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*
Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; and
Medical College of Georgia, Institute of Molecular Medicine and Genetics, Augusta, GA 30912
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A number of explanations have been proposed to account for the differences in susceptibility to rejection of the various types of allografts. These explanations include differences in the mode of revascularization, the lymphatic drainage, the presence of tissue-specific Ags, differences in the immunogenicity of the grafts, and graft size.
It is well established that nonvascularized grafts are subject to ischemic degeneration that can lead to inflammation and necrosis, even in syngeneic grafts (7). This nonspecific damage may well render nonvascularized grafts more susceptible to subsequent immune destruction. However, it has been demonstrated that MHC class I-mismatched nonvascularized heart allografts are rejected much more slowly than skin allografts in the same strain combination and are even on occasion accepted indefinitely (2). Furthermore, surgically vascularized skin allografts were found to be as vulnerable to rejection as conventional, naturally revascularized skin allografts (Ref, 8 ; A. R. Bushell and M. Liddington, unpublished observation). Thus, on balance, differences in the mode of vascularization are unlikely to fully explain the differential survival of heart, skin, and islet allografts. Other inherent differences between these grafts must therefore be responsible for the differences in their susceptibility to rejection.
A second potential explanation is the presence of tissue-specific Ags. Evidence for the existence of tissue-specific alloantigens arose from observations in hemopoietic chimeras. In this situation, although allogeneic hemopoietic cells survived indefinitely, such chimeras would not accept skin grafts from the same donor, suggesting that the skin-expressed Ags not found on the hemopoietic cells (5, 9). Indeed, Skn and Epa-1, two skin-specific Ags, have been implicated as targets for skin graft rejection in some models (5, 10, 11).
A third possible factor responsible for the sensitivity of skin grafts to rejection is the special immunological function of the skin, which may be subverted after transplantation to promote a vigorous rejection response. Skin contains numerous Langerhans cells (LC)5 which are professional APCs with the capacity to migrate from the graft and efficiently stimulate recipient T cells (12, 13). Thus, the potential for a skin graft to stimulate large numbers of alloreactive T cells may explain why these grafts are so susceptible to rejection.
The susceptibility of allografts to rejection may also in part be dictated by the actual size of the graft. Obviously, the smaller the graft the smaller is the number of cells that must be destroyed for the graft to be rejected. Evidence that graft size has a bearing on graft rejection has recently been presented by Sun et al. (14), who demonstrated that whereas a single allograft was acutely rejected, grafting a recipient with multiple grafts resulted in the prolonged survival of the transplanted organs. This observation is of particular relevance to small cell allografts such as islets.
Previously, it has not been possible to compare directly the immune response generated by different types of allografts due to an inability to identify alloantigen-specific T cells in vivo and the potentially confounding effects of T cells responding to tissue-specific Ags. To overcome these issues, we have developed an experimental strategy in which the rejection response is mediated by defined numbers of CD8+ T cells that are specific for the allogeneic MHC class I molecule H-2Kb. In this system, tissue-specific Ags do not play a role in rejection because rejection is dependent solely on the activation of the H-2Kb-specific T cells. Using four-color flow cytometry, we monitored the proliferation, activation, and homing of the alloreactive cells after exposure to heart, skin, and islet allografts. Heart, skin, and islet allografts were chosen as challenge grafts because these graft types are distributed evenly across the transplantation hierarchy.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CBA/Ca (H-2K) and C57BL/10 (H2b) mice were purchased from Harlan Olac, (Bicester, U.K.). BM3 (H-2K, BM3.3 TCR transgenic) mice have been described previously (15). All mice were housed in the part-barrier facilities of the Biomedical Services Unit, John Radcliffe Hospital (Oxford, U.K.). All donor and recipient experimental mice were sex and age matched between 8 and 12 wk of age at the time of first experimental procedure.
mAbs and hybridomas
YTA3.1 and YTS169 hybridomas were a gift from Professor H.
Waldmann (Sir William Dunn School of Pathology, Oxford University,
Oxford, U.K.) (16). Ti98 hybridoma has been described
previously (17). All hybridomas and cell lines were grown
in either RPMI 1640 or 
-MEM (Life Technologies, Paisley, U.K.),
supplemented with 2 mM glutamine, antibiotics, and 10% (v/v) FCS (Life
Technologies). Anti-CD4 (YTA3.1) and anti-CD8 (YTS169) mAbs were
purified and dialyzed into PBS before being used in vivo. Anti-CD8-APC
(53-6.7), anti-clonotypic TCR-biotin (Ti98), anti-CD25-PE
(PC61), anti-CD44-PE (IM7), anti-CD45RB-PE (16A),
anti-CD62L-PE (MEL-14), and anti-CD69-PE (H1.2F3) mAbs were
used in vitro for FACS analysis. For intracellular cytokine staining
anti-IL-2-PE (JES6-5H4), anti-IFN-
-PE (XMG1.2),
anti-IL-4-PE (11B11), and anti-IL-10-PE (JES5-16E3) were used.
Isotype-matched mAbs R3-34-PE (rat IgG1), and R35-38-PE (rat IgG2b)
were used as controls. All mAbs were obtained from PharMingen, Becton
Dickinson (Oxford, U.K.), unless stated otherwise.
Surgical procedures
Thymectomy. CBA/Ca mice were thymectomized under direct visualization, as previously described (18).
Heterotopic heart transplantation. Abdominal vascularized heterotopic heart transplants were performed essentially as documented by Corry et al. (19). The function of the transplanted hearts was followed by abdominal palpation, electrocardiogram, and laparotomy.
Skin transplantation. Individual full thickness tail skin grafts were prepared to fit the graft bed on the left lateral thorax of anesthetized recipients. The grafts were inspected regularly until they were completely destroyed, at which time the grafts were considered to have been rejected.
Islet transplantation. Islets were isolated from the donor pancreas using standard collagenase digestion followed by centrifugation through a discontinuous Ficoll gradient. Approximately, 600 freshly isolated islets were then mixed with a drop of the recipient’s blood before transplantation under the left kidney capsule.
Induction of diabetes and monitoring of blood glucose levels
Male CBA recipient mice were rendered diabetic by a single i.v. dose of streptozotocin (250 mg/kg; Sigma, St. Louis, MO), and blood glucose levels were monitored regularly (Glucose Analyser II; Beckman, Bucks, U.K.). Only those animals with blood glucose concentrations of >20 mmol/L were used as recipients. After islet transplantation, blood glucose levels were monitored every other day for the first week and then twice weekly thereafter. Those animals with three consecutive blood glucose readings of >12.5 mmol/L were considered to have rejected their islet grafts.
Cell purification and CFSE labeling
A single-cell leukocyte suspension was made from spleens and mesenteric lymph nodes harvested from BM3 TCR-transgenic mice. CD8+ T cells were purified by positive selection using anti-CD8 MACS beads (Miltenyi Biotec, Bergische Gladbach, Germany). Typically, CD8+ T cells were isolated to >95% purity; >95% of the CD8+ T cells expressed the H-2Kb-specific transgenic TCR (tg-TCR). The isolated cells were incubated for 10 min at 37°C with between 5 and 10 µM CFSE; Molecular Probes, Leiden, The Netherlands), washed twice, and resuspended in PBS ready for i.v. injection.
Standard experimental protocol
CBA/Ca mice were thymectomized (day -25) and rested for 2 wk before being treated with depleting anti-CD4 (YTA3.1; 100 µg/dose) and anti-CD8 (YTS169; 100 µg/dose) mAbs on day -12 and day -11. To allow time for the depletion of the majority of T cells, the mice were rested for a further 10 days at which time they were termed "empty" mice because they were severely depleted of peripheral T cells (95% T cell depletion). The mice were then reconstituted with an i.v. injection of the CFSE-labeled purified CD8+tg-TCR+ (BM3) T cells (day -1). The day after adoptive transfer (AT), i.e., day 0, mice received an H-2Kb+ (C57BL/10) heart, skin, or islet allograft.
Flow cytometric analysis
Leukocytes (1.5 x 106) were stained with anti-CD8-APC and Ti98-biotin mAbs. After washing, a streptavidin-conjugated fluorochrome was added (streptavidin-CyChrome (PharMingen)). The samples and fluorochrome were then incubated at 4°C before being washed twice. Finally, the samples stained with PE-labeled mAbs for detection of activation markers. All samples were then fixed with 250 µl PBS with 2% (v/v) paraformaldehyde, before being acquired on a FACSort (Becton Dickinson), and analyzed using the Cellquest software package (Becton Dickinson).
Intracellular cytokine staining
Spleen cells (1 x 106/ml) were
stimulated with PMA (50 ng/ml) plus ionomycin (500 ng/ml) for 4 h
at 37°C, with brefeldin A (10 µg/ml) added for the last 2 h.
Surface staining using anti-CD8-APC and Ti98-biotin mAbs was
performed in PBS-FCS-azide + brefeldin A. After two washes,
streptavidin-CyChrome was added for 15 min. The cells were then washed
and resuspended in PBS-brefeldin A-2% (v/v) formaldehyde. The
following day, cells were washed and preincubated for 10 min in
permeabilization buffer (PBS-1% FCS-0.5% saponin (Sigma)), and
incubated with anti-IL2 (2.5 µg/ml), anti-IFN- (5.0
µg/ml), anti-IL4 (5.0 µg/ml), anti-IL10 (5.0 µg/ml), or
an isotype control for 30 min. All of the cytokine Abs were PE
conjugated. After two washes with permeabilization buffer, the cells
were washed in PBS-1% FCS without saponin to allow membrane closure.
Samples were analyzed on a FACSort flow cytometer (BD, Oxford, U.K.).
Results were analyzed using CellQuest software (BD).
Immunohistochemistry
Thin frozen sections (7 µm) were cut, air-dried overnight, and fixed in acetone (BDH, Cardiff, U.K.). After inhibition of endogenous peroxidase activity and blockade of endogenous biotin, sections were incubated with the primary anti-CD8 mAb (YTS169). After incubation with a HRP-conjugated anti-primary species Ab, staining was developed by addition of diaminobenzidine substrate (Vector Laboratories, Burlingame, CA). Finally, sections were counterstained with Gill’s hematoxylin (BDH) and prepared for permanent mounting.
Statistical analysis
Statistical analysis was performed using Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In an initial set of experiments, we sought to quantify the number
of alloreactive T cells required to mediate rejection of heart, skin,
and islet allografts, where allograft rejection was dependent on the
response of a defined number of alloantigen-specific T cells
recognizing a single allogeneic MHC class I molecule
(H-2Kb). T cell-depleted recipient mice were
generated by thymectomy and T cell depletion. These animals were
severely immunocompromised and were unable to reject fully mismatched
H-2Kb+ (C57BL/10 (H-2b))
heart (median survival time (MST), >50 days; n = 8),
skin (MST >50 days; n = 8) or islet (MST >50 days;
n = 10) allografts (Table I
).
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).
In contrast to heart allograft rejection, as few as 1 x
103 H-2Kb-specific
CD8+ T cells were able to reject
H-2Kb+ skin allografts (MST = 35 days;
n = 3; Table I). In similar experiments, 1 x
103 H-2Kb-specific
CD8+ T cells were found to reject
H-2Kb+ islet allografts (MST 12 days;
n = 3) (Table I). Thus, many more alloreactive T cells
(
6000-fold more in this model) were required to mediate the
rejection of a heart allograft than were necessary to reject skin or
islet allografts.
Alloantigen-specific T cell activation in vivo in response to heart, skin, and islet allografts
It was possible that the vast discrepancy in the number of alloreactive T cells required to reject skin and islets, compared with heart allografts, was a reflection of the ability of the different graft types to activate alloreactive T cells. To characterize the kinetics of T cell division in vivo after transplantation, H-2Kb-specific T cells were labeled with the fluorescein-based dye CFSE before transfer. CFSE has been shown to segregate evenly between daughter cells on cell division, resulting in sequential halving of the fluorescent intensity which can be analyzed by flow cytometry (20, 21). Using four-color flow cytometry, we gated on the CD8+ tg-TCR+ cells, which allowed us to analyze the response of H-2Kb-specific T cells independently of other cells within the recipient (detailed in Ref. 18).
We analyzed the proliferative response of alloreactive T cells within
the spleen 1, 3, and 7 days after transplantation of either
H-2Kb+ heart, skin, or islet allografts into
immunocompromised recipients which had been reconstituted with 6
x 106 CD8+
H-2Kb-specific T cells. No proliferation occurred
within 24 h after transplantation of any of the grafts. By 3 days
after transplantation, H-2Kb-specific T cells had
begun to divide in response to H-2Kb+ heart
allografts, but not in response to H-2Kb+ skin or
islet grafts (Table II). When
proliferation was examined 7 days after transplantation, almost 50% of
the H-2Kb-specific T cell population within the
spleen had divided in response to the heart allografts, whereas in
animals that had received either skin or islet allografts no
proliferation above that seen in nongrafted mice was observed (Table II). The proliferation of the H-2Kb-specific T
cells to the three different grafts was also shown to correlate with
the up-regulation of CD69 and CD44 (markers of activation). Activated
H-2Kb-specific T cells were found in the spleen
only after transplantation of a heart allograft (data not shown).
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). By 7 days posttransplant,
CD8+ T cells were readily detected in all three
graft types. These data indicated that the
H-2Kb-specific T cells had infiltrated the skin
and islet grafts with slower kinetics than the heart grafts.
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).
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In the transplantation setting, T cell activation is thought to
occur within the lymphoid tissues draining the graft site (12, 13). Therefore, the spleen may not be the optimal location in
which to observe the activation of alloreactive T cells after skin and
islet transplantation. To address this possibility, we compared the
pattern of T cell proliferation and homing within the left axillary
lymph nodes 1, 3, and 7 days after either skin or heart
transplantation. The percentage of dividing
H-2Kb-specific T cells within the draining
axillary lymph nodes after skin transplantation was not increased
compared with either mice that had not received a transplant or over
the percentage of dividing cells within the spleen of skin grafted mice
(Fig. 3A). In fact, heart
allografts induced more alloantigen-specific T cell proliferation in
the left axillary lymph nodes, than the skin grafts. However, the
absolute number of H-2Kb-specific T cells present
in the left axillary nodes was dramatically increased in mice that had
received a skin graft (Fig. 3B; p <
0.05).
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Tc1-like memory cell generation after rejection of heart, skin, and islet allografts
Finally, H-2Kb-specific T cells were
analyzed in the spleen 25 days posttransplantation (i.e., after all
three graft types had been rejected). Analysis of the CFSE profile of
H-2Kb-specific T cells showed that in mice that
had received a heart allograft, 50% of cells had divided at least
six times in response to the graft (Fig. 4A). An identical assessment
of mice that had received a skin or islet graft revealed that these
mice also contained a significant proportion of
H-2Kb-specific T cells that had divided at least
six times, although the percentage of these cells was much lower than
in heart allograft recipients. Mice that were left untransplanted did
not contain cells that had divided more than six times (Fig. 4A). Therefore, although too few cells responded to the skin
and islet grafts to be detected at early time points, by 25 days
posttransplant a clear population of donor alloantigen-specific T cells
that had divided in response to the H-2Kb+ skin
and islet allografts could be identified. No difference in terms of the
absolute number of CD8+
Kb-specific T cells was noted between groups.
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on
restimulation (Fig. 4B). In contrast, the
H-2Kb-specific T cells that had failed to divide
in response to the grafts were unable to produce IL-2, and only a small
percentage (between 4 and 7%) were able to produce IFN-. No IL-4 or
IL-10 was produced by the H-2Kb-specific T cells
in any group irrespective of division (Fig. 4B). Cells
analyzed from mice that did not receive a transplant failed to produce
any cytokine on restimulation, consistent with their naive phenotype
(data not shown). Not only did the CFSE-negative cells rapidly produce
cytokine on restimulation but also phenotypic analysis of these cells
revealed a memory phenotype in that they expressed high levels of CD44
and low levels of CD45RB (data not shown). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Initially, we defined the number of
H-2Kb-specific T cells that were required to
reject the different H-2Kb+ allografts. In
concordance with many others studies and the current dogma, it was
found that indeed skin and islet grafts were far more susceptible to
rejection than heart allografts (requiring some 6000-fold less cells;
Table I). Importantly, because rejection was mediated by T cells
recognizing a single allogeneic donor MHC class I molecule, a response
to tissue-specific Ags could not explain the differential
susceptibility of these grafts to rejection. The same was true with
anti-MHC class II responses given that transfer of 6 x
106 naive CD4+ T cells into
immunocompromised recipients resulted in acute skin allograft rejection
but failed to reconstitute rejection of allogeneic heart allografts
(C. I. Kingsley and A. R. Bushell, unpublished
observations).
The observation that skin and islet grafts remain susceptible to graft rejection in the absence of tissue-specific Ags has important clinical and experimental ramifications when attempting the induction of transplantation tolerance to these different grafts. For example, many experimental models of tolerance induction involve some form of Ag pretreatment before transplantation (23, 24). Although most of these models are highly successful at inducing heart allograft acceptance, many fail to prevent skin or islet graft rejection (3, 25). This finding has often been attributed to the presence of tissue-specific Ags on the graft that were not on the original donor cell inoculum. However, the data presented here suggest an alternative explanation in that if a proportion of donor-reactive T cells escapes the initial tolerization process while there may be an insufficient number of these cells to adversely affect a resistant graft such as a heart graft. there may be high enough numbers to reject a susceptible graft such as a skin or islet graft.
This hypothesis could also explain why donor reactive T cells can frequently be detected by in vitro analysis in animals that have accepted a resistant allograft (although at much reduced numbers compared with naive controls), and why animals tolerant of a primary graft that is relatively resistant to rejection often reject a skin graft from a genetically identical donor (25, 26, 27).
Tolerance induction strategies are unlikely to regulate the activity of all potentially alloreactive T cells. Although solid vascularized organs, such as the heart allografts used in this study, were able to resist destruction mediated by large numbers of activated alloreactive T cells (4 x 106); nonvascularized grafts, such as islets and skin, were rapidly rejected by a very limited number of alloreactive T cells (1 x 103). In a similar manner, the lack of success of clinical islet transplantation may, in part, be due to the inability of pharmacological immunosuppression to regulate the activity of the complete alloreactive T cell repertoire.
In addition to the presence of tissue-specific Ags, the susceptibility
of skin grafts to rejection has often been attributed to the large
numbers of LC found within the skin. After transplantation, these LC
become activated, increase their expression of MHC class II and
costimulatory molecules, and migrate via the lymphatics to the T cell
areas of the draining lymph nodes where they can provide a powerful
stimulus for graft rejection. However, when we directly examined the
ability of a skin graft to activate donor-reactive T cells, it was
clear that the skin graft was relatively inefficient at stimulating T
cell activation and proliferation even in the lymph nodes draining the
graft bed, which is exactly the site where the potent immunostimulatory
LC have been shown to migrate (Fig. 3) (12, 13). Indeed,
the H-2Kb-specific T cells failed to proliferate
or become activated (data not shown) in any lymphoid tissue at any
time-point studied within the first 7 days after transplantation (Table II). However, by 7 days post transplant the
H-2Kb-specific T cells were present in increased
numbers in the draining node and within the graft itself.
It is likely that either migrating LC had activated a small number of
peripheral T cells (which our system was not sensitive enough to
detect) which had then homed to the graft or that a proportion of the
naive T cells had migrated to the graft and did not proliferate in the
peripheral lymphoid organs. We favor the former explanation as entry
into the graft was not immediate (Fig. 1); and few
CFSE+ cells were present in any of the grafts 7
days after transplantation, suggesting that the infiltrating T cells
had divided outside the graft (data not shown).
Thus, these data suggest that the susceptibility of skin allografts to rejection is not based on a profound T cell response generated by the migratory, immunostimulatory LC. However, even with the activation of a relatively small number of donor-specific T cells, the skin graft itself may amplify and exacerbate the inflammatory response. Keratinocytes possess the ability to secrete an array of inflammatory cytokines and will act as APC after up-regulation of MHC class II molecules (28). In addition, expression of T cell adhesion molecules, such as E-selectin (29), and the high concentration of extracellular matrix glycoproteins, including fibronectin and laminin (30), allow the skin graft to attract and engage activated T cells efficiently.
Islet allografts, like skin allografts, were rejected by as few as
1 x 103 donor-specific T cells (Table I).
Islets contain only limited numbers of intragraft APC, and islet
endocrine cells are unlikely to express significant levels of MHC class
II during an inflammatory response (31, 32). As a result,
islets may be less efficient at activating alloreactive T cells than
other graft types. This fact was borne out by the finding that
relatively few heavily divided memory cells were detected 25 days after
transplantation. Inflammation, and the production of IFN-, would
up-regulate MHC class I expression by the islets rendering them more
susceptible to killing by activated, directly alloreactive cytotoxic
CD8+ T cells (33). In addition, IL-1
is a potent modulator of insulin secretion and at high concentrations
is cytotoxic to 
-cells (34, 35). Thus, as expected,
migrating APC and the subsequent activation of peripheral
H-2Kb-specific T cells did not correlate with the
susceptibility to rejection of islet grafts. Therefore, the small graft
size, sensitivity to cytokines, and requirement for revascularization
are likely to be the main contributors to the sensitivity of islet
allografts to rejection.
Equally interesting is the relative resistance of heart allografts to
rejection despite the marked activation of the alloreactive T cell
population (Tables I and II). This resistance to rejection, compared
with islet and skin grafts, may be simply a reflection of the larger
size of the heart. Sun et al. (36) demonstrated that
increasing the mass of transplanted organs prolonged graft survival.
Single heart or kidney transplants in the rat strains investigated were
acutely rejected, whereas simultaneous transplantation of two hearts
and two kidneys into a single recipient resulted in prolonged survival
of all the grafted organs.
Alternatively, vascularized grafts may also be afforded some protection from alloreactive T cells due to the expression of Fas ligand (FasL) by vascular endothelial cells (37). In this situation, when an activated T cell expressing Fas comes into contact with the vascular endothelium expressing FasL, the activated T cell may be induced to undergo apoptosis. Although the in vivo relevance of FasL expression by graft endothelial cells is unknown, it may be an important factor in down-regulating T cell-mediated rejection of vascularized grafts.
It has been well documented that there is greater
CD8+ T cell dependency on
CD4+ T cells during cardiac allograft rejection
than with skin and islet allografts. We would argue that because heart
allografts are more resistant to rejection than skin or islet grafts,
either the response would need to be more aggressive per cell or a
greater number of cells would need to respond (as evidenced in Table I)
to cause rejection. CD4+ T cells therefore may be
required to a greater extent in heart allograft rejection to provide
growth factors such as IL-2 to either enable CD8+
T cells with low affinity for alloantigen to respond optimally or to
increase the ability of CD8+ T cells to induce
effector responses. However, when we have performed an analysis of the
response of the transgenic CD8+ T cells to a
cardiac allograft in the presence or absence of
CD4+ T cells, no difference was noted in the
response; we therefore favor the former explanation.
In conclusion, our results suggest that islet and skin allografts lie at the "difficult" end of the transplantation hierarchy due to the ability of very small numbers of alloreactive T cells to orchestrate their destruction in vivo, rather than the presence of tissue-specific Ags or the intrinsic ability of these nonvascularized grafts to stimulate T cells. The need for rigorous control of the alloreactive T cell population to ensure engraftment of skin and islet allografts has potential implications for the design of tolerance induction strategies and the need to tailor immunosuppressive drug regimens for these vulnerable allografts.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Nick D. Jones, Nuffield Department of Surgery, John Radcliffe Hospital, Oxford, OX3 9DU, U.K.
3 N.D.J. and S.E.T. contributed equally to this work.
4 Current address: Second Department of Surgery, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki-gun, Miyazaki, 889-1692, Japan.
5 Abbreviations used in this paper: LC, Langerhans cells; tg-TCR, transgenic TCR; AT, adoptive transfer; FasL, Fas ligand.
Received for publication January 18, 2000. Accepted for publication December 5, 2000.
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regulation of Fas ligand expression on the vascular endothelium modulates leukocyte extravasation. Nat. Med. 4:415.[Medline]
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K. R. Garrod, C. K. Chang, F.-C. Liu, T. V. Brennan, R. D. Foster, and S.-M. Kang Targeted Lymphoid Homing of Dendritic Cells Is Required for Prolongation of Allograft Survival J. Immunol., July 15, 2006; 177(2): 863 - 868. [Abstract] [Full Text] [PDF]
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N. D. Jones, M. Carvalho-Gaspar, S. Luo, M. O. Brook, L. Martin, and K. J. Wood Effector and Memory CD8+ T Cells Can Be Generated in Response to Alloantigen Independently of CD4+ T Cell Help J. Immunol., February 15, 2006; 176(4): 2316 - 2323. [Abstract] [Full Text] [PDF]
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I. I. Singer, M. Tian, L. A. Wickham, J. Lin, S. S. Matheravidathu, M. J. Forrest, S. Mandala, and E. J. Quackenbush Sphingosine-1-Phosphate Agonists Increase Macrophage Homing, Lymphocyte Contacts, and Endothelial Junctional Complex Formation in Murine Lymph Nodes J. Immunol., December 1, 2005; 175(11): 7151 - 7161. [Abstract] [Full Text] [PDF]
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L. Wang, R. Han, I. Lee, A. S. Hancock, G. Xiong, M. D. Gunn, and W. W. Hancock Permanent Survival of Fully MHC-Mismatched Islet Allografts by Targeting a Single Chemokine Receptor Pathway J. Immunol., November 15, 2005; 175(10): 6311 - 6318. [Abstract] [Full Text] [PDF]
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S. A. Quezada, K. Bennett, B. R. Blazar, A. Y. Rudensky, S. Sakaguchi, and R. J. Noelle Analysis of the Underlying Cellular Mechanisms of Anti-CD154-Induced Graft Tolerance: The Interplay of Clonal Anergy and Immune Regulation J. Immunol., July 15, 2005; 175(2): 771 - 779. [Abstract] [Full Text] [PDF]
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S. Schenk, D. D. Kish, C. He, T. El-Sawy, E. Chiffoleau, C. Chen, Z. Wu, S. Sandner, A. V. Gorbachev, K. Fukamachi, et al. Alloreactive T Cell Responses and Acute Rejection of Single Class II MHC-Disparate Heart Allografts Are under Strict Regulation by CD4+CD25+ T Cells J. Immunol., March 15, 2005; 174(6): 3741 - 3748. [Abstract] [Full Text] [PDF]
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K. Oh, S. Kim, S.-H. Park, H. Gu, D. Roopenian, D. H. Chung, Y. S. Kim, and D.-S. Lee Direct Regulatory Role of NKT Cells in Allogeneic Graft Survival Is Dependent on the Quantitative Strength of Antigenicity J. Immunol., February 15, 2005; 174(4): 2030 - 2036. [Abstract] [Full Text] [PDF]
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 T. Pearson, P. Weiser, T. G. Markees, D. V. Serreze, L. S. Wicker, L. B. Peterson, A.-M. Cumisky, L. D. Shultz, J. P. Mordes, A. A. Rossini, et al. Islet Allograft Survival Induced by Costimulation Blockade in NOD Mice Is Controlled by Allelic Variants of Idd3 Diabetes, August 1, 2004; 53(8): 1972 - 1978. [Abstract] [Full Text] [PDF]
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 Y. Chen, Y. Demir, A. Valujskikh, and P. S. Heeger Antigen Location Contributes to the Pathological Features of a Transplanted Heart Graft Am. J. Pathol., April 1, 2004; 164(4): 1407 - 1415. [Abstract] [Full Text] [PDF]
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S. Goddard, J. Youster, E. Morgan, and D. H. Adams Interleukin-10 Secretion Differentiates Dendritic Cells from Human Liver and Skin Am. J. Pathol., February 1, 2004; 164(2): 511 - 519. [Abstract] [Full Text] [PDF]
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C. He, S. Schenk, Q. Zhang, A. Valujskikh, J. Bayer, R. L. Fairchild, and P. S. Heeger Effects of T Cell Frequency and Graft Size on Transplant Outcome in Mice J. Immunol., January 1, 2004; 172(1): 240 - 247. [Abstract] [Full Text] [PDF]
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N. E. Phillips, T. G. Markees, J. P. Mordes, D. L. Greiner, and A. A. Rossini Blockade of CD40-Mediated Signaling Is Sufficient for Inducing Islet But Not Skin Transplantation Tolerance J. Immunol., March 15, 2003; 170(6): 3015 - 3023. [Abstract] [Full Text] [PDF]
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A. v. Maurik, M. Herber, K. J. Wood, and N. D. Jones Cutting Edge: CD4+CD25+ Alloantigen-Specific Immunoregulatory Cells That Can Prevent CD8+ T Cell-Mediated Graft Rejection: Implications for Anti-CD154 Immunotherapy J. Immunol., November 15, 2002; 169(10): 5401 - 5404. [Abstract] [Full Text] [PDF]
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Y. Bai, J. Liu, Y. Wang, S. Honig, L. Qin, P. Boros, and J. S. Bromberg L-Selectin-Dependent Lymphoid Occupancy Is Required to Induce Alloantigen-Specific Tolerance J. Immunol., February 15, 2002; 168(4): 1579 - 1589. [Abstract] [Full Text] [PDF]
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