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.
Highlights
Transplantation is a life-saving treatment for end-stage organ failure, but for the majority of recipients, ongoing graft function relies on long-term maintenance immunosuppression, with the attendant complications of cancer, opportunistic infection, and metabolic derangement [1]
Using hepatocytespecific associated virus (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
While there were no significant changes in overall CD4+ or CD8+ T cell numbers in the liver following inoculation with AAV-Kd, forkhead box P3 (FoxP3)+ cell density increased from 0.7 ± 0.3 cells/high-power field (HPF) to 18.3 ± 4.9 cells/HPF on d14 (P = 0.002, Supplemental Figure 3, B–D)
Summary
Transplantation is a life-saving treatment for end-stage organ failure, but for the majority of recipients, ongoing graft function relies on long-term maintenance immunosuppression, with the attendant complications of cancer, opportunistic infection, and metabolic derangement [1]. Primary viral infections of hepatocytes frequently persist [6,7,8], while tolerance of various transgene products expressed in the liver following transduction of hepatocytes with viral vectors has been documented [9,10,11,12,13]. Recombinant vectors based on the Adeno-associated virus (AAV) are promising candidates for liver-directed gene transfer — for the treatment of monogenic liver diseases [14, 15], and for the induction of systemic, antigen-specific tolerance [16], an application that may be of great benefit to transplant recipients.
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