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Department of Surgery, University of Cambridge, Cambridge, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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1 and 2 domains
of the RT1.Aa molecule. Several peptides were able to
accelerate both the alloantibody response to the intact
RT1.Aa Ag and PVG.R8 heart graft rejection. An
immunodominant epitope was identified within the hypervariable region
of the 1 domain. Fine mapping of this region with a second series of
peptides overlapping by single amino acids confirmed the presence of an
eight-amino acid core determinant. Additional "subdominant"
epitopes were identified, two of which were located within regions of
amino acid homology between the RT1.Aa and
RT1.Au molecules and not, as had been expected, within
other hypervariable regions. The contribution of self-epitopes to
indirect allorecognition was emphasized by the demonstration that i.v.
administration of a 15-mer peptide encompassing one of the subdominant
self-determinants diminished the recipient’s ability to mount an
alloantibody response on challenge with intact Aa
alloantigen. Our findings suggest that cryptic self-epitopes recognized
by autoreactive T cells may contribute to allograft rejection and
should be considered when designing novel strategies for inducing
tolerance to alloantigen. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Indirect T cell responses to allogeneic MHC are dependent on the ability of recipient APC to process and present MHC-derived peptides that can be recognized as immunogenic by recipient T cells. Few studies have attempted to comprehensively map the number and location of T cell epitopes that are involved in indirect allorecognition, but analysis of the T cell responses to nominal protein Ags has shown that constraints in Ag processing and presentation usually limit the T cell response to one or two dominant determinants (12, 13). The indirect T cell response to allogeneic MHC may similarly be limited to a small number of dominant epitopes that generally correspond to the hypervariable regions of donor MHC (8, 14, 15). However, there is also evidence highlighting the polyclonal nature of the indirect T cell response, suggesting the participation of multiple T cell determinants (5, 16, 17) and this may have important implications for the design of strategies for inducing specific immunosuppression.
We have previously demonstrated that the indirect pathway is responsible for the rejection of allografts between two rat strains differing only at the classical MHC class I locus RT1.A (2, 18, 19, 20, 21). PVG.R8 (RT1.Aa) cardiac allografts are rejected acutely by naive PVG.RT1u (RT1.Au) recipients, and T cell depletion and passive transfer studies have shown that CD4 T cell-dependent alloantibody mediates graft rejection in this experimental model. We hypothesized that CD4 T cells recognize the Aa molecule after it has been processed and presented in the context of class II MHC by recipient APC. A role for the indirect pathway was confirmed by the demonstration that recipients primed with synthetic RT1.Aa allopeptides rejected heart allografts more rapidly (18). Rejection was attributable to an accelerated alloantibody response, resulting from the provision of cognate B cell help by allopeptide-primed CD4 T cells.
In the present study, we used this model system to identify the T cell
determinants involved in the indirect recognition of class I MHC
alloantigen. A series of overlapping peptides spanning the 1 and
2 domains of the RT1.Aa molecule were used to
map the T cell epitopes responsible for generating help for
alloantibody production in vivo. We reasoned that assaying the
anti-Aa alloantibody response following
priming with synthetic Aa peptides would, in
contrast to relying on the use of in vitro T cell proliferation assays
alone, provide a functionally relevant assessment of the indirect T
cell response, since alloantibody is a known effector mechanism for
graft rejection in this experimental model. Using this approach, an
immunodominant epitope corresponding to the hypervariable region of the
1 domain was identified. Several subdominant epitopes were also
identified and, unexpectedly, at least two of these were located in
regions of amino acid identity in the Aa and
Au haplotypes. The implications of this finding
and the potential contribution of autoreactive T cells to allograft
rejection are discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Congenic PVG.RT1u (Au B/Du Cu) and recombinant PVG.R8 (Aa B/Du Cu) rats were purchased from Harlan U.K. (Bicester, Oxon, U.K.). The derivation of the PVG.RT1u and PVG.R8 rat strains is cross-referenced elsewhere (21). All animals were maintained under standard conditions and used when 8–12 wk old.
Allopeptides
Epitope mapping was undertaken using a series of eighteen 15-mer
peptides (designated peptides 1–18), each overlapping by 5 aa and
spanning the 1 and 2 domains of the RT1.Aa
molecule (residue 1 (glycine) to residue 185 (proline) of the 1
domain) (22). Peptides were obtained from Immune Systems
(Paignton, U.K.) and were synthesized by standard F-moc chemistry,
purified by HPLC, and assessed by mass spectrometry (peptide purity
>80%). An additional 15-mer peptide (YAQWEIQKERERQTI) was synthesized
for use as an irrelevant control peptide. It comprised the same amino
acids as those in peptide 7, but in random order.
Fine epitope mapping was performed using another series of 15-mer
peptides overlapping by single amino acids and spanning the
hypervariable region of the 1 domain of the
RT1.Aa molecule (residue 57 (proline) to residue
85 (tyrosine) of the 1 domain, see Fig. 1
).
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PVG.RT1u rats were immunized by s.c. injection into each hind footpad of 50 µg of peptide dissolved in 50 µl of distilled water and emulsified with a comparable volume of CFA (Sigma, Dorset, U.K.).
Cardiac transplantation
PVG.R8 heart grafts were transplanted into PVG.RT1u recipients according to the modified technique of Ono and Lindsey (23). The donor heart was transplanted heterotopically into the abdomen using standard microsurgical techniques with end-to-end anastomosis of the donor aorta and pulmonary artery to the recipient infrarenal aorta and vena cava, respectively. Cold ischemic times were <30 min. Grafts were assessed by daily palpation and rejection was defined as the complete cessation of myocardial contraction.
Skin transplantation
PVG.RT1u recipients were grafted on the flank with full-thickness PVG.R8 skin grafts as described elsewhere (24).
Blood transfusion
PVG.RT1u rats were injected with 1.5 ml of heparinized PVG.R8 blood i.v. into the dorsal penile vein.
Cytotoxic alloantibody determination
Lymphocytotoxic Abs in serum samples were detected by their ability to lyse 51Cr-labeled, Con A-transformed splenic blasts in the presence of guinea pig complement, as described elsewhere (25). Percent specific 51Cr release was calculated by the formula: (experimental release - spontaneous release)/(maximum release - spontaneous release) x 100.
Anti-peptide Ab determination
Peripheral blood serum samples were tested for the presence of Abs to synthetic peptides using an indirect radioactive binding assay. Briefly, 96-well plates were coated with 50 µl/well peptide at 100 µg/ml in 0.15 M NaCl for 18 h at 4°C and then washed three times with PBS/0.1% BSA. Plates were blocked with 200 µl of Meggablock III (Bionostics, Wyboston, Bedfordshire, U.K.) for 2 h at 37°C and washed before adding tripling dilutions of test serum diluted in PBS/0.5% BSA (50 µl/well). After a 2-h incubation at 37°C, plates were washed and bound anti-peptide Ab was detected with 50 µl/well 125I-labeled sheep F(ab')2 anti-rat Ig (Amersham International, Amersham, U.K.) diluted 100-fold in PBS/0.5% BSA. Following incubation for 1 h at 37°C, plates were washed and bound radioactivity was measured.
T cell proliferation assays
Lymph node cells (LNC)3 were prepared from pooled popliteal, cervical, and mesenteric lymph nodes and resuspended at a concentration of 4 x 106 cells/ml in RPMI 1640 enriched with 2% heat inactivated syngeneic normal rat serum, 100 U/ml penicillin, 100 µg/ml streptomycin, 2 mM L-glutamine, and 50 µM 2-ME. LNC (100 µl) were added to 96-well U-bottom plates and peptide was added to a final concentration of 40 µg/ml in a final volume of 200 µl/well. Plates were incubated at 37°C in 5% CO2 for 72 h, pulsed with 1 µCi/well [3H]thymidine, and incubated for another 24 h before harvesting. Incorporated [3H]thymidine was determined using a liquid scintillation beta counter. Results are expressed as a stimulation index, calculated as experimental counts/control counts.
Statistical analysis
Differences between groups were compared by nonparametric analysis using the Mann-Whitney U test. All p (two tailed) <0.05 were considered to be significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 and
2 domains of the Aa molecule were used. The
initial set of peptides used were designated peptides 1–18. As shown
in Fig. 1
, peptides 7 and 8
(corresponding to the hypervariable region of the 1 domain) and
peptides 15, 16, and 17 (corresponding to the hypervariable regions of
2 domain) contained the greatest number of amino acid disparities
(4–9 residues). Eight of the 18 RT1.Aa-derived
peptides used had identical sequences to the corresponding region of
the RT1.Au molecule. Immunogenicity of allopeptides
Peptides encompassing T cell epitopes involved in the indirect allorecognition of Aa class I MHC would be expected to stimulate a peptide-specific in vitro T cell proliferative response and/or anti-peptide Ab response. We therefore sought to establish which of the 15-mer Aa peptides were immunogenic by immunizing PVG.RT1u rats s.c. with individual peptides emulsified in CFA. Twelve days later, LNC were assessed for their ability to proliferate in vitro to peptide and circulating serum was assayed for the presence of anti-peptide Ab by an indirect radioactive binding assay.
The proliferative response of lymphocytes to the immunizing peptide was
weak and only LNC obtained from animals immunized with either peptide 1
or peptide 7 showed a stimulation index of >2 (Fig. 2a). LNC from rats immunized
with peptide 7 did not proliferate to peptide 1 in vitro and vice
versa, suggesting the presence of distinct peptide 1- and peptide
7-specific T cells rather than T cells recognizing both peptides (data
not shown). The 18 peptides tested also displayed limited ability to
stimulate anti-peptide Abs. Only animals immunized with peptides 7 and
16 developed a detectable Ab response (Fig. 2b), suggesting
that these two peptides encompass CD4 T cell determinants. It was not
surprising that peptides 7 and 16 (which correspond to the
hypervariable regions of the 1 and 2 domains of the
RT1.Aa Ag, respectively) were immunogenic. The
ability of peptide 1 to stimulate a T cell proliferative response was
not predicted from the amino acid sequence data, since the 15-mer
sequence corresponded to a region of the 
-pleated sheet of the 2
domain that is identical in the RT1.Aa and
RT1.Au molecules. It is likely that peptide 1
failed to stimulate an anti-peptide Ab response because the linear
peptide does not constitute a B cell determinant.
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To determine the T cell epitopes involved in the indirect
allorecognition of the RT1.Aa molecule,
PVG.RT1u animals were immunized with a
vascularized PVG.R8 cardiac allograft or a skin allograft and their LNC
were tested for in vitro proliferation against individual peptides. LNC
from PVG.RT1u rats primed with either a PVG.R8
heart graft or a PVG.R8 skin graft alone showed minimal proliferation
to the panel of Aa peptides (data not shown). The
lack of in vitro lymphocyte proliferation to allopeptide after
transplantation with a single graft is consistent with the findings of
Fangmann et al. (26), who noted that lymphocytes obtained
from rats primed by one transplant alone did not proliferate
effectively to donor allopeptides. PVG.RT1u rats
were, therefore, primed with a full-thickness R8 skin graft followed 10
days later by a PVG.R8 cardiac allograft. LNC from such animals
displayed a modest proliferative response to peptide 7 and a weaker
response to peptide 8, suggesting the presence of a dominant T cell
determinant within the hypervariable region of the 1 domain (Fig. 3).
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PVG.RT1u rats develop a CD4 T cell-dependent
anti-Aa lymphocytotoxic alloantibody response
following exposure to intact Aa alloantigen in
the form of a PVG.R8 blood transfusion (25). Blood
transfusion, therefore, provides a straightforward and reproducible
model in which to determine the ability of peptide immunization to
influence the kinetics of this alloantibody response. Those peptides
that accelerate the alloantibody response can be assumed to encompass a
linear T cell epitope that is presented to CD4 T cells by
Aa-specific B cells after internalization and
processing of the intact RT1.Aa Ag.
PVG.RT1u rats were immunized with individual
15-mer peptides in CFA and then 7 days later challenged with a PVG.R8
blood transfusion. Serum samples were obtained on days 4 and 7 after
blood transfusion and the level of anti-Aa
alloantibody was determined by assaying against PVG.R8 lymphoblast
target cells. In this, as in our previous studies (18, 19), immunization with Aa peptides did
not, in the absence of blood transfusion, stimulate the development of
anti-peptide Abs cross-reactive with intact
RT1.Aa on target cells (data not shown). By day 4
after blood transfusion, recipients that had been immunized with
peptides 1, 7, 8, and 9 showed significantly higher levels of
circulating cytotoxic anti-RT1.Aa
alloantibody than animals immunized with control peptide (Fig. 4). This experiment therefore confirmed
the presence of a dominant T cell determinant(s) corresponding to the
hypervariable region of the 1 domain. Additional T cell epitopes
encompassed by peptides 1 and 9 were revealed and categorized as
subdominant because they influenced the recall response to challenge
with intact alloantigen. Peptide 9, like peptide 1, is consensual in
the corresponding regions of the RT1.Aa and
RT1.Au molecules. None of the other consensual
peptides (peptides 2, 3, 5, 12, 13, and 14) primed for
RT1.Aa alloantibody production. A possible
explanation for their lack of immunogenicity is that they may encompass
immunodominant self-epitopes, resulting in thymic deletion of
peptide-specific T cells. Alternatively, some of the consensual
peptides tested may lack immunogenicity because they do not bind with
sufficient avidity to MHC class II to stimulate a T cell response.
Peptide binding studies would help to distinguish these two
possibilities.
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b),
did not lead to an accelerated anti-RT1.Aa
alloantibody response. Presumably, the T cell epitope encompassed by
peptide 16 is not presented by Aa-specific B
cells that encounter intact Aa alloantigen.
Peptides that had been shown to accelerate the alloantibody response to
a PVG.R8 blood transfusion (peptides 1, 7, and 8), along with selected
uninvolved peptides (peptides 4, 12, and irrelevant peptide), were
tested further for their ability to influence the alloimmune response
to a PVG.R8 heart graft. As shown in Table I (group 1), naive
PVG.RT1u rats reject
Aa-disparate PVG.R8 heart grafts rapidly (mean
survival time (MST), 7 days). Of the peptide-immunized animals,
recipients immunized with peptide 7 (encompassing an immunodominant T
cell determinant; Table I, group 4) rejected their grafts most rapidly
and rejection was significantly faster than that of control animals
(MST, 4 days vs 7 days, respectively, p < 0.05).
Recipients immunized with peptides 1 and 8 (groups 2 and 5,
respectively) also displayed accelerated allograft rejection (MST, 5
days, p < 0.05), whereas immunization with peptides 4
and 12 (groups 3 and 6, respectively) did not accelerate graft
rejection (MST, 7 days). The effects of peptide priming were not
synergistic; immunizing with all 18 peptides (group 8) resulted in a
similar acceleration in PVG.R8 heart graft rejection as immunizing with
individual peptides alone. The accelerated kinetics of heart graft
rejection corresponded to a more rapid
anti-Aa alloantibody response; sera from
PVG.RT1u animals primed with peptides 1, 7, and 8
contained higher levels of cytotoxic alloantibody at day 4 following
heart grafting than peptides 4, 12, and the irrelevant peptide (Fig. 5).
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1 domain of RT1.Aa
The above analysis revealed that peptides 7 and 8 both encompassed
a Th cell determinant, but not whether this represented a shared,
rather than two distinct, T cell determinant. Moreover, it was not
clear whether the immunodominant T cell determinant identified was
optimally represented by peptide 7 and did not, for example, extend to
include adjacent C-terminal amino acids. A second set of fifteen 15-mer
peptides (designated peptides A–O, Fig. 6), overlapping by single amino acid
residues and spanning the hypervariable region of the 1 domain of
RT1.Aa (from residue 57 [proline] to residue 85
[tyrosine], see Fig. 1), were therefore used to map this region more
precisely. Animals were primed by s.c. injection of individual peptides
in CFA and the alloantibody response to challenge with a PVG.R8 blood
transfusion determined. Peptides E through to L all caused accelerated
alloantibody production (Fig. 7). This
suggests the presence of a T cell determinant with a core amino acid
octamer comprising KEWEQIYR that is located at the C-terminal end of
peptide 7 (designated peptide E in this analysis), and contains four
disparate amino acid residues. In addition peptides A, B, and O also
accelerated alloantibody production (Fig. 7), suggesting the presence
of further T cell epitopes flanking the central octamer and
attributable to the presence of additional amino acid disparities
within the hypervariable region of the helix.
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The identification of subdominant determinants within peptides 1
and 9 raised the question as to whether these self-determinants were of
relevance as potential targets for manipulating the indirect helper T
cell response to intact Aa alloantigen. In animal
models of autoimmune disease, the i.v. administration of pathogenic
peptide at a high dose may attenuate disease progression (27, 28). We therefore examined the ability of selected peptides
(peptides 1, 7, and 15) when given i.v. to down-regulate the subsequent
Ab response to Aa alloantigen. Peptides 1 and 7
both effectively down-regulated the cytotoxic alloantibody response to
a PVG.R8 blood transfusion (Fig. 8). The
functional relevance of our mapping studies was confirmed by the
demonstration that the i.v. administration of peptide 15 (that
corresponds to the hypervariable region of the 2 domain and contains
6 disparate amino acids) did not reduce the
anti-Aa alloantibody response (Fig. 8). This
experiment suggests that self-determinants may be legitimate targets
for inhibiting T cell-dependent alloantibody production.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 and 2 domains of
RT1.Aa for their ability to prime CD4 T cells in
PVG.RT1u rats and thereby accelerate the
alloantibody response to subsequent challenge with intact
Aa alloantigen. Two principal findings emerged.
First, multiple T cell epitopes were identified within the
Aa molecule, recognition of which provided T cell
help for alloantibody production. Second, the T cell determinants
identified were located not only in the hypervariable region of
RT1.Aa but also in regions of the
Aa molecule where there was sequence identity
with RT1.Au.
Comprehensive mapping of the T cell epitopes involved in indirect
allorecognition by analysis of their ability to prime the response to
challenge with intact alloantigen has not previously been undertaken.
Earlier studies have assessed the ability of T cells from recipients
primed with intact alloantigen to respond in vitro to challenge with
allopeptides (8, 16, 17, 29). The most detailed study of
this type was performed by Benichou et al. (14). In each
of three different mouse strain combinations tested, T cells from
animals immunized with allogeneic MHC proliferated in vitro to a single
immunodominant epitope that was located in the hypervariable region of
the donor class II MHC. When, in the present study, the in vitro
proliferative response of lymphocytes from recipients primed by
sequential class I MHC-disparate allografts was examined, an
immunodominant T cell epitope (encompassed by peptide 7) corresponding
to the hypervariable region of the 1 domain of
RT1.Aa was identified. The location of an
immunodominant epitope within the hypervariable region of the
RT1.Aa molecule is consistent with previous less
detailed mapping studies (16, 30). There are several amino
acid disparities between the 1 domains of
RT1.Aa and RT1.Au, and
presumably the four disparate amino acid residues within the core
octameric epitope identified in this study provide a recognition motif
for alloreactive T cells.
The additional T cell epitopes identified in this study were not apparent from measurement of either the proliferative response or the Ab response to linear peptide. They were instead identified through an in vivo functional readout that reflected priming of T cells providing help for alloantibody production. Previous studies have also found that the nature of the T cell epitopes differs according to whether an in vitro or in vivo approach was adopted (31, 32). In the present study, failure of in vitro proliferation assays to reveal all of the immunogenic peptides can be explained on the basis that lymphocyte proliferation correlates poorly with T cell cytokine production. We chose, for the reasons already outlined, to map T cell epitopes through their ability to promote T cell help for B cells, but it would also be of interest to examine whether alternative in vivo assays of T cell cytokine production, such as a delayed-type hypersensitivity assay, reveal the same or a different set of immunogenic epitopes.
Epitopes identified through the ability of peptide immunization to
influence the recall response to intact protein Ag can be designated
subdominant (12). The location of subdominant T cell
epitopes within the RT1.Aa molecule could not
have been predicted on the basis of amino acid disparity alone. It is
notable that immunization with peptides corresponding to the
hypervariable region of the 2 domain, where there are several amino
acid disparities between RT1.Aa and
RT1.Au, did not prime for accelerated
alloantibody production. Conversely, immunization with peptides 1 and 9
(derived from the -pleated sheets of the 1 and 2 domains,
respectively) resulted in an accelerated alloantibody response and this
correlated with accelerated heart graft rejection. Both peptides
correspond to regions of RT1.Aa where there is
amino acid identity with RT1.Au. They therefore
encompass cryptic self-epitopes (33) recognized by
potentially autoreactive T cells, and immunization with these peptides
in the presence of adjuvant is evidently sufficient to overcome the
peripheral mechanisms that normally prevent the development of
autoimmunity. Benichou and colleagues (34) have recently
reported that immunization of mice with allogeneic splenocytes led to
an autoimmune T cell response directed against a self class I MHC
peptide. A subsequent study by the same group demonstrated that cardiac
transplantation in the mouse triggered a T cell autoimmune response
directed against cardiac myosin and that sensitization of recipient
mice with cardiac myosin accelerated heart graft rejection
(35). The results of the present study and those of
Benichou and colleagues (33, 34, 35) highlight the potential
contribution of T cells directed against cryptic self-epitopes to
allograft rejection.
The identification of subdominant epitopes through their ability to prime helper T cells for B cell help may be of particular relevance to the investigation of chronic allograft rejection. In the early phase of the alloimmune response, the direct pathway of allorecognition may be dominant due to the large precursor frequency of recipient T cells that recognize intact donor MHC on the surface of donor APC (36). Because donor APC within a graft are soon replaced by APC from the recipient (37), T cells that recognize donor MHC indirectly as peptide fragments are likely to play an increasingly important role and may be responsible for chronic rejection (1). A role for indirect allorecognition in chronic rejection is supported by the recent observation that allograft vasculopathy is accelerated in animals primed with donor MHC class I-derived peptides (38). Moreover, chronic allograft vasculopathy is still observed in experimental models in which the graft lacks donor strain APC (39). Evidence that indirect allorecognition contributes to chronic allograft rejection in humans is provided by the demonstration that T cells obtained from patients with chronic rejection display specificity for donor MHC-derived peptides (40, 41, 42, 43).
As the alloimmune response develops, indirect T cell specificity spreads to include additional epitopes other than the immunodominant epitopes that were the focus of the initial acute response (41). Similar shifts in T cell reactivity have been noted in experimental models of autoimmunity (13) and rather than simply representing a marker of ongoing immune activation, they appear integral to the progression of disease (44). B cells may play a pivotal role in epitope spreading because their unique efficacy for capturing Ag-Ab complexes confers them with the potential to present additional donor epitopes at levels above the threshold required for T cell activation (45, 46). In the present study, the T cell epitopes identified reflect not only the presence of an appropriate T cell repertoire, but also the ability of the B cell to process the intact class I alloantigen and present a relevant T cell epitope. We hypothesize that, in the context of chronic rejection, presentation of subdominant epitopes by B cells results in the activation of additional helper T cell clones and that this spreading of T cell reactivity contributes to the development of chronic rejection.
The effector mechanisms by which T cells with indirect specificity for alloantigen effect chronic rejection remain unclear. One of the likely mechanisms is through provision of B cell help for alloantibody production (11, 47), and several recent studies have emphasized the role of anti-MHC class I alloantibody in the development of chronic allograft vasculopathy (48, 49, 50). In addition, helper T cells with indirect specificity for donor alloantigen may effect chronic graft rejection by initiating a delayed-type hypersensitivity-like response (10), or by providing help for CD8 T cell effector functions (51).
The results from the present study clearly demonstrate the ability of cryptic self-epitopes to provide help for alloantibody production. It is interesting to speculate that during chronic allograft rejection, T cell-B cell determinant spreading results in the activation of autoreactive T cells recognizing cryptic self-epitopes. This may promote alloantibody production and augment chronic rejection. The observation in the present study that the i.v. administration of a self-peptide reduced the subsequent alloantibody response suggests that peptide-based strategies for inducing Ag-specific tolerance may be more effective if cryptic self-epitopes are additionally targeted.
In conclusion, our results highlight the complexity of the indirect T cell response to alloantigen. They suggest that cryptic self-epitopes recognized by autoreactive T cells may contribute to the alloimmune response and might be an important consideration in the design of novel strategies for inducing tolerance to alloantigen.
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Footnotes |
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2 Address correspondence and reprint requests to Prof. J. Andrew Bradley at the current address: Department of Surgery, Box 202, Addenbrooke’s Hospital, Cambridge, CB2 2QQ, U.K. E-mail address: jab52{at}cam.ac.uk
3 Abbreviations used in this paper: LNC, lymph node cell; MST, median survival time.
Received for publication June 14, 2001. Accepted for publication August 21, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-helices of allogeneic class I major histocompatibility complex antigens are potent inducers of CD4+ and CD8+ T cell and B cell responses after cardiac allograft rejection. Transplantation 59:401.[Medline]
-dependent switching of IgG alloantibody subclass. Eur. J. Immunol. 26:1217.[Medline]
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