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*
Department of Surgery and Immunogenetics and Transplantation Laboratory,
Microsurgical Laboratory, and
Department of Pathology, Davies Medical Center, University of California School of Medicine, San Francisco, CA 94114.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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334–352, a known myocarditogenic determinant, were
detected in heart-transplanted mice. No responses to CM were observed
in mice that had received an allogeneic skin graft or a syngeneic heart
transplant, demonstrating that this response is tissue specific and
that allogeneic response is necessary to break tolerance to CM. Next,
we showed that sensitization of recipient mice with CM markedly
accelerates the rejection of allogeneic heart. Therefore,
posttransplant autoimmune response to CM is relevant to the rejection
process. We conclude that transplantation-induced autoimmune response
to CM represents a new mechanism that may play a significant role in
cardiac transplant rejection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cell responses to intact or processed allogeneic MHC molecules displayed on the donor tissues initiate allograft rejection (4, 5, 6). We recently reported that, following injection of recipient mice with allogeneic cells, in vivo T cell response to donor MHC molecule resulted in the breakdown of immune T cell tolerance to a recipient self Ag (7). In this model, the self MHC class I peptide Dd 61–80 was dominant in syngeneic BALB/c mice (H-2d). T cell tolerance to Dd 61–80 in this mouse strain resulted in the absence of T cell proliferation following in vivo priming with Dd 61–80 peptide. However, we showed that transplantation of BALB/c mice with allogeneic B10.A (H-2a) splenocytes led to an autoimmune T cell response toward the dominant self peptide Dd 61–80. This phenomenon was Ag specific, since no T cell responses to Dd 61–80 peptide were observed after transplantation of "third party" C57BL/6 (H-2b) splenocytes into BALB/c recipients (7). In addition, we provided evidence that indicated that the breakdown of tolerance to Dd 61–80 self peptide resulted from the presentation of the donor cross-reactive peptide Kk 61–80 at the surface of recipient APCs. This previous study demonstrated that T cell-mediated alloresponse can induce autoimmune responses to a previously tolerogenic autoantigen. However, whether this type of immune response occurs following organ transplantation and the relevance of this phenomenon to the rejection process remained open to question.
In the present article, to investigate whether heart autoimmunity is
induced during the rejection of cardiac allografts, we tested T and B
cell responses to cardiac myosin (CM)4 in
transplanted mice. CM was chosen because it is a well characterized
cardiac tissue-specific protein that has been identified as the target
autoantigen in autoimmune myocarditis. This cardiac autoimmune disease
causes severe cardiac malfunction and ultimate failure in patients.
Experimental autoimmune myocarditis (EAM) in mice represents the best
characterized animal model for human myocarditis. In EAM, chronic
inflammation and myocyte damage are associated with activation of
CD4+ T lymphocytes specific to CM and with local deposition
of anti-CM autoantibodies. Furthermore, immunization of susceptible
mice with CM is sufficient to elicit EAM in rodents (8, 9, 10, 11). In the
present article, we observed that, after transplantation of allogeneic
heart in mice, B and T cell immune tolerance to CM self protein was
broken, as demonstrated by the presence of activated anti-CM
autoreactive lymphocytes in graft recipients. Tansplantation of mice
with allogeneic hearts triggered a vigorous T cell autoimmune
response to CM and its dominant determinant myhc
334–352. This phenomenon was associated with a histopathology that is
typical of EAM (12). Importantly, we then provided direct evidence
showing that this postheart transplant autoimmune response to CM can
enhance antigraft immunity, thus contributing to the rejection process.
The implications of this finding for understanding the immunological
mechanisms underlying allotransplant rejection are discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The A/J (Kk Ak Ek Dd) and A.TL (Ks Ak Ek Dd) mice were obtained from The Jackson Laboratory (Bar Harbor, ME). The care of all animals involved in this study was in accordance with institutional guidelines. Vascularized heterotopic cardiac transplantation was performed as described by Corry et al. (13). Briefly, mice were anesthetized with pentobarbital injected i.p. (2 mg/mouse) and used either as donors or recipients. Donor hearts were anastomosed to recipient aorta and vena cava using microsurgical procedures. The function of transplanted hearts was monitored daily by palpation through the abdominal wall. Heart beat intensity was graded on a scale of 0 (no palpable impulse) to 4 (strong impulse). Rejection was determined to be the time when heart impulse declined to 1–0 for two consecutive days. Statistical analysis was performed using paired t test.
Peptides
Peptides were synthesized utilizing F-moc chemistry by Research
Genetics (Huntsville, AL) and purified by HPLC (purity >95%). The
amino acid sequences of the peptides were as follows:
myhc 334–352: DSAFDVLSFTAEEKAGVYK; P12–26:
LEDARRLKAIYEKKK.
Histology
At the time of rejection, mice were sacrificed; then donor hearts were removed, fixed in neutral buffered formalin (Sigma, St. Louis, MO), and embedded in paraffin. Several cross-sections of each heart in the atrial-apical axis were then prepared. Sections were stained with hematoxylin and eosin.
Induction of EAM
To induce EAM, mice were injected into rear footpads and i.p. with 80 µg of murine CM emulsified in CFA on days 0 and 7. Mice also received a single i.p. injection of 500 ng of pertussis toxin (List Biologicals, Detroit, MI) on day 0 (10). Murine CM was purified as described by Schiverick et al. (14). The purity of preparations (>95%) was determined by SDS-PAGE. The myosin concentration was assessed spectrophotometrically using BCA Protein Assay kit (Pierce, Rockford, IL). Myosin was dissolved in 50 mM sodium pyrophosphate and stored at -80°C.
Cytokine measurement
At the time of rejection (10–13 days posttransplant), spleens
were harvested from recipient A/J mice transplanted with either
syngeneic (A/J) or allogeneic A.TL hearts. Suspensions of
106 spleen cells were plated in 96-well dishes in AIM-V
medium (Life Technologies, Grand Island, NY) supplemented with 1% of
FCS (Gemini Bioproducts, Calabases, CA). IFN-
production was
measured using ELISA assay. Briefly, 96-well microtiter ELISA plates
(Corning, Corning, NY) were coated with capturing rat anti-mouse
IFN- mAb R4-6A2 (PharMingen, San Diego, CA) at 1 µg/ml in
bicarbonate coating buffer (pH 8.2) and incubated overnight at 4°C.
After blocking with PBS containing 2% BSA (Sigma), supernatants from
cell cultures were added to the wells and incubated overnight at 4°C.
For detection of bound IFN-, biotinylated rat anti-mouse IFN-
mAb XMG 1.2 (PharMingen) was used, followed by incubation with avidin
D-coupled HRP (Vector, Burlingame, CA). Peroxidase activity was
revealed with 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)
(ABTS) tablets (Sigma) dissolved in phosphate-citrate substrate buffer
(pH 5.0) containing H2O2. Absorbance was
measured at 405 nm. Concentration of detected IFN- (pg/ml) was
calculated using recombinant murine IFN- (PharMingen) as a standard.
Detection of anti-CM serum Abs
Mouse sera were tested for Abs to CM by ELISA as described elsewhere (15).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have previously reported that allotransplantation can disrupt
immune tolerance to some self proteins (7). Here, we investigated
whether this phenomenon occurs after cardiac transplantation and
whether it is associated with the rejection process. To address this, T
cell response to purified mouse CM was investigated in the spleen of
mice transplanted with allogeneic hearts. CM was chosen because it
represents a major contractile protein of heart tissue and because it
is a well-characterized cardiac tissue-specific Ag that has been
implicated in heart autoimmune pathology. In our study, single MHC
class I allele-mismatched A/J (Kk) and A.TL
(Ks) mice were used either as donors or recipients in
vascularized heterotopic cardiac transplant model (13). Allogeneic
hearts were consistently rejected at day 9.4 ± 0.3 (A/J 
A.TL)
and at day 8.6 ± 0.5 (A.TL A/J) after transplantation. In
contrast, syngeneic grafts survived indefinitely (>100 days). As shown
in Fig. 1
A, vigorous
anti-CM T cell response, as determined by IFN- production, was
observed in mice tested 10–13 days after transplant, and it was found
to be mediated by CD4+, MHC class II
(Ak)-restricted T cells (data not shown). No IL-4 and IL-5
production was detected, indicating that anti-CM response was
mediated by Th1 cells. No response was detected in the absence of Ag or
in the presence of the irrelevant hen eggwhite lysozyme (HEL) control
Ag (Fig. 1). No anti-myosin T cell autoimmunity was observed in
normal mice and in those grafted with syngeneic hearts (Fig. 1) as well
as in mice that received an allogeneic skin transplant (data not
shown). These control experiments demonstrated that this phenomenon was
Ag and tissue specific. Most importantly, the absence of anti-CM
response after syngeneic heart graft showed that donor MHC-mediated
allogeneic response was necessary to break tolerance to CM. We conclude
that, following cardiac allograft, T cell tolerance to CM had been
disrupted, a phenomenon that resulted in de novo activation of
anti-CM CD4+ autoreactive T cells displaying Th1
phenotype.
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B, high titers of CM-specific autoantibodies were
detected in transplanted mice sera. Similar to EAM, the vast majority
of these anti-myosin Abs were of IgG1 isotype (15). No
anti-myosin B cell responses were observed in normal mice, or in
mice grafted with syngeneic hearts (Fig. 1B). The divergence
between the prevalent Th1-type cell response to CM and IgG1 isotype Ab
production may reflect a preexisting IgG1-type B cell memory to CM.
Taken together, our results demonstrate that, during acute cardiac
allograft rejection in mice, alloresponses to donor MHC Ags lead to the
induction of both humoral and cellular autoimmunity to CM.
CM has been shown to induce EAM in mice (12). Based upon the data
presented in Fig. 1, we investigated whether similar immune response to
CM in both EAM and allotransplantation would be associated with
comparable histopathology between hearts with EAM and cardiac
allografts. It has been reported that, following induction of EAM,
heart infiltration by anti-CM T cells is associated with adjacent
myocyte damage. To perform histologic examination of rejected hearts
and hearts with EAM, A/J mice were either transplanted with A.TL heart
allografts or injected with mouse CM along with CFA and pertussis toxin
to cause EAM (12). Hearts were removed following graft rejection (10
days posttransplant) or EAM induction (21 days postimmunization),
fixed, and embedded in paraffin. Cross-sections were stained with
hematoxylin and eosin. Histologic analysis revealed epicardial and
endocardial interstitial inflammatory cell infiltrates, myocyte
dropout, and necrosis in both transplanted and myocarditic hearts (Fig. 2, B and C). We
therefore conclude that, following cardiac allotransplantation,
allogeneic immune response leads to breakdown of tolerance to CM and
the subsequent induction of an autoimmune histopathology that is
characteristic of autoimmune myocarditis.
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Next, it was crucial to investigate whether the anti-CM
autoimmune response does actually influence the allograft rejection
process. To address this, we tested the effect of pretransplant
sensitization of recipients with CM on the course of cardiac transplant
rejection. Recipient mice were immunized i.p. with CM and then
transplanted 21 days later with allogeneic hearts. As shown in Fig. 3, CM-sensitized mice rejected donor
grafts in an accelerated fashion (5.2 ± 0.6 days,
p < 0.001; n = 5). Sensitization with
a control Ag, OVA, had no effect on transplant survival (9.5 ±
0.6; n = 4).
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). In addition, rejected syngeneic
hearts displayed histopathological features that were similar to those
of allogeneic transplants undergoing rejection (Fig. 4). This result demonstrated that, in the
absence of allogeneic stimulation, anti-myosin autoimmune response
per se is sufficient to elicit graft rejection.
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Taken together, our results show that 1) initial response to donor MHC molecule is a prerequisite for breaking tolerance to CM and, 2) once it has been elicited, anti-CM response alone can cause the rejection of transplanted heart. Therefore, posttransplant autoimmune response to CM is likely to represent an essential element of the rejection of allogeneic cardiac transplants.
myhc 334–352 CM-derived peptide is presented after
cardiac allograft
Next, we investigated the nature of the determinant(s) on CM
presented to T cells during heart allograft rejection. A previous study
by Donermeyer et al. has shown that immunization of A/J mice with the
peptide 334–352 of CM H chain (myhc 334–352)
induces EAM (16). It was possible that the same determinant could be
involved in anti-CM autoimmune responses occurring after heart
transplant. As shown in Fig. 5, when
tested 10–13 days after allogeneic cardiac transplantation, no T cell
response to myhc 334–352 peptide was detected in
recipient A.TL mice. However, at 50 days posttransplant, vigorous T
cell proliferative response (Fig. 5A) and IFN- production
(Fig. 5B) to myhc 334–352 were observed in
recipient spleens. Moreover, immunization of mice with
myhc 334–352 before transplantation resulted in modest
but statistically significant accelerated allograft rejection (7.3
± 0.4 days, p < 0.03). Therefore, in contrast to EAM,
initial anti-CM T cell response (day 10) is apparently not directed
to myhc 334–352 peptide but to another yet unidentified
CM determinant. However, at day 50 after grafting, secondary T cell
response to myhc 334–352 peptide occurs. This result
shows that 1) initial posttransplant T cell response to CM is directed
to a CM determinant that is distinct from the myhc
334–352 EAM-inducing peptide and, 2) after transplant rejection has
occurred, autoimmunity to CM persists and spreads to other determinants
on CM. This suggests that anti-CM autoimmune responses may play an
important role in long-term or chronic rejection of allotransplanted
hearts.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Two non-mutually exclusive mechanisms described in Fig. 6 may explain how the autoimmune process
is triggered by the alloresponse. 1) Inflammatory cytokines produced by
activated alloreactive T cells at the site of the graft may up-regulate
the presentation of existing CM/MHC class II complexes and induce the
expression of costimulatory molecules on cardiac APCs. Efficient
presentation of myocarditogenic CM determinants in the transplanted
heart may lower the threshold required for activation of formerly
silent CM-specific autoreactive T lymphocytes. 2) Alternatively,
myocardial damage by alloreactive T cells may cause the release of
circulating CM. De novo exogenous processing of extracellular
autoantigen by recipient APCs in peripheral lymphoid organs and/or in
the grafted heart might result in the presentation of new CM
determinants, thus sensitizing myocarditogenic T cells.
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334–352 peptide on CM (16). In the same study,
immunization with this peptide was shown to be sufficient to mediate
EAM. In our model, at day 10, no T cell response to myhc
334–352 peptide could be detected in transplanted mice while strong
autoimmune response to CM was measured. This indicates that, in heart
grafted mice, initial anti-CM immune response is directed to
determinants other than the myhc 334–352 peptide.
However, diversification of T cell response to myhc
334–352 self peptide occurs at a later time point (50 days) after
transplantation. Therefore, Ag spreading, a phenomenon previously
described in autoimmune diseases such as multiple sclerosis and
insulin-dependent diabetes (17, 18, 19), is also a feature of T cell
response to CM determinants during cardiac graft rejection. It is noteworthy that allotransplanted mice bear two vascularized hearts, their original heart and the transplanted hearts located in the thoracic and abdominal cavities, respectively. Interestingly, we observed only marginal focal inflammatory cell infiltration in the mouse’s own original heart, and, in contrast to the transplanted heart, no obvious signs of myocyte necrosis were observed. It may seem surprising that autoimmunity had apparently not spread from the transplanted to the native mouse’s cardiac tissue. However, the absence of trauma and of local inflammation in the nontransplanted heart may have resulted in the lack of chemokine and inflammatory cytocine production and of adhesion molecule up-regulation, thereby accounting for the absence of infiltration by immunocompetent cells. It is also important to note that initiation of autoimmunity to the unmanipulated heart in EAM model requires coinjection of the Ag and pertussis toxin. By activating APCs, pertussin toxin may elicit or exacerbate the presentation of self determinants to autoreactive T cells, thereby promoting local inflammation and cellular infiltration in the otherwise unmanipulated heart tissue.
Previous studies have provided some evidence for the involvement of tissue-specific Ags in allotransplant rejection (20, 21, 22). These responses were directed to minor histocompatibility Ags, i.e., tissue-specific proteins differing between donors and recipients. In addition, little information exists about their precise nature and the degree of their involvement in the rejection process. In contrast, in our model, CM is identical between donor and recipient mice, and it therefore does not represent a minor histocompatibility Ag. For the first time, to our knowledge, our study clearly identifies a tissue-specific Ag shared by donor and recipient that is involved in cardiac transplantation, and it establishes its contribution to the rejection process.
It is possible that anti-CM autoreactive responses account for the following clinical observations in heart transplant patients: 1) patients originally diagnosed with chronic myocarditis experience more frequent and severe rejection episodes than patients with other heart diseases (23); 2) an increase in the amounts of circulating CM following transplantation is associated with poor prognosis for cardiac transplant survival (24). Thus, heart transplantation-induced anti-CM autoimmunity is clinically relevant. Together with our observations, this suggests the need for monitoring this response as a diagnostic indicator of rejection.
Induction of autoimmunity may represent a general phenomenon in allotransplantation. Tissue Ags known to induce autoimmune disease, such as glutamic acid decarboxylase (insulin dependent diabetes) and type IV collagen (Goodpasture’s syndrome), could also be involved in the rejection of donor islets and kidney transplants, respectively (17, 25, 26, 27, 28, 29). Therefore, pathologies observed in transplanted patients and often diagnosed as recurrent autoimmune diseases may instead be the result of de novo autoimmunity caused by the transplantation itself (30). While T cell response to donor MHC alloantigens undoubtedly initiates graft rejection, secondary autoreactive responses to some organ-specific Ags may perpetuate and amplify the immune destruction of transplanted tissues. This implies that, in addition to the inhibition of T cell responses to donor MHC molecules, blocking of autoimmune responses to key tissue Ags, such as CM in heart transplantation, may represent a necessary therapeutic approach to achieve immune tolerance to donor cells and subsequent long-term transplant survival.
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Acknowledgments |
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Footnotes |
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2 Current address: Harvard Medical School, Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114.
3 Address correspondence and reprint requests to Dr. Gilles Benichou at the current address: Harvard Medical School, Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114.
4 Abbreviations used in this paper: CM, cardiac myosin; EAM, Experimental autoimmune myocarditis; HEL, hen eggwhite lysozyme.
Received for publication January 14, 1999. Accepted for publication March 19, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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3 chain of type IV collagen. J. Clin. Invest. 89:592.
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repressor peptide P12–26 (circles), or medium
alone for 4 days. Data are expressed as 
cpm (experimental
counts - medium counts). Data for an individual mouse are shown,
representative of three to eight mice tested. B,
myhc