to remove TGF-2, Ag, and nonadherent cells. Adherent cells
were harvested by vigorous pipetting and administered to naive mice
i.v. 7 days before subsequent sensitization.
Bronchoalveolar lavage (BAL)
Mice were euthanized by an i.p. injection of sodium pentobarbital 1 or 3 days after i.t. challenge with OVA. The trachea was dissected free from the underlying soft tissues and an 0.58-mm diameter tube was inserted through a small incision in the trachea. BAL was performed 10 times through the tracheal cannula with 1-ml aliquots of pyrogen-free PBS warmed to 37°C. BAL fluid harvested in the first 1 ml was centrifuged and the supernatant was collected and kept at -70°C until use for cytokine assay. A hemocytometer was used to count the total number of BAL cells under phase-contrast microscopy. For differential cell count, cytospin preparations were made and stained with Diff-Quik (Green Cross, Osaka, Japan). A total of 1000 cells was counted to calculate the differential populations of alveolar macrophages, neutrophils, eosinophils, lymphocytes, and monocytes that were identified by standard morphology.
Cytokine production of lung-draining lymph node (LN) cells
Lung-draining LN cells were harvested 1 or 3 days after i.t. challenge with OVA. The LN cells (2 x 105/well) were cultured for 120 h in the absence or presence of OVA (1 mg/ml) in 96-well plates, as first described by Janssen et al. (21). The LN cells were also cultured in a plate coated with anti-CD3 Ab (2C11, 10 µg/ml in PBS). Cells were cultured in medium consisting of RPMI 1640 (BioWhittaker), 10% heat-inactivated FCS (HyClone, Logan, UT), 2 mM L-glutamine, 10 mM HEPES buffer, 100 U/ml penicillin G sodium, 100 µg/ml streptomycin sulfate, and 1 x 10-5 M 2-ME (Sigma-Aldrich). Supernatants were harvested and stored at -70°C until use for cytokine assays.
Cytokine assays
Content of cytokines in BAL and culture supernatants was
analyzed by quantitative capture ELISA, according to the
manufacturer’s instructions for IL-4, IL-5, IFN- (BD PharMingen,
San Diego, CA), and IL-13 (R&D Systems). The detection limits of the
ELISAs were 16 pg/ml for IL-4 and IL-5, 62.5 pg/ml for IL-13, and 290
pg/ml for IFN-. In some experiments, samples were diluted with PBS
containing 2% BSA to an appropriate concentration.
Measurement of OVA-specific IgG1, IgG2a/2b, IgG3, and IgE in sera
Serum samples were taken 10 days after the first sensitization with alum-OVA mixture. The concentration of OVA-specific IgG1, IgG2a/2b, IgG3, or IgE in the serum was determined by sandwich ELISA using alkaline phosphatase-conjugated ExtrAvidin (1/10,000 dilution; Sigma-Aldrich) and substrate p-nitrophenyl phosphate (Sigma-Aldrich) for color development. To determine serum levels of OVA-specific IgE, anti-IgE mAb (R35-72; BD PharMingen) was used as capture Ab and biotin-conjugated OVA was used as detecting reagent. Microtiter plates (96 well) were coated overnight at 4°C with 2 µg/ml anti-IgE mAb diluted in PBS. After blocking with 2% BSA in PBS, diluted serum samples were added to the plate and incubated overnight at 4°C. After washing, biotin-conjugated OVA (2 µg/ml) was added into each well and incubated for 1 h at room temperature before color development. For OVA-specific IgG1, IgG2a/2b, and IgG3, OVA (10 µg/ml in carbonate buffer, pH 9.4) was used as capture reagent and biotin-conjugated anti-IgG1 (A85-1), IgG2a/2b (R2-40), or IgG3 (R40-82) (2 µg/ml; BD PharMingen) was used as detecting Ab. Sera were diluted 100 times for optimal detection of IgG1, IgG2a/2b, and IgG3 and 1/5 for detection of IgE.
Delayed hypersensitivity assay
Mice were challenged by intradermal injection of Ag (200 µg of OVA/10 µl of HBSS) into the ear pinnae 7 days after final exposure to OVA. Ear swelling was measured 24 and 48 h later with an engineer’s micrometer (Mitutoyo; MTI, Paramus, NJ). Mice sensitized with OVA emulsified with CFA 7 days before challenge were used as positive control.
Statistical analyses
In experiments with groups of mice, each group contained at least five animals, and all experiments (both in vitro and in vivo) were repeated at least twice with similar results. The results displayed in the figures are representative of three or more experiments; SEM were calculated from a single experiment. Data were subjected to analysis by Student’s t test as appropriate. A p < 0.05 was considered to be significantly different.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2 on OVA-specific humoral immune responses of
mice with Th2 immunity
The first experiments were designed to determine whether mice
initially exposed to OVA via an intracameral injection were able to
develop the typical Th2-dependent spectrum of Abs when immunized
subsequently with OVA and alum. Panels of adult BALB/c mice received
OVA (50 µg/3 µl) into the AC of one eye. Seven days later these
mice received an i.p. injection of OVA (10 µg) in aluminum hydroxide
(alum), followed 7 days later by a second i.p. injection of OVA plus
alum. Three days later tail vein blood was collected, and sera were
separated and assayed quantitatively by ELISA for levels of
OVA-specific IgG1, IgG2a, IgG2b, IgG3, and IgE Abs. Positive control
mice received two i.p. immunizations with OVA plus alum, but no
intracameral injection of OVA. An additional panel of BALB/c mice
received a s.c. immunization with OVA (50 µg) in CFA; their sera were
collected 10 days later. The results of this experiment are presented
in Fig. 1
A. Mice that received
only i.p. injections of OVA plus alum (positive controls) generated
high titers of OVA-specific IgE and IgG1, but low levels of IgG2a, 2b,
and 3 Abs. By contrast, mice that similarly received i.p. injections of
OVA plus alum following an AC injection of OVA (ACAID group) had barely
detectable levels of OVA-specific IgE, but otherwise their levels of
serum OVA-specific Abs were similar to the positive controls. As
anticipated, mice immunized with OVA plus CFA produced high levels of
IgG2a, IgG2b, and IgG3 Abs, but low levels of IgE and IgG1 (data not
shown).
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2 and OVA. As before, these mice were immunized
subsequently with two i.p. injections of OVA plus alum. Positive
controls received only two i.p. injections of OVA plus alum, while an
OVA-CFA control panel received a single s.c. injection of OVA plus CFA.
The sera obtained from these mice were assayed for OVA-specific Abs. As
revealed in Fig. 1
B, mice that first received OVA-pulsed PEC
treated with TGF-2 displayed low levels of OVA-specific IgE, but
levels of IgG1 and IgG3 that were higher than the positive controls.
Together these findings indicate that mice first exposed to OVA via the
AC or via OVA-pulsed, TGF-2-treated PEC displayed an impaired
capacity to produce IgE Abs when subjected subsequently to an
immunizing regimen that, in normal mice, generated high titer IgE
responses. Thus, the humoral immune response of ACAID is distinctly
different from a typical Th2-type humoral response, and ACAID
suppresses IgE Abs to the Ag first encountered through the AC.
Effects of OVA injected intracamerally or of OVA-pulsed PEC
pretreated with TGF-2 on airway inflammation of mice with a Th2 OVA
pulmonary response
As before, positive control panels of BALB/c mice received an
immunizing regimen of OVA plus alum designed to elicit an experimental
model of allergic asthma. Five days after the second i.p. injection of
OVA plus alum, the mice were challenged i.t. with OVA (50 µg). Three
days later, the mice were euthanized, their bronchoalveolar spaces
lavaged, and the fluid analyzed for its content of cells and cytokines.
Experimental panels were pretreated as before with either an AC
injection of OVA or an i.v. injection of OVA-pulsed, TGF-2-treated
PEC. Negative control mice received only an i.t. challenge with OVA.
The results of these experiments are summarized in Fig. 2. As anticipated, the BAL of positive
control mice contained a significant increase in total cells, compared
with negative controls. By contrast, the BAL obtained from mice
pretreated with OVA in the AC contained no more cells than the BAL of
negative controls. The increased cellular content of positive control
BAL was ascribable to eosinophils, lymphocyte, neutrophils, and
monocytes. Similar results were observed with BAL from mice pretreated
with an i.v. injection of OVA-pulsed, TGF-2-treated PEC (data not
shown). The accumulation of eosinophils in BAL is a characteristic
feature of airway inflammation in experimental allergic lung disease of
this type. Therefore, the virtual absence of eosinophils in the BAL of
mice pretreated with OVA in the AC or by OVA-pulsed, TGF-2-treated
PEC indicates that these pretreatments mitigated this aspect of
Th2-mediated pathology.
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reveal, only
the BAL from mice pretreated with OVA in the AC lacked high
numbers of eosinophils. By contrast, the number of total cells and
eosinophils were comparable to positive controls in the BAL of mice
pretreated in the AC with KLH, but immunized and challenged i.t. with
OVA. Thus, the changes observed in pulmonary inflammation of ocularly
pretreated mice were Ag dependent and specific.
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reveal, the BAL fluids from positive control mice contained large
amounts of all three cytokines, whereas the BAL fluids obtained from
mice pretreated with OVA in the AC contained much lower levels of IL-4,
IL-5, and IL-13. Similar results were obtained with BAL from mice
pretreated with OVA-pulsed, TGF-2-treated PEC (data not shown).
Together, the fluids obtained from lavaging the bronchoalveolar spaces
of mice pretreated with OVA in the AC or with OVA-pulsed,
TGF-2-treated PEC were deficient in the cells (eosinophils) and
cytokines (IL-4, IL-5, and IL-13) that are believed to play a prominent
role in the pathogenesis of Th2-mediated allergic asthma.
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2 on phenotype of OVA-specific lymphoid cells in
lung-draining LN
In experimentally induced allergic lung disease in mice, the LN
that drain the airways of the lung (hilar and mediastinal) are
documented to contain T cells of the Th2 phenotype that are responsible
for causing the disease (21, 22). Therefore, we postulated
that intracameral OVA pretreatment of mice destined to develop
experimental allergic lung disease would impact the phenotype of
OVA-specific cells in the draining LN. As before, panels of
BALB/c mice were immunized i.p. with two injections of OVA plus alum;
some panels were pretreated with AC injection of OVA, while other
panels were pretreated with i.v. injections of OVA-pulsed,
TGF-2-treated APCs. All mice were then challenged i.t. with OVA.
After 1 or 3 days, their lung-draining LN were harvested and cultured
in vitro with anti-CD3 Abs or with OVA, respectively, for 120
h. The supernatants were then harvested
and assayed by ELISA for IL-4, IL-5, IL-13, and IFN-. The results
are displayed in Figs. 5 and 6. When
exposed in vitro to anti-CD3, LN cells from positive controls
secreted all four cytokines at easily measurable levels. However, when
lymphoid cells were obtained from mice pretreated with OVA in the AC
(Fig. 5A) or with i.v. injected OVA-pulsed,
TGF-2-treated PEC (Fig. 5B), anti-CD3-responding
cells produced significantly less IL-5 and IL-13, but not less IFN-,
compared with positive controls. Similarly, positive control draining
LN cells exposed in vitro to OVA (Fig. 6) produced large amounts of
IL-5 and IL-13 compared with mice pretreated with OVA in the AC.
Increased expression of Th2 cytokine mRNA levels (IL-4, IL-5, and
IL-13) in lung draining LN correlated positively with levels of their
protein production (data not shown). Thus, ACAID inhibits the
generation of lymphoid cells in draining LN that produce IL-5 and
IL-13, two cytokines strongly implicated in the pathogenesis of
experimental allergic lung disease.
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-producing Th1-type cells are
present. To examine this possibility, BALB/c mice received first an AC
injection of OVA, followed 1 wk later by immunization with OVA plus
alum. The delayed hypersensitivity of these mice was then assessed and
compared with that of mice that received OVA plus alum or OVA plus CFA
immunization alone. The mice pretreated with OVA in the AC displayed no
evidence of OVA-specific delayed hypersensitivity (data not shown). We
conclude that Th1 cells are not present in mice pretreated with
OVA in the AC and that ACAID is responsible for the failed IL-5 and
IL-13 production in the lung draining LN of mice pretreated with OVA in
the AC before immunization and intratracheal challenge with
OVA. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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when
stimulated with OVA in vitro. Second, mice deficient in IL-4 (because
the relevant gene has been disrupted) readily acquire ACAID when Ag is
injected into the AC. Because these genetically manipulated mice are
incapable of developing Th2 responses, it seems unlikely that the ACAID
they acquire can be Th2 mediated.
The results of the studies reported here diminish the possibility that
the regulation of ACAID and Th2 are identical, at least for the
heterologous protein Ag, OVA. Mice pretreated with either an AC
injection of OVA or an i.v. injection of OVA-pulsed, TGF-2-treated
APCs failed to generate OVA-specific IgE responses when immunized i.p.
with OVA plus alum. Moreover, when these mice were challenged i.t. with
OVA, their BAL fluids contained few if any traces of a Th2-dependent
inflammatory response: sparse eosinophils and lymphocytes were present,
and only trivial amounts of IL-4, IL-5, and IL-13 were detected. By
contrast, the positive control mice immunized with OVA plus alum
generated robust OVA-specific IgE responses, and their BAL following
intratracheal challenge with OVA was rich in cells, especially
eosinophils, and in IL-4, IL-5, and IL-13.
The failure of mice pretreated with OVA in the AC or with the surrogate
ACAID-inducing APCs generated in vitro to generate intrapulmonary Th2
responses to OVA challenge was also evident when lymphoid cells were
evaluated in the lung-draining LN. Whether stimulated in vitro
with anti-CD3 Abs or with OVA, draining LN cells of OVA-pretreated
mice failed to secrete significant amounts of IL-5 or IL-13. RT-PCR
analysis of LN cells and BAL cells showed that the genes for IL-5,
IL-13, and IFN- were either silenced or greatly repressed by OVA-AC
treatment. These findings lead us to conclude that pretreatment of mice
with AC injection of OVA or with an i.v. injection of OVA-pulsed,
TGF-2-treated APCs suppressed OVA-specific Th1 and Th2 responses
comparably.
Our finding that induction of ACAID inhibits Th2-dependent pathology extends our knowledge of the range of immune effector systems altered in ocular immune privilege. Suppression of Th2-dependent pathology joins suppression of delayed hypersensitivity and suppression of complement-dependent inflammation. Yet even with the addition of suppressed Th2 responses to the immune privilege repertoire, there are immune effector systems that remain intact in ACAID. Mice with ACAID produce large amounts of IgG1 Abs. In that regard, it was of interest to learn in our present studies that, even though IgG1 is usually included among the Abs promoted by Th2 cells, IgG1 production persisted at high levels in mice that were pretreated with OVA in the AC followed by an i.p. immunization with OVA plus alum. Only IgE production, another Ab thought to be facilitated by Th2 cells, was diminished in these mice. Previous reports have demonstrated that mice with ACAID induced by minor histocompatibility Ag-bearing tumor cells acquire large numbers of activated CD8+ cytotoxic T cell precursors in their secondary lymphoid organs (27). Thus, on the cell-mediated arm of immune responses, mice with ACAID can still mount cytotoxic T cell responses and, on the humoral immune side, mice with ACAID can still mount robust IgG1 responses to eye-derived Ags (3). In these animals, promotion of CD8+ T cell and IgG1 responses at the expense of Th1, Th2, and complement-fixing Ab responses serves to emphasize that the systemic immune response to eye-derived Ags is "deviant," ergo the term ACAID.
Mice with Th2-biased immune responses produce large amounts of noncomplement-fixing IgG1 Abs as well as IgE. Our evidence indicates that induction of ACAID in mice that are subsequently exposed to a Th2-biasing immunization regimen prevents their production of IgE, while the production of IgG1 is preserved. At the very least, this outcome suggests that the regulations by T cells of IgG1 and IgE are distinct and that the regulatory T cells of ACAID suppress both complement-fixing Abs (IgG2a, IgG2b, IgG3) and IgE, whereas Th2 cells suppress complement-fixing IgG Abs, but not IgE.
It is worth pointing out that induction of ACAID offers for consideration a novel strategy with which to suppress an important Th2-dependent immunopathologic condition, allergic asthma. Previously, ACAID has been used experimentally to suppress or prevent rejection of orthotopic corneal allografts in mice (28, 29) as well as experimental autoimmune uveitis (30, 31), both of which are Th1-dependent pathologic conditions. Alternatively, attempts to use ACAID experimentally to prevent rejection of solid tissue allografts such as skin and heart have met with no success (J. W. Streilein, unpublished observations). We believe that the explanation for this conundrum resides in the fact that ACAID is immune deviation, i.e., a selective deficiency of one or more immune effector modalities, but not of all effector modalities. Whereas experimental allergic lung disease appears to be mediated solely by Th2 responses, and experimental autoimmune uveitis and acute rejection of orthotopic corneal allografts appear to be mediated solely by Th1 responses, rejection of skin or heart allografts can also be achieved by CD8+ T cells and perhaps by Ab-dependent cell-mediated cytotoxicity that uses noncomplement-fixing Abs. One prediction from these considerations is that induction of ACAID may be a useful therapeutic strategy, but only if the pathologic condition in question is mediated purely by the effector modalities that ACAID suppresses.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Dermatology, Oita Medical University, Oita, Japan.
3 Address correspondence and reprint requests to Dr. J. Wayne Streilein, Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114. E-mail address: waynes{at}vision.eri.harvard.edu
4 Abbreviations used in this paper: ACAID, anterior chamber-associated immune deviation; AC, anterior chamber; BAL, bronchoalveolar lavage; KLH, keyhole limpet hemocyanin; LN, lymph node; PEC, peritoneal exudate cell; i.t., intratracheal.
Received for publication November 20, 2001. Accepted for publication April 29, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-10 in the induction of immune privilege. J. Immunol. 160:2089. and induction of TGF- and IL-4 production. J. Immunol. 161:5382.. Eur. J. Immunol. 22:1031.[Medline]
. Eur. J. Immunol. 22:165.[Medline]
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J. Andrassy, S. Kusaka, E. Jankowska-Gan, J. R. Torrealba, L. D. Haynes, B. R. Marthaler, R. C. Tam, B. M.-W. Illigens, N. Anosova, G. Benichou, et al. Tolerance to Noninherited Maternal MHC Antigens in Mice J. Immunol., November 15, 2003; 171(10): 5554 - 5561. [Abstract] [Full Text] [PDF]
|
|
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T. Nakamura, K.-H. Sonoda, D. E. Faunce, J. Gumperz, T. Yamamura, S. Miyake, and J. Stein-Streilein CD4+ NKT Cells, But Not Conventional CD4+ T Cells, Are Required to Generate Efferent CD8+ T Regulatory Cells Following Antigen Inoculation in an Immune-Privileged Site J. Immunol., August 1, 2003; 171(3): 1266 - 1271. [Abstract] [Full Text] [PDF]
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, alveolar macrophages; 
,
eosinophils; 
, lymphocytes; neutrophils and monocytes were
undetectable. Mean content of different cell types is presented ±
SEM. Asterisk indicates mean values significantly less than those of
positive controls, p < 0.05.
