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Departments of
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Surgery and
Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53792;
Department of Gastroenterological Surgery, Transplant, and Surgical Oncology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan;
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; and
¶ ICN Pharmaceuticals, Costa Mesa, CA 92626
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-producing T cells responding to H-2d-expressing APC in NIMAd-exposed vs control mice. Injection of pregnant BALB/c-dm2 (H-2Ld-negative) female mice i.v. with H-2Ld61–80 peptide profoundly suppressed the offspring’s indirect pathway alloreactive CD4+ T cell response to H-2Ld. These results suggest that the natural exposure of the fetus and newborn to maternal cells and/or soluble MHC Ags suppresses NIMA-allospecific T cells of the offspring, predisposing to organ transplant tolerance in adult mice. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study we tested the hypothesis that maternal Ag exposure alone can induce tolerance to a primarily vascularized organ allograft in mice. Our results are consistent with this hypothesis and further suggest that a NIMA effect is due to a profound inhibition of allospecific T and B cell responses in the offspring rather than to immune deviation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (H-2b/b), DBA/2 (H-2d/d), and (C57BL/6 x DBA/2)F1 (B6D2F1; H-2b/d) mice were obtained from Harlan Sprague Dawley (Indianapolis, IN). BALB/c-dm2 mice breeding pairs were obtained from The Jackson Laboratory (Bar Harbor, ME). The care and breeding of animals was in accordance with institutional guidelines. Offspring of F1 backcross breeding pairs (NIMA and noninherited paternal Ag (NIPA) offspring) were nursed by the mother, weaned after 21 days, and typed for H-2 locus encoded Ags. To investigate the effect of oral vs in utero exposure to NIMA, offspring from NIMA and homozygous C57BL/6 breedings were exchanged for each other directly after birth and foster-nursed. Typing was performed either by flow cytometry using Abs specific for H-2KbDb (clone 5041.16.1; Cedarlane, Westbury, NY) and H-2Dd (clone 34-5-8S, Cederlane) or by a genomic DNA-based typing described previously (21). Offspring typed as positive for both b and d haplotype Ags were used as skin and organ donors of semiallogeneic (H-2b/d) grafts to H-2b/b homozygous recipients. Both donors and recipients were 6–12 wk old at the time of transplantation.
Skin grafting
Skin transplantation was performed using a modification of a technique described previously (22). Ear skin was harvested from a donor as well as the recipient mouse (autologous skin graft), and both were then placed in graft beds prepared on the back of the recipient. The grafts were secured using gauze and a bandage, which were removed for scoring purposes 7 days later. The allograft was considered fully rejected when it was >90% necrotic.
Heart transplantation and histopathologic analysis
Heterotopic vascularized heart transplantation was conducted using the intra-abdominal microsurgical technique described by Corry et al. (23). The grafts were monitored by daily palpation and graded from 4+ (strongest beat) to 0 (no beat). Graft rejection was determined by complete cessation of heartbeat (grade 0) and was confirmed by laparotomy. Histopathologic analysis was performed on paraffin-embedded sections of heart allografts removed at necropsy. Sections were stained with either H&E or Trichrome and were scored blindly according to the established clinical criteria for diagnosing heart transplant rejection (24).
Analysis of maternal cell microchimerism by nested PCR
Cells from spleens, lymph nodes, and thymuses were harvested, and genomic DNA was isolated using the Wizard Genomic DNA Purification Kit (Promega, Madison, WI). The purity and concentration of the DNA were analyzed by spectrophotometry, and 0.5 µg was used for nested PCR. A region of the MHC class II Eb gene nonspecific for the d haplotype was amplified for 30 cycles (75 s at 94°C, 60 s at 56°C, and 105 s at 72°C). This was followed by a second amplification of a d-specific region for 14 cycles (60 s at 94°C, 60 s at 56°C, and 60 s at 72°C). Primers for nonspecific amplification were: A, 5'-ACCCTGGCAACATTGAAGTC-3'; and B, 5'-TTCCTGGT-CATGTTGAGAAA-3'. Primers for d-specific amplification were: A, 5'-AGACTCTGTGAATGCCTGCCT-3'; and B, 5'-AGCTAGCGGCAGAGGCTACAGCA-3'.
Peptides
The peptides used in this study were synthesized at Norris Cancer Center Microchemistry Laboratory, University of Southern California, with a PE Applied Biosystems model 430A automated peptide synthesizer (Foster City, CA) using modified Merrifield chemistry and were purified by Sephadex Glo chromatography to a purity of >95%. Peptides were dissolved at a concentration of 1 mg/ml in PBS (10 mM phosphate and 150 mM NaCl, pH 7.2) and further diluted to appropriate concentrations with assay medium.
Preparation of responder cells
Spleen cells were used as a source of responder T cells. RBC were lysed for 2 min in Tris-NH4Cl solution. Spleen cells were washed twice in AIM-V (Life Technologies, Grand Island, NY) culture medium containing 0.5% FCS and resuspended at 107 cells/ml. In some experiments T cells were isolated from mouse spleen cells by negative selection using commercially available T cell purification columns according to the manufacturer’s instructions (Accurate Chemical & Scientific Corp., Westbury, NY; R&D Systems, Minneapolis, MN). Purified T cells were washed in HBSS and used at 5 x 105 cells/well in ELISPOT assays.
Preparation of APCs and donor cell sonicates
Splenocytes from donor and recipient naive mice were used as a source of allogeneic stimulator cells or syngeneic APCs, respectively. Single-cell suspensions of splenocytes devoid of RBC were prepared in culture medium and were gamma-irradiated (3000 rad). The irradiated cells were washed in HBSS, incubated for 10 min at 37°C, washed again, and finally resuspended in culture medium at 1–3 x 107 cells/ml. In some experiments allogeneic spleen cells were suspended at 3 x 107 cells/ml in culture medium and sonicated with 10 pulses of 1 s. The resulting suspension was frozen in a dry ice/ethanol bath, thawed at room temperature, centrifuged at 1200 rpm for 10 min to remove intact cells, and used to stimulate recipient splenocytes.
ELISPOT assay
ELISPOT assay was conducted as described previously (25), using either a 1:2 responder to donor stimulator cell ratio for mixed lymphocyte cultures or syngeneic APCs together with donor sonicate to detect a response to soluble alloantigens and allopeptides. Briefly, ELISPOT plates (Polyfiltronics, Rockland, MA) were coated with mAb in PBS overnight. Anti-IL-2, -IFN-, -IL-4, and -IL-5 mAbs were used at 3, 4, 2, and 5 µg/ml (BD PharMingen, San Diego, CA). Plates were blocked with PBS containing 1% BSA for 1.5 h before cells were added and incubated at 37°C in 7% CO2 for different periods of time (20 h for IL-2, 42 h for IFN- and IL-4, and 48 h for IL-5). After washing, biotinylated anti-lymphokine mAbs were added at 2 µg/ml (BD PharMingen) and incubated for 5 h at room temperature or overnight at 4°C. Plates were washed three times with PBS containing 0.025% Tween (PBST), and avidin-HRP (diluted 1/2000) was added for 1.5 h. Four washes with PBS were performed before spots were revealed by the addition of developing solution (800 µl of 3-amino-9-ethylcarbazole (Sigma-Aldrich, St. Louis, MO) in 24 ml of 0.1 M sodium acetate, pH 5.0, catalyzed by 12 µl H2O2).
Allopeptide-specific proliferation assay
Popliteal lymph node cells and splenocytes were obtained 10 days after s.c. immunization with Ld61–80 peptide and were used in Ag-induced proliferation assays. Cell suspensions were cultured in 0.2 ml of serum-free HL-1 medium (Ventrex, Portland, ME) containing 2 mM glutamine in 96-well plates for 4 days (5 x 105 cells/well). T cells were stimulated in vitro with Ld61–80 peptide or an irrelevant hen egg lysozyme peptide (HEL46–61; 5–20 µg/ml). Proliferation was assessed by the incorporation of 1 µCi of [3H]thymidine during the last 18 h of culture.
Ab detection
Serum samples were taken from the tail of tolerant NIMAd-exposed (H-2b/b) (>100 days post-transplant with a DBA/2 heart graft), B6 mice with a rejected DBA/2 heart graft and nontransplanted (naive) C57BL/6 mice. Varying concentrations of the serum samples were incubated with 2 x 105 thymocytes/tube from DBA/2 or C57BL/6 for 30 min. After washing, secondary Abs, anti-mouse IgG1-FITC or anti-mouse IgG2a-FITC (Southern Biotechnology Associates, Birmingham, AL) were added. After 30-min incubation, cells were washed, and propidium iodide (5 µg/ml) was added to exclude dead cells from analysis. The mean fluorescence intensity was determined by flow cytometry (Calibur; BD Biosciences, San Jose, CA).
Statistical analyses
Statistical analysis of ELISPOT and graft survival data was performed using Student’s t test and Wilcoxon’s log rank test, respectively.
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Results |
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As illustrated in Fig. 1, we used the F1 x P backcross breeding scheme of Zhang and Miller (26) to generate H-2b/b mice that had a B6D2F1 mother and thus were NIMA-H-2d exposed. In addition, we prepared an NIPA control consisting of F1 x P backcross breeding of a B6 female with a B6D2F1 father, generating H-2b/b offspring that had not been exposed to maternal H-2d-Ags during development, but had a similar genetic background. These F1 backcross NIPA mice were used along with inbred B6 mice as H-2b/b (nonexposed to H-2d) controls.
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Histopathological analysis of no longer functional DBA/2 heart grafts transplanted into NIMAd-exposed animals (Fig. 3B, 24 days post-transplant) showed a less severe acute rejection pattern compared with the NIPA control (Fig. 3A, 8 days post-transplant). DBA/2 grafts from tolerant NIMA animals (Fig. 3, C and D, 293 and 338 days post-transplant) showed only mild leukocyte infiltrates and well preserved myocytes. A series of five tolerant animals (not shown) had varying degrees of acute rejection grades from IA to IIIA. The rejection grades were inversely correlated with the strength of the heart beat (1+ to 3+; see also Fig. 3, C–F).
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Prolongation of skin graft survival in NIMA-exposed offspring
Control B6 mice failed to reject semiallogeneic (H-2b/d) heart allografts (data not shown). However, they did reject semiallogeneic skin grafts, making it possible to compare the DBA/2 and B6D2F1 as donors in the same allograft system. NIMAd-exposed mice as well as NIPA and B6 controls were transplanted with semiallogeneic (H-2b/d) skin. All skin allografts were rejected. We observed a 3-day prolongation in median survival time of semiallogeneic (H-2b/d) skin grafts in NIMAd-exposed mice that was statistically significant compared with either NIPA (p < 0.01) or B6 (p < 0.02) control mice (Table I) and was consistent with a previous report (26). There was a slight increase in the mean graft survival time of fully allogeneic DBA/2 skin allografts in NIMAd mice compared with B6 control mice (p < 0.01; Table I); however, this was not significant when compared with NIPA controls (p = NS).
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To study the immunologic mechanism of the tolerogenic NIMA effect on heart allograft survival in vitro, we examined the frequency of cytokine-producing alloreactive T cells from nongrafted mice. As shown in Table II, we detected a potent primary response of IFN--, IL-2-, and IL-5-producing T cells from B6 control mice to both DBA/2 and B6D2F1 stimulator cells, the response to fully allogeneic APC being 
2- to 3-fold higher. Strikingly, all NIMAd-exposed F1 backcross mice (H-2b/b) displayed markedly lower cytokine responses; the frequency of cytokine-producing T cells responding to semiallogeneic splenocytes in NIMAd-exposed mice was reduced by 68–85%, while the average number of T cells responding to fully allogeneic DBA/2 stimulators was reduced by 36–75% relative to B6 controls (Table II).
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- and IL-2-producing) cells (78–85%-reduction; p < 0.01; Table II), we found no evidence for Th1 to Th2 immune deviation as a result of exposure to maternal alloantigens. Influence of NIMA exposure on alloreactive T cell responses after skin graft challenge
The influence of the semiallogeneic mother on the developing immune system of the NIMA offspring, while sufficient to overcome a full major plus minor histocompatibility barrier in the DBA/2 to B6 heart transplant model, was not able to induce tolerance to skin allografts. Nonetheless, the profound (68–85%) reduction in the pretransplant frequency of cytokine-responsive anti-F1 T cells relative to controls as well as the F1 skin graft prolongation data hinted that the NIMA effect in mice, as in humans (13), may, in fact, be strongest in the recipient of a semiallogeneic (partially MHC-matched) allograft. To verify this, we transplanted NIMAd-exposed and control B6 mice with skin allografts from either fully (H-2d/d) or semiallogeneic (H-2b/d) donors. Ten days later we measured the frequency of IFN--, IL-2-, IL-5-, and IL-4-producing T cells, the latter as an additional marker of Th2 cells. As shown in Fig. 4, left panel, the frequencies of both IL-2- and IFN--producing T cells from NIMA animals responding to the semiallogeneic donor APC were significantly reduced (p < 0.01) relative to those of skin-grafted B6 controls to levels comparable to those observed in nongrafted mice (Table II). Interestingly, no significant differences in type 2 cytokine (IL-4, IL-5)-producing T cells between control and NIMA mice were seen.
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cytokine responses compared with naive B6 controls (Table II). While there was a highly significant (p < 0.001) reduction in IL-2-producing cells relative to the controls in NIMAd-exposed mice, the same mice showed no deficit in IFN- response to a fully allogeneic DBA/2 skin challenge. Influence of maternal injection with allopeptide on indirect pathway alloresponses in offspring
In the setting of fetal-maternal microchimerism as well as in transplantation of bone marrow or organ allografts containing passenger leukocytes (27), APCs from both host and donor are available to the host T cells. This unique situation is the basis for the duality of indirect (host APC-dependent) (28) and direct (donor APC-dependent) (29, 30) allorecognition pathways. While the use of F1 stimulator cells may partly detect the response of allopeptide-specific, self MHC-restricted T cells (31), we could not assess the NIMA effect on purely indirect pathway Th1 or Th2 cells in the C57BL/6-anti-DBA/2 model, since the frequency of T cells responding via an indirect pathway to DBA/2 spleen cell sonicates and autologous APC was extremely low (<15 spots/106 cells; data not shown). We therefore used the well-characterized indirect pathway response of CD4+ T cells from H-2Ld-negative BALB/c-dm2 mice to the Ld61–80 peptide (32). This immunodominant peptide or saline alone was injected i.v. into pregnant BALB/c-dm2 mice. Two weeks after weaning, offspring were primed s.c. with either Ld61–80 peptide or HEL46–61, an irrelevant third-party peptide, also recognized in the context of IAd. Responder spleen cells from all mice were restimulated in vitro with the same peptide used for s.c. priming. T cells from control offspring of saline-treated mothers showed a normal dose-dependent response to the Ld61–80 peptide (Fig. 5). T cells from offspring of Ld peptide-treated mothers, however, failed to react to the Ld61–80 peptide, but responded normally to HEL46–61 (Fig. 5). This result indicates that exposure to a maternally derived soluble MHC allopeptide Ag in utero can lead to a specific reduction of alloreactivity mediated via the indirect pathway.
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A sensitive indicator of the indirect pathway response to alloantigens is the ability of the host to mount Th-dependent IgG responses to donor MHC Ags (33). We therefore compared the IgG1 and IgG2a Ab responses of tolerant NIMAd-exposed and control C57BL/6 mice (rejectors), both >100 days post-transplant with DBA/2 heart grafts. As shown in Fig. 6, rejectors produced significantly higher levels of Th2-dependent IgG1 (p < 0.05) and Th1-dependent IgG2a (p < 0.05) Abs compared with the tolerant NIMA animals. No autoantibodies could be detected when serum was incubated with C57BL/6 cells (data not shown).
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Discussion |
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Maternal cells and soluble MHC Ags may cause clonal deletion of fetal/neonatal T cells responding to NIMA via the direct and indirect allorecognition pathways. Maternal cell microchimerism in the thymus of both mouse (37) and human (38) newborns has been reported, and this could cause deletion of newly arising donor-reactive T cells (39, 40). The abrogation of allopeptide-specific proliferative responses in offspring of mothers injected with allopeptide during pregnancy (Fig. 5) and the pronounced decrease in direct pathway T cell responses to H-2d-positive APC in NIMAd-exposed offspring (Table II) are also consistent with this possibility. However, while the numbers of IFN--producing T cells responding to DBA/2 stimulator cells was suppressed pretransplant (Table II), a donor DBA/2 skin allograft challenge restored this response in NIMAd-exposed mice to a level indistinguishable from that in skin-grafted control B6 mice (Fig. 4). Since the IFN--producing T cells responding to skin allograft challenge are mainly CD8+, while the IL-2 responders are mainly CD4+ (41), the low IL-2, but high IFN-, response to DBA/2 skin graft challenge (Fig. 4) suggests a more profound inhibitory effect of NIMA exposure on allo-specific CD4+ than on CD8+ T cells. While skin transplants seem to be rejected by both the CD4+ and CD8+ T cell compartments (25), with a stronger contribution by the latter (42), heart transplant rejection appears to be more dependent on a functioning CD4+ alloresponse (43, 44). Thus, if the mother’s tolerogenic effect in the heart transplant model is deletional, it is not uniformly so, but rather seems biased toward CD4+, MHC class II-restricted T cells. These could very well include CD4+ T cells specific for allopeptides presented by host MHC class II+ APC, as suggested by the profound inhibition of proliferative CD4 T cell response to Ld61–80 in offspring of mothers injected with this allopeptide during pregnancy (Fig. 5). However, this experiment is open to an alternative interpretation, that the mother’s T cells impose a regulated state of unresponsiveness in the offspring, since she herself lacks the alloantigen Ld. For this reason we have conducted preliminary experiments in the NIMAd F1 backcross model, using the E
52–67 peptide derived from the d haplotype (45, 46). We found a 27–32% reduction of IFN- and IL-2 ELISPOT responses to E52–67 in NIMAd-exposed animals compared with B6 controls (J. Andrassy, G. Thomas, and W. J. Burlingham, unpublished observation).
An alternative to the idea of central deletion is the induction of anergy in NIMA-reactive T cells due to maternal microchimerism in peripheral lymphoid tissues. The anergy hypothesis predicts that the NIMA-specific T cells will not proliferate when they encounter NIMA+ APC soon after allograft challenge due to maternal inactivation, but will still persist and retain certain functions (47). Zhang and Miller (26) reported higher levels of donor T cells (microchimerism) in NIMA-exposed, long-term skin graft acceptors compared with NIMA-exposed F1 backcross mice that rapidly rejected NIMA+ skin and suggested that anergy due to a veto effect (48) might be responsible. We found varying degrees of maternal cell microchimerism in nongrafted NIMAd-exposed animals. The results indicated higher levels of d-positive cells in oral plus in utero exposed NIMA animals compared with only in utero exposed NIMAd mice and NIPA controls. We have shown in a previous human study that rare maternal cells in a patient accepting a maternal renal allograft without immunosuppression could specifically inhibit anti-donor CTL activity in vitro, accounting for a state of functional unresponsiveness (anergy) of these CTL in vivo (49).
A third possible mechanism for the specific tolerance to NIMA+ heart transplants and prolongation of NIMA+ semiallogeneic skin allografts involves active immune regulation, a common feature of organ allograft acceptance in mice and humans (50, 51). This seems likely in view of the importance of oral exposure to the maternal d Ags, since oral tolerance is known to depend upon TGF-
production by Th3 or T regulatory cells (52, 53). While the ELISPOT data tend to rule out Th1 to Th2 immune deviation induced by neonatal T cell priming (54, 55), inhibition of both Th1 and Th2 responses by a T regulatory cell is a distinct possibility (56, 57). Since maternal APC encountered during development are semiallogeneic, they may carry allopeptides naturally processed and presented via the shared class II allorecognition pathway (32) and thus provide the first stimulus for development of NIMA allopeptide-specific T regulatory cells. Maternal induction of a metastable balance between primed effector and regulatory T cells might explain the paradox of the early rejection crises at a time when levels of donor APC (58) and chemokines (59) are highest in the NIMAd-exposed host. The observation of an early diminution of heartbeat in NIMAd-exposed mouse allograft recipients is consistent with the increased incidence of early acute rejection episodes in patients receiving a NIMA+ kidney transplant from a sibling donor and who go on to accept their grafts long term (13).
Lastly, the alloantibody response is known to be a risk factor for the development of chronic heart allograft rejection, particularly complement-fixing Ig isotypes (60). Fetal and neonatal exposure to NIMA may directly inhibit the alloreactive B cells of the offspring (12). Our data suggest that NIMAd exposure both inhibits the development of Th1 responses to H-2d both before and after transplant. This along with direct effects on developing B cells may account for the marked reduction of Th1-dependent, complement-fixing IgG2a Abs after transplant and may contribute to the absence of chronic vascular changes in the long-surviving hearts.
In conclusion, we have found a powerful NIMA effect, promoting tolerance to a primarily vascularized organ allograft in mice. The mechanism of this effect, which closely parallels the NIMA effect seen in human renal and bone marrow transplantation, involves profound suppression of Th indirect and direct pathway responses following fetal/neonatal exposure to maternal cells and alloantigens.
Note added in proof.
Recent ELISPOT analysis of NIPA pre-transplant controls indicate a reduced Th-1 response relative to B6 controls; however, NIMA Th-1 responses are consistently lower.
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Acknowledgments |
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Footnotes |
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2 J. A. and S. K. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. William J. Burlingham, Department of Surgery, Room G4/702 CSC, University of Wisconsin, Madison, WI 53792. E-mail address: burlingham{at}surgery.wisc.edu
4 Abbreviations used in this paper: NIMA, noninherited maternal Ag; HEL, hen egg lysozyme; NIPA, noninherited paternal Ag.
Received for publication April 28, 2003. Accepted for publication September 2, 2003.
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References |
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-actin gene expression as an early indicator of dysfunctional remodeling following heart transplant. Cardiovasc Res. 54:539.Related articles in The JI:
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; n = 21). As controls, NIPA backcross (H-2b/b; 
; n = 5) and C57BL/6 mice (
; n = 7) were also transplanted with DBA/2 hearts. As a third-party control (
; n = 5) NIMAd-exposed, F1 backcross (H-2b/b) were transplanted with C3H hearts (H-2k/k). *, p < 0.003 vs NIPA, p < 0.0004 vs B6, p < 0.0009 vs C3H. B, Importance of oral vs in utero exposure to NIMA on the survival of primary vascularized, fully allogeneic heart grafts. NIMA offspring (H-2b/b) was transferred and nursed by either a foster B6D2F1 (H-2b/d) mother (
, response to donor APCs by skin grafted NIMAd-exposed F1 backcross mice; 
, response to B6 APCs by skin grafted NIMAd-exposed F1 backcross mice (negative control).
). Offspring (when 6–8 wk old) were primed with Ld61–80 allopeptide (•) or HEL46–61 peptide (
) Abs in NIMA-tolerant animals, transplanted with a fully allogeneic heart from DBA/2 (>100 days post-transplant; n = 5), C57BL/6 mice with a rejected heart graft from DBA/2 (>100 days post-transplant; n = 2), and naive (nontransplanted) C57BL/6 (n = 3). *, p < 0.05.