Direct recognition of hepatocyte-expressed MHC class I alloantigens is required for tolerance induction

doi:10.1172/jci.insight.97500

. 2018 Aug 9;3(15):e97500.

doi: 10.1172/jci.insight.97500.

Direct recognition of hepatocyte-expressed MHC class I alloantigens is required for tolerance induction

Moumita Paul-Heng¹, Mario Leong¹, Eithne Cunningham¹, Daniel L J Bunker¹, Katherine Bremner², Zane Wang¹, Chuanmin Wang¹, Szun Szun Tay², Claire McGuffog², Grant J Logan³, Ian E Alexander^{3

4}, Min Hu⁵, Stephen I Alexander⁶, Tim D Sparwasser⁷, Patrick Bertolino², David G Bowen^{1

2}, G Alex Bishop¹, Alexandra Sharland¹

Affiliations

¹ Transplantation Immunobiology Group, University of Sydney Central Clinical School, Charles Perkins Centre, Faculty of Medicine and Health, Sydney, NSW, Australia.
² Liver Immunology Group and AW Morrow Gastroenterology and Liver Centre, The University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.
³ Gene Therapy Research Unit, Children's Medical Research Institute, The University of Sydney, Faculty of Medicine and Health and Sydney Children's Hospitals Network, Westmead, Australia.
⁴ The University of Sydney, Sydney Medical School, Discipline of Child and Adolescent Health, Westmead, Australia.
⁵ Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia.
⁶ Centre for Kidney Research, Children's Hospital at Westmead, The University of Sydney, NSW, Australia.
⁷ Institute of Infection Immunology, Twincore, Centre for Experimental and Clinical Infection Research, Hannover Medical School, Germany.

PMID: 30089715
PMCID: PMC6129134
DOI: 10.1172/jci.insight.97500

Direct recognition of hepatocyte-expressed MHC class I alloantigens is required for tolerance induction

Moumita Paul-Heng et al. JCI Insight. 2018.

. 2018 Aug 9;3(15):e97500.

doi: 10.1172/jci.insight.97500.

Authors

Affiliations

¹ Transplantation Immunobiology Group, University of Sydney Central Clinical School, Charles Perkins Centre, Faculty of Medicine and Health, Sydney, NSW, Australia.
² Liver Immunology Group and AW Morrow Gastroenterology and Liver Centre, The University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.
³ Gene Therapy Research Unit, Children's Medical Research Institute, The University of Sydney, Faculty of Medicine and Health and Sydney Children's Hospitals Network, Westmead, Australia.
⁴ The University of Sydney, Sydney Medical School, Discipline of Child and Adolescent Health, Westmead, Australia.
⁵ Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia.
⁶ Centre for Kidney Research, Children's Hospital at Westmead, The University of Sydney, NSW, Australia.
⁷ Institute of Infection Immunology, Twincore, Centre for Experimental and Clinical Infection Research, Hannover Medical School, Germany.

PMID: 30089715
PMCID: PMC6129134
DOI: 10.1172/jci.insight.97500

Abstract

Adeno-associated viral vector-mediated (AAV-mediated) expression of allogeneic major histocompatibility complex class I (MHC class I) in recipient liver induces donor-specific tolerance in mouse skin transplant models in which a class I allele (H-2Kb or H-2Kd) is mismatched between donor and recipient. Tolerance can be induced in mice primed by prior rejection of a donor-strain skin graft, as well as in naive recipients. Allogeneic MHC class I may be recognized by recipient T cells as an intact molecule (direct recognition) or may be processed and presented as an allogeneic peptide in the context of self-MHC (indirect recognition). The relative contributions of direct and indirect allorecognition to tolerance induction in this setting are unknown. Using hepatocyte-specific AAV vectors encoding WT allogeneic MHC class I molecules, or class I molecules containing a point mutation (D227K) that impedes direct recognition of intact allogeneic MHC class I by CD8+ T cells without hampering the presentation of processed peptides derived from allogeneic MHC class I, we show here that tolerance induction depends upon recognition of intact MHC class I. Indirect recognition alone yielded a modest prolongation of subsequent skin graft survival, attributable to the generation of CD4+ Tregs, but it was not sufficient to induce tolerance.

Keywords: Antigen presentation; Gene therapy; Hepatology; Tolerance; Transplantation.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: EC has been employed in a medical-scientific liaison role by Shire Pharmaceuticals since April 2016. This position is not connected to the research work described in this article.

Figures

**Figure 1. Dose-dependent prolongation of K^d-bearing skin graft survival after transduction of recipient hepatocytes with AAV-K^d.**
(A) C57BL/6 mice (n = 6/group) were inoculated with AAV-K^d at doses ranging from 5 × 10⁹ to 5 × 10¹¹ vector genome copies (vgc) or with 5 × 10¹¹ vgc of a control vector encoding the third-party MHC class I molecule H-2K^k. Skin grafts were performed 7 days later. Graft survival was analyzed using the log-rank (Mantel-Cox) test. Syngeneic skin grafts from C57BL/6 donors survived indefinitely. Median survival time (MST) of B6.Kd skin grafts to uninjected C57BL/6 recipients (n = 12) was 15 days. AAV-K^k did not extend survival (MST 19 days; P = 0.58), whereas a dose-dependent survival prolongation was noted with AAV-K^d, culminating in 100% survival at d100 after transplantation in mice receiving 5 × 10¹¹ vgc AAV-K^d (P = 0.0008 vs. 5 × 10¹¹ vgc AAV-K^k). (B) C57BL/6 mice were first primed by receiving a B6.Kd skin graft. Mice were rested for 30–35 days to allow a memory response to develop and then received a secondary graft of B6.Kd skin. A modest acceleration of rejection tempo was observed in primed mice (n = 6), compared with unprimed recipients of grafts from the same donor (n = 6; MST 17 days vs. 22.5 days; P = 0.03; Gehan-Breslow-Wilcoxon test). (C) C57BL/6 mice were primed and rested as above and were then inoculated with AAV-K^d at 5 × 10¹⁰ (n = 3) or 5 × 10¹¹ (n = 6) vgc i.v., followed after an additional 7 days by a secondary graft. Skin graft survival was analyzed as for A. Median survival of secondary B6.Kd grafts was not prolonged in primed mice treated with 5 × 10¹⁰ vgc AAV-K^d, while all mice inoculated with 5 × 10¹¹ vgc AAV-K^d accepted a secondary graft indefinitely (P = 0.0039 compared with 5 × 10¹⁰ vgc AAV-K^d). (D) At d14–16 after transplant, histological examination of B6.Kd allografts to control mice showed complete rejection, with extensive infiltration of the graft and loss of the graft epithelium. (**E–G**) In contrast, B6.Kd grafts to B10.BR mice inoculated with 5 × 10¹¹ vgc AAV-K^d had normal histological appearances at d14–16 (E) and d100 (G), comparable with those of syngeneic grafts (F). (**H–J**) Expression of H-2K^d in the tolerated grafts increased early after transplantation (I and J) compared with that in freshly collected B6.Kd tail skin (H). (K) Ongoing H-2K^d expression was detectable in tolerated grafts and had returned to baseline levels by d100. Magnification, 200× for **D–K**.

**Figure 2. Comparable expression of D227K-mutant and WT MHC class I molecules in recipient hepatocytes.**
Flow cytometry was used to determine expression of MHC class I transgenes in recipient liver at d7 after inoculation with AAV-K^b, K^b-D227K, K^d, and K^d-D227K vectors. The epitopes recognized by the monoclonal antibodies B8-24.2 (K^b) or 15-5-5S (K^d) do not include the α3 domain containing the D227K mutation. Comparable expression of K^b was detected in B10.BR hepatocytes isolated from mice transduced with either AAV-K^b or AAV-K^b-D227K (A). Similarly, equivalent levels of K^d expression were detected on hepatocytes from C57BL/6 mice inoculated with AAV-K^d or K^d-D227K (B). Experiments were performed twice with 2 replicate mice per group on each occasion. Representative histograms are shown.

**Figure 3. The D227K mutation of H2-K^b impairs direct recognition by K^b-specific CD8⁺ Des-RAG T cells.**
(A) B10.BR mice were inoculated with 5 × 10¹¹ vgc AAV-K^b or K^b-D227K. Two days later, 1 × 10⁶ CFSE-labeled Des-RAG lymph node cells were adoptively transferred to these recipient mice. After a further 48 hours, liver leucocytes were isolated, stained, and examined by flow cytometry. (B and C) Des-RAG cells transferred into mice transduced with AAV-K^b expressed the activation markers CD69 (B) and PD-1 (C) and had started to divide. In contrast, Des-RAG cells recovered from the livers of mice inoculated with AAV-K^b-D227K showed no signs of activation or proliferation. (D) Consistent with the observed difference in the extent of proliferation between Des-RAG cells transferred to mice inoculated with AAV-K^b or K^b-D227K vectors, the absolute number of Des-RAG cells recovered from the Kb-expressing livers was 56,421 ± 13,959, compared with 2,482 ± 861 cells recovered from livers expressing K^b-D227K; P = 0.02. (E) Des-RAG T cells comprised 3.78% ± 1.12% of leucocytes recovered from the livers of mice transduced with AAV-K^b and 0.19% of liver leucocytes in AAV-K^b-D227K–treated mice (P = 0.04). This experiment was performed twice with 3–4 mice/group for each experiment. Representative dot plots are shown. Box shows minimum to maximum, with a line at the mean. Data are described as mean ± SEM and were analyzed using an unpaired t test.

**Figure 4. The D227K mutation does not impede indirect recognition of K^d by indirectly alloreactive TCR75-RAG T cells.**
(A) C57BL/6 mice were inoculated with 5 × 10¹¹ vgc AAV-K^d or K^d-D227K. B6.Kd mice, which constitutively express the IA^b-K^d(54-68) epitope on antigen-presenting cells, were positive-control recipients, while C57BL/6 mice were used as negative controls. CFSE-labeled TCR75-RAG lymphocytes (1 × 10⁷) were transferred to vector-transduced and control mice 7 days after inoculation. After a further 3 days, leucocytes were isolated from the spleen, liver, and liver-draining LN; stained; and examined by flow cytometry (n = 3–4/group). (B) The congenic marker CD45.1 was used, along with CD4, to identify transferred TCR75-RAG cells. TCR75-RAG cells proliferated to a similar extent when transferred to mice transduced with either AAV-K^d (red line) or AAV-K^d-D227K (black line). TCR75-RAG cells transferred into C57BL/6 recipients did not divide (gray filled histogram). In the liver and draining LN, the extent of proliferation was similar to that in positive control B6.Kd mice, while in the spleen, proliferation had progressed further in the positive control than in the transduced mice. Representative histograms are shown (n = 3–4/group). (C and D) In mice inoculated with either AAV-K^d or K^d-D227K, similar patterns of expression of CD69 and PD-1 on TCR75-RAG cells were observed. CD69 surface expression declined with successive cell divisions (C), while PD-1 expression levels increased as division progressed (D). Representative plots from the draining LN (n = 3/group) are shown.

**Figure 5. Activation of endogenous CD8⁺ alloreactive T cells in the presence or absence of direct recognition of allogeneic MHC class I.**
C57BL/6 mice were transduced with 5 × 10¹¹ vgc AAV-K^d or K^d-D227K. At intervals between 48 hours and 10 days after inoculation, leucocytes were isolated from liver, draining LN, and spleen, and CD3⁺CD8⁺ T cells were analyzed for expression of the activation markers CD44 and PD-1. (A) The frequency of PD-1^hi cells among CD8⁺ T cells from liver increased substantially during the first 10 days after inoculation in mice treated with AAV-K^d and, to a lesser extent, in mice transduced with K^d-D227K. n = 3–6 mice/group; representative plots shown. (B) Data were analyzed using a 2-way ANOVA with Sidak’s and Tukey’s post tests; the proportion of activated (CD44⁺PD-1^hi) CD8⁺ T cells in liver peaked at 36.8% ± 2.0% on d10 after inoculation with AAV-K^d compared with 1.2% ± 0.3% on d2 (P < 0.0001). In mice that had received AAV-K^d-D227K, the proportion of CD44⁺PD-1^Hi CD8⁺ T cells was 9.5% ± 3.8% on d10, compared with 0.95% ± 0.52% on d2 (P = 0.014, n = 3–6/group). From d4–10, the proportion of activated CD8⁺ T cells was significantly greater in the livers of mice transduced with AAV-K^d than those treated with AAV-K^d-D227K (P < 0.0001). (C) Parallel changes were noted in splenocytes and LN cells (not shown) from inoculated mice (n = 3–6/group), although the proportions of activated CD8⁺ T cells in spleen or LN were much smaller than those in liver, and the peak proportions of activated CD8⁺ T cells were attained on d7 (0.85% ± 0.08% for AAV-K^d–transduced mice, 0.34% ± 0.7% for mice receiving AAV-K^d-D227K, and 0.11% ± 0.02% in untransduced mice). Statistical analysis employed 2-way ANOVA with Sidak’s and Tukey’s post tests. Box shows minimum to maximum with a line at the mean. Data are described as mean ± SEM.

**Figure 6. Allogeneic skin graft tolerance induction requires recognition of intact donor MHC class I.**
(A) B10.BR mice were injected with 5 × 10¹¹ vgc AAV-K^b (n = 6) or K^b-D227K (n = 6), or were not transduced (n = 16). Seven days later, mice received 178.3 skin grafts, which express K^b on an H-2^k background. Statistical analysis of graft survival was carried out using the log-rank (Mantel-Cox) test. Modest graft survival prolongation was observed in mice transduced with AAV-K^b-D227K (MST 26 days vs. 16 days in uninjected controls, P = 0.0016), but tolerance was not achieved. Conversely, all mice inoculated with AAV-K^b accepted 178.3 skin grafts indefinitely (P = 0.0005 vs. K^b-D227K). (B) C57BL/6 mice received 5 × 10¹¹ vgc AAV-K^d or K^d-D227K (n = 6 per group) or no vector (n = 12) and, after a further 7 days, were transplanted with B6.Kd skin (K^d-transgenic on an H-2^b background). Survivals were analyzed as for A. Skin graft survival was increased to 28.5 days in mice transduced with AAV-K^d-D227K compared with 15 days in untransduced recipients (P = 0.001), but again, tolerance was not induced. All grafts survived beyond 100 days in mice transduced with AAV-K^d (P = 0.0005 vs. K^d-D227K).

**Figure 7. IFN-γ production by alloreactive responder cells is reduced by recognition of intact but not processed MHC class I.**
(A) Anti-K^d alloresponses were estimated using IFN-γ ELISpot. C57BL/6 mice were primed against K^d by rejection of a B6.Kd skin graft. Thirty to 35 days later, some mice were injected with 5 × 10¹¹ vgc AAV-K^d or K^d-D227K. After a further 7 days, splenocytes from inoculated mice, primed mice that were not inoculated with vector, or unprimed C57BL/6 controls (n = 9–10/group) were prestimulated in a 1-way multiple linear regression (MLR) with irradiated B6.Kd splenocytes, and IFN-γ–producing cells were enumerated using ELISpot. (B) Statistical analysis was performed using 1-way ANOVA in conjunction with Sidak’s multiple comparisons test. The number of responder cells producing IFN-γ in response to K^d-bearing stimulators increased from 41.78 ± 16.45 spot-forming cells/million unfractionated splenocytes (SFC/1 × 10⁶) in naive C57BL/6 to 336.1 ± 71.67 SFC/1 × 10⁶ in primed mice (P = 0.0009). Inoculation of primed C57BL/6 mice with AAV-K^d significantly decreased IFN-γ production (117.4 ± 32.63 SFC/1 × 10⁶, P = 0.015 compared with primed mice not receiving vector), while treatment with AAV-K^d-D227K did not reduce the anti-K^d response (247.4 ± 66.33 SFC/1 × 10⁶, P = 0.55). Parallel results were obtained when pooled, CD8-enriched splenocytes from primed mice were used as responders (n = 3/group). Results were analyzed as for A. CD8-enriched splenocytes from unprimed C57BL/6 mice contained 807.6 ± 23.84 SFC/1 × 10⁶, while 2,324 ± 525.8 SFC/1 × 10⁶ were detected in the primed animals (P = 0.0265). In primed mice transduced with AAV-K^d, the number of IFN-γ–producing cells fell to 384.4 ± 122 SFC/1 × 10⁶ (P = 0.007), whereas a nonsignificant reduction was noted when primed mice received AAV-K^d-D227K (1,014 ± 313.5 SFC/1 × 10⁶, P = 0.053). Box shows minimum to maximum with a line at the mean. All data are described as mean ± SEM.

**Figure 8. A monoclonal antibody against FR4 reduces Treg numbers in peripheral blood and spleen.**
Administration of the anti-FR4 monoclonal antibody TH6 (100 μg), i.v., was used to deplete the population of CD4⁺ Tregs from B10.BR mice. The nondepleting anti-FR4 antibody 12A5 does not compete for epitope binding against TH6 (Supplemental Figure 6) and was used for FR4 detection. TH6 treatment significantly reduced the numbers of both CD4⁺FoxP3⁺ T cells (gated on CD3⁺) and of the CD25⁺FR4⁺ fraction (gated on CD4⁺FoxP3⁺) in the peripheral blood (A and C) and spleen (B and D) of B10.BR mice at 24 hours after injection. CD4⁺FoxP3⁺ T cells in peripheral blood declined substantially from 6.98 × 10⁴ ± 9.72 × 10³ in controls to 1.09 × 10⁴ ± 5.38 × 10³ in TH6-treated mice (C) (P = 0.008), while a lesser reduction in CD4⁺FoxP3⁺ T cells (from 1.03 × 10⁶ ± 2.19 × 10⁴ to 7.86 × 10⁵ ± 5.17 × 10⁴, P = 0.01) was detected in the spleen (D). CD25⁺FR4⁺ T cells in peripheral blood decreased from 3.45 × 10⁴ ± 5.59 × 10³ to 216 ± 131(P = 0.0036) following anti-FR4 administration (C), whereas in spleen, the reduction in CD25⁺FR4⁺ T cells was from 3.86 × 10⁵ ± 7.75 × 10³ to 3.42 × 10⁴ ± 3.02 × 10³, P < 0.0001. While decline of the FR4⁺ fraction in spleen was accompanied by an overall reduction in CD4⁺FoxP3⁺ T cell numbers, there was also an increase in the proportion of CD25⁺FR4^- cells upon TH6 treatment (B), suggesting that FR4 engagement may have resulted in shedding or internalization of this receptor on some cells. n = 3/group for all experiments. A and B show representative flow plots. In C and D, box shows minimum to maximum with a line at the mean. Data are described as mean ± SEM, and statistical analyses were performed using an unpaired t tests.

**Figure 9. Depletion of CD4⁺ Tregs blocks prolongation of K^b-bearing skin graft survival by AAV-K^b-D227K.**
B10.BR mice inoculated with either AAV-K^b or K^b-D227K (5 × 10¹¹ vgc) 7 days prior to a K^b-bearing 178.3 skin graft received i.v. injections of 100 μg TH6 or isotype control mAb every 4 days between d–4 and d20 (A). Skin graft survivals (B) were compared using the logrank test. Skin grafts to B10.BR mice transduced with AAV-K^b survived indefinitely, irrespective of the coadministration of anti-FR4 (n = 4) or isotype control antibody (n = 4), as did syngeneic grafts (not shown). Conversely, the survival prolongation obtained through treatment of recipient mice with AAV-K^b-D227K (MST 26 days, compared with 16 days in untransduced mice, P = 0.015) was maintained when the isotype control mAb was coadministered (MST 27 days; n = 3) but abolished when anti-FR4 was given (MST 17.5 days; n = 6; P = 0.0046).

**Figure 10. Depletion of CD4⁺FoxP3⁺ Tregs abrogates the survival prolongation of K^d-bearing skin grafts to b-haplotype DEREG mice.**
DEREG or C57BL/6 mice were treated with 12 ng/g Diphtheria toxin (DT) i.p. for 3 consecutive days, following which blood and splenocytes were collected and stained for the presence of FoxP3⁺ T cells. A and B are gated on CD3⁺CD4⁺ cells and show representative plots (n = 3). DT administration did not alter the percentage of FoxP3⁺ cells in the blood (A) or spleen (B) of C57BL/6 mice. In contrast, CD3⁺CD4⁺ T cells expressing the GFP reporter under the control of FoxP3 were almost completely absent from DT-treated DEREG mice, while a small residual population of FoxP3⁺GFP^– cells remained following depletion. C (gated on CD3⁺CD4⁺ cells) summarizes the proportion of cells expressing FoxP3 in all DT-treated mice. In DEREG mice, FoxP3 cells declined from 14.4% ± 1.7% to 0.96% ± 0.19% of CD4⁺ T cells in blood (P = 0.015) and from 23.1% ± 1.8% to 5.7% ± 0.8% of CD4⁺ T cells in spleen (P = 0.010), upon DT administration. (D) Absolute numbers of CD4⁺FoxP3⁺ T cells were reduced from 42,067 ± 3,982 to 971 ± 192 in the peripheral blood of DT-treated DEREG mice (P = 0.0005) and from 1.5 × 10⁶ ± 0.5 × 10⁶ to 1.08 × 10⁵ ± 0.63 × 10⁵ in spleen (P = 0.0038). Boxes in C and D show minimum to maximum with a line at the mean. Data described as mean ± SEM, statistical analyses were performed using an unpaired t test; n = 3/group. (E and F) Survival of B6.Kd skin grafts to DEREG mice transduced with AAV-K^d was not influenced by DT treatment. Conversely, B6.Kd skin graft survival in DEREG mice inoculated with AAV-K^d-D227K was reduced from 27 to 18 days (P = 0.0046) when DT was coadministered, abrogating the survival prolongation due to expression of the K^d-D227K transgene. n = 6/group; survival analysis was performed using the log-rank test.

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References

1. ANZDATA Registry. 39th Report, Chapter 8: Transplantation. Australia and New Zealand Dialysis and Transplant Registry, Adelaide, Australia. 2017 . http://www.anzdata.org.au/anzdata/AnzdataReport/39thReport/c08_transplan... Accessed July 12, 2018.
1. Kamada N, Davies HS, Roser B. Reversal of transplantation immunity by liver grafting. Nature. 1981;292(5826):840–842. doi: 10.1038/292840a0. - DOI - PubMed
1. Calne RY, et al. Induction of immunological tolerance by porcine liver allografts. Nature. 1969;223(5205):472–476. doi: 10.1038/223472a0. - DOI - PubMed
1. Benseler V, McCaughan GW, Schlitt HJ, Bishop GA, Bowen DG, Bertolino P. The liver: a special case in transplantation tolerance. Semin Liver Dis. 2007;27(2):194–213. doi: 10.1055/s-2007-979471. - DOI - PubMed
1. Lerut J, Sanchez-Fueyo A. An appraisal of tolerance in liver transplantation. Am J Transplant. 2006;6(8):1774–1780. doi: 10.1111/j.1600-6143.2006.01396.x. - DOI - PubMed

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[1] ANZDATA Registry. 39th Report, Chapter 8: Transplantation. Australia and New Zealand Dialysis and Transplant Registry, Adelaide, Australia. 2017 . http://www.anzdata.org.au/anzdata/AnzdataReport/39thReport/c08_transplan... Accessed July 12, 2018.

[2] ANZDATA Registry. 39th Report, Chapter 8: Transplantation. Australia and New Zealand Dialysis and Transplant Registry, Adelaide, Australia. 2017 . http://www.anzdata.org.au/anzdata/AnzdataReport/39thReport/c08_transplan... Accessed July 12, 2018.

[3] Kamada N, Davies HS, Roser B. Reversal of transplantation immunity by liver grafting. Nature. 1981;292(5826):840–842. doi: 10.1038/292840a0. - DOI - PubMed

[4] Kamada N, Davies HS, Roser B. Reversal of transplantation immunity by liver grafting. Nature. 1981;292(5826):840–842. doi: 10.1038/292840a0. - DOI - PubMed

[5] Calne RY, et al. Induction of immunological tolerance by porcine liver allografts. Nature. 1969;223(5205):472–476. doi: 10.1038/223472a0. - DOI - PubMed

[6] Calne RY, et al. Induction of immunological tolerance by porcine liver allografts. Nature. 1969;223(5205):472–476. doi: 10.1038/223472a0. - DOI - PubMed

[7] Benseler V, McCaughan GW, Schlitt HJ, Bishop GA, Bowen DG, Bertolino P. The liver: a special case in transplantation tolerance. Semin Liver Dis. 2007;27(2):194–213. doi: 10.1055/s-2007-979471. - DOI - PubMed

[8] Benseler V, McCaughan GW, Schlitt HJ, Bishop GA, Bowen DG, Bertolino P. The liver: a special case in transplantation tolerance. Semin Liver Dis. 2007;27(2):194–213. doi: 10.1055/s-2007-979471. - DOI - PubMed

[9] Lerut J, Sanchez-Fueyo A. An appraisal of tolerance in liver transplantation. Am J Transplant. 2006;6(8):1774–1780. doi: 10.1111/j.1600-6143.2006.01396.x. - DOI - PubMed

[10] Lerut J, Sanchez-Fueyo A. An appraisal of tolerance in liver transplantation. Am J Transplant. 2006;6(8):1774–1780. doi: 10.1111/j.1600-6143.2006.01396.x. - DOI - PubMed

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Direct recognition of hepatocyte-expressed MHC class I alloantigens is required for tolerance induction

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Direct recognition of hepatocyte-expressed MHC class I alloantigens is required for tolerance induction

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