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*
Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114;
Core Research and Evolutional Science and Technology Project and Department of Molecular Immunology, Chiba University, Chiba, Japan;
Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115; and
Department of Ophthalmology, Kyushu University School of Medicine, Fukuoka, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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281 knockout (KO) mice, which lack NKT cells, was
measured. While there were no difference in the early phase of
rejection, the survival rates at 12 wk after grafting for BALB/c and
J281 KO mice were 50 and 0%, respectively. Because anti-CD1d
mAb abrogated the corneal graft survival in the wild-type mice we
concluded that CD1d-reactive NKT cells were essential for graft
survival. Moreover, allospecific T regulatory (Tr) cells correlated
with acceptance of B6 grafts in BALB/c mice, and the adoptive transfer
of these allospecific Tr cells to J281 KO mice allowed a 50%
survival rate of B6 cornea grafts. In conclusion, CD1d-reactive NKT
cells are required for induction of allospecific Tr cells and are
essential for survival of corneal allografts. Mechanisms that
contribute to cornea graft acceptance may lead to new therapies for
improvement in graft survival in high-risk corneas and other
transplanted tissues and grafts. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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10% of patients lose their sight because of corneal
graft failure (8). Inoculation of allogeneic tissue into the anterior chamber (a.c.)3 of the eye suppresses allospecific systemic delayed-type hypersensitivity (DTH) (10, 11). The model of peripheral tolerance termed a.c.-associated immune deviation (ACAID) is a systemic mechanism that contributes to the active maintenance of immune privilege of the eye. Hosts bearing a long-term clear corneal allograft display an Ag-specific down-regulation of DTH response to donor alloantigens that is reminiscent of ACAID (12). In contrast, hosts that developed donor-specific DTH following keratoplasty invariably rejected their corneal allografts (13, 14). Because orthotopically grafted corneas form the anterior wall of the a.c., grafted endothelial cells express histocompatibility Ags within this immune-privileged site and induce ACAID (14, 15). It was noted that during ACAID induction donor Ag-specific T regulatory (Tr) cells were induced in the spleen (12, 13, 16) and contributed to long-term allograft survival.
Recently we reported that CD1d-reactive NKT cells are central to the
development of the Ag-specific Tr cells in ACAID (17). NKT
cells belong to a specialized population of lymphocytes that coexpress
the TCR
chain and NK markers (18, 19). A major
subpopulation of murine NKT cells expresses a unique invariant
V14J281 Ag receptor not expressed by conventional T cells
(18, 20, 21, 22, 23). Similarly, NKT cells exist in the human and
express the invariant V24JQ TCR chain (24, 25).
NKT cells are restricted by MHC class I-like CD1d molecules
(26, 27, 28). The CD1d molecule is also required for the
development of NKT cells, because CD1d knockout (KO) mice selectively
lack NKT cells (29, 30, 31). Moreover, the NKT cell must
interact with the CD1d molecule for the induction of tolerance, because
blocking the CD1d interaction with a CD1d-specific Ab, either in vivo
(17) or in vitro (52), blocks
the development of Ag-specific Tr cells.
In this report, we show that when a C57BL/6 (B6) donor graft was transplanted to a BALB/c recipient, removal of the CD1-reactive invariant NKT cells from the recipient mice resulted in 0% survival of donor corneas, whereas there was 50% survival if NKT cells were intact. Because NKT cell deficiency prevented the induction of allogeneic Tr cells that facilitate graft survival, the NKT cells are required for ACAID induction to alloantigens as well as soluble Ags (17). Moreover, our data suggest that methods that induce CD1d-reactive NKT cell-dependent tolerance before grafting corneas may lead to prevention of graft rejections in high-risk corneas and suggest novel therapies for patients.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female 8- to 10-wk-old mice were used in all experiments. BALB/c
mice were obtained from Taconic Farms (Taconic, NY). J281 KO mice
(NKT KO mice) were generated at Chiba University (Chiba, Japan) and
back-crossed eight times to BALB/c mice (N8) (23). All
mice were maintained on food and water ad libitum until they reached
the desired weight (20–24 g). All animals were treated humanely and in
accordance with the Schepens Animal Care and Use Committee and National
Institutes of Health guidelines.
Orthotopic corneal allograft
As described previously (32), before all surgical procedures, recipient mice were anesthetized with an i.p. injection of a mixture of 3 mg of ketamine and 0.0075 mg of xylazine. The central 2 mm of the donor cornea was excised and secured in recipient graft beds with eight interrupted 11-0 nylon sutures (Sharppoint; Vanguard, Houston, TX). Antibiotic ointment was applied to the corneal surface, and the eyelids were closed for 72 h with an 8-0 nylon tarsorrhaphy. All grafted eyes were examined after 72 h. At that time, all grafts with technical difficulties (hyphema, infection, or loss of a.c.) were excluded from further consideration. The transplant sutures were removed in all cases on day 7.
Evaluation and scoring of orthotopic corneal allograft
At weekly intervals, grafts were evaluated by slit lamp microscopy and scored for opacification and neovascularization. As previously described (33), the scoring system from 0 to 5+ included the following characteristics: 1) degree of opacification: 0, clear and compact graft; 1+, minimal superficial opacity; 2+, mild deep (stromal) opacity with pupil margin and iris (iris structure) visible; 3+, moderate stromal opacity with only pupil margin visible; 4+, intense stromal opacity with a.c. visible; 5+, maximal corneal opacity with total obscuration of the a.c. (grafts with an opacity score of 2+ or greater after 3 wk were considered rejected (immunological failure)) (33); and 2) degree of neovascularization: 0, no vessels; 1+, vessels in one or two quadrants of recipient bed only; 2+, vessels in three or four quadrants of recipient bed only; 3+, vessels at recipient-graft border in one or two quadrants; 4+, vessels at recipient-graft border in three or four quadrants; 5+, vessels in peripheral stroma of graft, one or two quadrants; 6+, vessels in peripheral stroma of graft, three or four quadrants; 7+, vessels in central stroma of graft, one or two quadrants; 8+, vessels in central stroma of graft, three or four quadrants.
Direct assessment of DTH
Mice were sensitized to the alloantigen with an inoculation s.c. of 107 allogeneic splenocytes. On the seventh day after sensitization, mice received 2 x 106 irradiated (2000 rad) allogeneic donor splenocytes injected into the right pinnae and ear thickness was measured with an engineer’s micrometer (Mitutoyo, Paramus, NJ) 24 h post ear pinnae inoculation (12).
LAT assay for DTH
Allogeneic-specific regulatory Tr cells were detected by local adoptive transfer (LAT) assay as described before (12, 16). BALB/c mice were sensitized with an inoculation (s.c.) of 107 allogeneic (B6) splenocytes. Fourteen days postsensitization, the T cells that were primed to the allogeneic Ags were enriched from the dissociated spleen cells by removing B cells and macrophages using IMMULAN columns (Biotecx Laboratories, Houston, TX) and were used as DTH effector cells in a LAT assay. Irradiated (2000 rad) B6 spleen cells were used as stimulator cells. Regulator cells were column-enriched splenic T cells harvested from BALB/c mice 7 days post a.c. inoculation of 5 x 105 irradiated B6 splenocytes. Effector, stimulator, and regulator cells (5 x 105 of each) were mixed and resuspended in 10 µl of HBSS for inoculation into the right ear pinnae of naive mice. Ear swelling was measured with an engineer’s micrometer 24 h post ear pinnae inoculation. Naive T cells from unmanipulated BALB/c mice were used as effector cells and regulator cells for the negative control. T cells primed to allogenic Ags were used as effector cells and naive T cells from unmanipulated mice were used as regulator cells for positive control.
Antibodies
The Abs used for flow cytometry analysis were as follows: Fc
block (anti-mouse FcR
II/III mAb, 2.4G2), biotin-conjugated
anti-Ly49C (5E6), biotin-conjugated anti-CD1 mAb (1B1),
FITC-conjugated anti-CD3 mAb (145-2C11), and CyChrome 5-conjugated
anti-TCR mAb (H57-597) were all purchased from BD PharMingen
(San Diego, CA). PE-conjugated anti-B220 mAb (RA3-6B2) and
PE-conjugated Mac-1 (M1/70.15) were purchased from Caltag Laboratories
(South San Francisco, CA). Streptavidin-PE was purchased from Jackson
ImmunoResearch Laboratories (West Grove, PA).
The Abs used for in vivo treatment were as follows: anti-CD1 mAb (3C11, rat IgM) was also purified from mouse ascites using protein A columns. Purified rat Ig was purchased from Sigma-Aldrich (St. Louis, MO) and used as control for anti-CD1 mAb. Abs were inoculated i.p. (50 µg each) every 4 days after grafting until the grafted corneas were rejected.
Flow cytometry
Splenic NK and NKT cells were analyzed by flow cytometry. RBC
were lysed by adding Tris-buffered ammonium chloride to a cell pellet
of spleen cells and incubated for 2 min at room temperature.
After washing, staining was performed in the presence of saturating
concentrations of Fc block (blocks FcRII/IIIs). Cells were stained
with the following three reagents and colors (using concentrations
recommended by the manufacturer): biotin-conjugated
anti-Ly49c mAb counterstained with streptavidin-PE, CyChrome
5-conjugated anti-TCR chain mAb, and FITC-conjugated
anti-CD3 mAb. Stained cells were analyzed on an EPICS XL flow
cytometer (Beckman Coulter, Miami, FL).
Blocking of NKT/CD1 cell interaction in vivo
Purified anti-CD1 mAb (3C11; 50 µg in 100 µl of PBS) or
control rat Ig (50 µg in 100 µl of PBS) was injected i.p. into
recipient BALB/c mice to block the subsequent interaction of CD1d with
NKT cells (17). Flow cytometry studies of spleen cells
harvested from the 3C11-treated mice confirmed that the CD1-positive
cells (biotin-conjugated anti-CD1 mAb (1B1) counterstained by
streptavidin-PE) neither were depleted nor showed changes in the
populations of T cells (FITC-conjugated anti-CD3 mAb), B cells
(PE-conjugated anti-B220 mAb), NK/NKT cells (triple staining:
FITC-conjugated anti-CD3 mAb, CyChrome 5-conjugated anti-TCR
chain mAb, and biotin-conjugated anti-Ly49c mAb counterstained by
streptavidin-PE), and macrophages (PE-conjugated Mac-1) (data not
shown).
Adoptive transfer of Tr cells into grafted J281 KO mice
After RBC lysis, T cells were enriched from dissociated spleen
cells from naive or B6 graft-accepted mice by removing B cells and
macrophages using IMMULAN columns (Biotecx Laboratories, Houston, TX).
Enriched T cells were treated with biotin-conjugated anti-Ly49c,
MicroBeads-conjugated anti-mouse pan-NK cells (DX5) (Miltenyi
Biotec, Auburn, CA) and anti-NKT cell (U5A2-13, rat IgG2a)
(34, 35) (kindly provided by Dr. H. Wakasugi (National
Cancer Center Research Institute, Tokyo, Japan)), washed twice in PBS
(pH 7.2) containing 0.5% BSA and 2 µM EDTA. Ab-labeled cells were
treated with anti-rat Ig MicroBeads and streptavidin MicroBeads
(Miltenyi Biotec) for 15 min and washed twice. To harvest NK/NKT
cell-depleted population, cells were applied to type
MS+ positive selection column with MiniMACS
(Miltenyi Biotec) and collected eluted population. Cells were stained
with CyChrome 5-conjugated anti-TCR chain mAb and
streptavidin-PE. T cell enrichment and NKT cell depletion were
confirmed by flow cytometry.
Recipient J281 KO mice grafted with allogeneic corneas were
inoculated (i.v.) with 107 mouse enriched T cells
(NKT/NK-depleted cells) harvested from either naive BALB/c mice or
BALB/c mice with accepted B6 corneas of 8-wk duration, 4 wk after
grafting. Following this treatment, grafts were evaluated by slit lamp
microscopy at weekly intervals.
Statistics
Data were analyzed for significant differences in ear swelling
among experimental groups by ANOVA and Scheffe’s test. A value of
p 
0.05 was considered significant. Kaplan-Meier
survival curves were constructed and the Mantel-Cox test was used to
compare the probability of corneal graft survival. A value of
p 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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14+ NKT cells in early inflammation and
graft rejection
To investigate the role of NKT cells in the corneal allograft, we
compared the allograft (B6) survival between BALB/c and J281KO
(BALB/c background). During the natural time course of corneal
allograft in BALB/c mice, the maximum inflammation was observed 7 days
after grafting (Fig. 1
A). The
early inflammation was thought to be caused mainly by interrupted
sutures or surgical treatment, and not mediated by allospecific immune
response, because the same level of inflammation was observed in
syngeneic graft controls (33). Most of the allografts that
did not suffer from technical problems became clear (a score of <2 in
opacity) by day 14 or 7 days after removal of sutures on
day 7.
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281 KO
mice (Fig. 1
). Thus V14J281 NKT cells do not participate in
rejection or survival during the early inflammatory phase of corneal
grafting. Role of NKT cells in survival of cornea grafts
Three weeks after grafting, grafted corneas began to show
signs of allospecific immune rejection (33). As documented
before, 50% of B6 cornea grafts survive in BALB/c mice
(33), and the 50% of grafted corneas that were rejected
occurred between the third and seventh week after transplantation. The
surviving grafted corneas were accepted by 12 wk in BALB/c mice (Fig. 2A). Although there were no
differences in opacity until the sixth week, all B6 grafted corneas in
J281 KO mice were rejected by 8 wk after grafting (Fig. 2A). After the third week the persistently opaque corneas
were ultimately rejected (Fig. 2B). Thus the long-term graft
survival was dependent on the NKT cells expressing the invariant
TCR.
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Invariant (V14J281) NKT cells are restricted by CD1d. To
confirm that the NKT cells must interact with CD1d to achieve tolerance
of the allografts, we blocked the NKT cell CD1d interaction with
specific Ab in vivo. Previous studies showed that anti-CD1d mAb,
3C11, indeed blocks the interactions between NKT cells and CD1d
molecule and abrogated generation of ACAID induced by a protein Ag
(OVA) (17). Again, there were no critical differences
between control Ig-treated and anti-CD1d-treated mice in the
inflammation for the first 14 days (data not shown). Nor were there
remarkable changes in the rejection rate between these two groups
before 6 wk after grafting. However, between 6 and 8 wk postgrafting
all BALB/c mice treated with the anti-CD1d Ab rejected their B6
corneas. Mice treated with control Ab accepted the corneas (Fig. 3). Therefore, CD1d-reactive NKT cells
are essential for long-term allograft survival in B6 donor cornea
grafts to BALB/c recipients.
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281 KO mice receiving allografts failed to induce DTH
suppression
To explore the potential mechanism of late-phase graft rejection
in J281 KO mice, we compared the allospecific DTH response in
grafted BALB/c mice and J281 KO mice. Twelve weeks after corneas
were grafted, mice received a s.c. inoculation of B6 splenocytes
(107). After 7 days, mice were challenged
intradermally in the ear pinnae with 2 x
106 irradiated B6 splenocytes and ear swelling
was measured 24 h later. It is well documented that suppression of
allospecific DTH response is correlated with graft acceptance (8, 12). BALB/c mice that rejected their allografts (50%) responded
to the Ag challenge with ear swelling equal to the positive control
(Fig. 4); however, BALB/c mice that
accepted the allografts (50%) exhibited reduced ear swelling (Fig. 4).
It is known that BALB/c mice with accepted corneal allografts induce
allospecific Tr cells that effectively suppress peripheral DTH
(12, 13). In contrast to the BALB/c mice that induced Tr
cells, all J281 KO mice demonstrated ear swelling to the Ag
challenge (DTH response) after allogeneic sensitization (Fig. 4). Thus,
the grafted J281 KO mice rejected their allografts because they
failed to induce allospecific, efferent Tr cells.
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281 KO mice
The precise role and mechanism of the involvement of NKT cells in
corneal graft survival were further investigated by adoptively
transferring splenic Tr cells harvested from BALB/c mice that displayed
long-term accepted corneal grafts into J281 KO mice 4 wk after
receiving B6 corneal grafts. At this time, NKT cells were depleted from
enriched T cells by treatment with a combination of biotinylated
anti-Ly49C mAb (5E6) and anti-NK1.1 cell mAb (U5A2-13) before
passing them over a mixture of streptavidin and goat anti-rat
conjugation magnetic beads. The quality of depletion technique was
confirmed by flow cytometry (Fig. 5A). In these studies NKT cell
KO mice that received the adoptive transfer of Tr cells accepted their
corneal allografts (Fig. 5B). Although NKT cells are known
to produce immunosuppressive cytokines (30, 31, 36, 37),
our data indicate that NKT cells themselves are not the regulatory
cells functioning in corneal allograft survival but that the Tr cells
are conventional Ag-specific T cells. CD1d-reactive NKT cells are
essential for the generation of Tr cells, but once the Ag-specific Tr
cells are generated the NKT cell is no longer needed for the effector
phase of suppression. Thus, CD1d-reactive NKT cells are essential for
the generation of allogeneic Tr cells that promote corneal
acceptance.
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281 KO mice failed to induce allogeneic-specific ACAID and Tr
cells
Previously, we showed a role for NKT cells in OVA-induced ACAID.
To further examine the role of NKT cells in the generation of Tr cells
(ACAID) to alloantigens, we injected B6 spleen cells into the a.c. of
J281 KO mice. The successful grafting of an allogeneic cornea is
equal to putting the alloantigens into the noninflamed a.c. for
induction of ACAID against allogeneic Ags (15). In fact,
individual animals develop allospecific Tr cells in the spleen within a
week of inoculation of allogeneic cells into noninflamed eyes by
the same mechanism that leads to acceptance of grafts (11, 38).
One panel each of BALB/c or J281 KO mice was inoculated (a.c.) with
5 x 105 irradiated B6 splenocytes 7 days
before receiving an s.c. inoculation of 107 B6
splenocytes. Seven days after allogeneic cell immunization, mice were
challenged in the ear pinnae with 2 x 106
irradiated B6 splenocytes and ear swelling was measured 24 h
later. We found that DTH responses were suppressed in a.c. inoculated
BALB/c but not in J281 KO mice that received the a.c. inoculation of
B6 splenocytes (Fig. 6A). A
direct measure of Tr cell induction was assessed in a LAT assay.
Inoculation (a.c.) induced allospecific Tr cells in BALB but not
J281 KO mice (Fig. 6B). Thus, in the absence of NKT
cells, a.c. inoculation does not induce the generation of efferent
allogeneic Tr cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Compared with other organ transplantation (skin, heart, liver, kidney, etc.), corneal transplantation has some unique features. Corneal transplantation is the most successful type of solid tissue transplantation in humans (1) and long-term acceptance is achieved without immunosuppressive therapy. The success of corneal transplantation was originally explained by the lack of lymphatic drainage in the cornea. Aqueous humor contains the nutrition for donor cornea instead of blood vessels. Thus, the surgeon does not need to do angiostomy for corneal transplantation.
The success of corneal transplantation is also correlated with the immune-privileged status of the eye. In addition to the immune-privileged quality of the corneal tissue itself (4, 39, 40), the orthotopic cornea graft becomes part of the a.c. of the eye, which is an immune-privileged site. It is well documented that corneal allograft acceptance is closely related to allospecific Tr cell induction, which imparts allogeneic ACAID (5, 12, 41). However, not all orthotopic allografts actually succeed in humans (42). Grafts are rejected in so-called "high-risk" recipients. The high-risk condition appears to occur when the immune privilege state is compromised. Grafts that follow corneal herpes infection, burning, etc., are unable to induce allospecific Tr cells and therefore are rejected (8, 9, 43). To achieve graft acceptance in a high-risk patient, the precise mechanism of allospecific Tr cell induction in corneal transplantation needs to be elucidated.
Recently, several reports showed that CD1d-reactive V14 NKT cells
were involved in transplantation tolerance induced by systemic
administration of Ab to the donor organ. Such Ab treatment apparently
induced tolerance and promoted graft survival even in
nonimmune-privileged sites (44, 45). Ikehara et al.
(46) demonstrated that NKT cells were crucial for
acceptance of islet xenografts in mice treated with anti-CD4 Ab.
Also, Seino et al. (47) showed that NKT cells played a
crucial role in the induction of cardiac allograft tolerance in an
experimental model of tolerance that follows anti-LFA-1/ICAM-1 or
anti-B7-1/B7-2 Ab treatment, and Terabe et al. (48)
reported that NKT mediated repression of tumor immunosurveillance.
These studies support our notion that V14 NKT cells are required for
the induction of allospecific Tr cells and perhaps in a variety of
tolerance models that may share the commonality of efferent Tr cells
(6).
The timing of corneal graft rejection in J281 KO mice and
anti-CD1d mAb-treated mice is a point for discussion. Mice rejected
their allograft between 6 and 8 wk (
Figs. 1–3). There may be at least
two different mechanisms involved in the host immune reaction against
an allograft. One mechanism is clinically effective during the first
6–8 wk after grafting and independent of CD1d-reactive NKT cells. In
both NKT cell KO-deficient mice and anti-CD1d mAb-treated mice
corneal grafts were rejected at the same rate as grafts in the control
group (Figs. 1 and 2). The other mechanism appears to be effective
after this initial rejection phase and conspires to maintain clarity of
the allograft. This relatively late-phase immune response was closely
correlated to CD1d activation of invariant NKT cells. In human corneal
transplantation, most of the immunological graft rejection suddenly
occurs between 2 and 7 wk postoperation. The relationship
between the time course of cornea graft rejection in human and mouse is
not clear. However, CD1d-reactive invariant NKT cells do exist in
humans (24, 25) and may have influence in corneal graft
survival as well.
Another point to consider is why Tr cells appear to be generated more
slowly in the allograft system compared with when OVA is inoculated
into the eye. It is thought that CDld-restricted NKT cell-dependent
tolerance is induced more slowly in mice after cornea grafting than
after direct injection (a.c.) of Ag because the release of the
eye-derived APCs carrying the alloantigens from the graft is delayed.
It is reported that the innervation (3) (and it is
postulated that the cellular traffic patterns) are disrupted by the
surgical manipulation needed for placement of the graft. Moreover, we
show in this manuscript that direct injection of allospleen cells into
the a.c. induces Tr cells at a time course similar to OVA
inoculation (Fig. 6).
The elucidation of mechanisms for tolerance that use CD1d-reactive NKT cells to induce allogeneic Tr cells in grafted mice or allogeneic cell inoculated (a.c.) mice can be guided by studies in a similar model of CD1d/NKT cell-dependent tolerance induced to a.c. inoculation of soluble protein Ags (OVA) (17). In this model, we found that NKT cells produced IL-10 in response to CD1d stimulation and that NKT cell-derived IL-10 was critical to the development of the Ag-specific Tr cells as well. By extrapolation, we predict that IL-10-mediated mechanisms are involved with the generation of allogeneic-specific Tr cells. Further investigations are needed to clarify this point.
Our data do not deny the possible contribution of other type of cells
in the induction of allogeneic tolerance. Above all, several
CD1d-reactive cells other than V14 NKT cells (49, 50, 51)
may contribute to the acceptance of corneal allograft. Also, multiple
cell types express CD1d and could provide essential signals to V14
NKT cells for Tr cell induction. However, the inability to show
survival of grafts in J281 KO mice is strong evidence that corneal
graft survival in this mouse strain combination is dependent on
CD1d-restricted NKT cells.
These data have fomented ideas for developing therapeutic maneuvers based upon those that promote the generation of Ag-specific, CD1d-reactive, NKT cell-dependent Tr cells to prevent and reverse allogeneic sensitization in mice and humans. Thus, the mouse studies will be extended into humans with the goal of therapeutic applications for rejecting corneal graft leading to tolerance involving CD1d/NKT cell interactions.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Joan Stein-Streilein, Schepens Eye Research Institute, Harvard Medical School, 20 Staniford Street, Boston, MA 02114. E-mail address: jstein{at}vision.eri.harvard.edu
3 Abbreviations used in this paper: a.c., anterior chamber; ACAID, a.c.-associated immune deviation; DTH, delayed-type hypersensitivity; LAT, local adoptive transfer; KO, knockout; WT, wild type; Tr, T regulatory.
Received for publication August 28, 2001. Accepted for publication December 17, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4-8- T cells in mice and humans. J. Exp. Med. 180:1097.14+ TCR chain in NK1.1+ T cell populations. Int. Immunol. 7:1157.14-J281 rearrangements in NK1+ T cells. Eur. J. Immunol. 27:1576.[Medline]
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P. M. Stuart, F. Pan, X. Yin, Z. Haskova, S. Plambeck, and T. A. Ferguson Effect of Metalloprotease Inhibitors on Corneal Allograft Survival Invest. Ophthalmol. Vis. Sci., April 1, 2004; 45(4): 1169 - 1173. [Abstract] [Full Text] [PDF]
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 O. Shibolet, Y. Kalish, A. Klein, R. Alper, L. Zolotarov, B. Thalenfeld, D. Engelhardt, E. Rabbani, and Y. Ilan Adoptive transfer of ex vivo immune-programmed NKT lymphocytes alleviates immune-mediated colitis J. Leukoc. Biol., January 1, 2004; 75(1): 76 - 86. [Abstract] [Full Text] [PDF]
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J. Y. Niederkorn The immune privilege of corneal grafts J. Leukoc. Biol., August 1, 2003; 74(2): 167 - 171. [Abstract] [Full Text] [PDF]
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 J. E. Boyson, B. Rybalov, L. A. Koopman, M. Exley, S. P. Balk, F. K. Racke, F. Schatz, R. Masch, S. B. Wilson, and J. L. Strominger CD1d and invariant NKT cells at the human maternal-fetal interface PNAS, October 15, 2002; 99(21): 13741 - 13746. [Abstract] [Full Text] [PDF]
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) in
ear swelling measurements (24 h post ear challenge) are shown on the
ordinate. •, Individual mice that rejected their allografts; *,
significant differences (p 
