MHC Class II Sharing Appears to Promote Intestinal Allograft Tolerance Through Linked Suppression in a Large Animal...

Area of Science:

• Transplantation immunology
• Immunogenetics

Background:

• The role of major histocompatibility complex (MHC) class I versus class II matching in achieving transplantation tolerance is not fully understood.
• Investigating selective mismatches in intestinal transplantation (ITx) is crucial for clinical application.

Purpose of the Study:

• To determine the impact of MHC class I and class II matching on inducing transplantation tolerance.
• To elucidate the mechanisms underlying tolerance induction in a swine model of ITx.

Main Methods:

• Orthotopic ITx performed in swine with varying degrees of MHC matching: haplotype-matched, partially matched (class II overlap), and fully mismatched.
• Standard immunosuppression followed by a weaning protocol (days 90-140).
• In vitro analyses including a novel mucosal mixed lymphocyte reaction assay.

Main Results:

• Fully mismatched ITx did not achieve tolerance.
• Partially matched ITx resulted in "split tolerance" characterized by local graft acceptance mediated by donor regulatory T cells (Treg).
• Haplotype-matched ITx led to peripheral Treg, donor-specific hyporesponsiveness, and durable mixed chimerism, suggesting linked suppression via shared class II alleles on antigen-presenting cells.

Conclusions:

• Sharing of MHC class II specificities, often identifiable by pre-transplant tissue typing, is critical for Treg-mediated tolerance in ITx.
• These findings have significant implications for developing strategies to induce clinical tolerance in human intestinal transplantation.