Oral alloantigen exposure promotes donor‐specific tolerance in a mouse model of minor‐mismatched skin transplantation

Oral antigen exposure is a powerful, non‐invasive route to induce immune tolerance to dietary antigens, and has been modestly successful at prolonging graft survival in rodent models of transplantation. To harness the mechanisms of oral tolerance for promoting long‐term graft acceptance, we developed a mouse model where the antigen ovalbumin (OVA) was introduced orally prior to transplantation with skin grafts expressing OVA. Oral OVA treatment pre‐transplantation promoted permanent graft acceptance and linked tolerance to skin grafts expressing OVA fused to the additional antigen 2W. Tolerance was donor‐specific, as secondary donor‐matched, but not third‐party allografts were spontaneously accepted. Oral OVA treatment promoted an anergic phenotype in OVA‐reactive CD4(+) and CD8(+) conventional T cells (Tconvs) and expanded OVA‐reactive Tregs pre‐transplantation. However, skin graft acceptance following oral OVA resisted partial depletion of Tregs and blockade of PD‐L1. Mechanistically, we revealed a role for the proximal gut draining lymph nodes (gdLNs) in mediating this effect, as an intestinal infection that drains to the proximal gdLNs prevented tolerance induction. Our study extends previous work applying oral antigen exposure to transplantation and serves as proof of concept that the systemic immune mechanisms supporting oral tolerance are sufficient to promote long‐term graft acceptance.