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JCI Insight. 2018 Aug 9;3(15). pii: 97500. doi: 10.1172/jci.insight.97500. eCollection 2018 Aug 9.

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

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


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.


Antigen presentation; Gene therapy; Hepatology; Tolerance; Transplantation

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