Theory 01/Transplant & Immune Tolerance/Transplant immunology
Acceptance Is a Local Ratio
Tolerance is measured in the blood. The decision may be made in the tissue.
Graft acceptance is set by the ratio of regulatory to effector T cells inside the graft rather than by systemic chimerism, so a systemically tolerant animal can still reject and a non-tolerant one can still accept.
01The evidence
Transplant tolerance protocols produce systemic markers that correlate weakly with graft survival, and grafts can be accepted while peripheral assays show reactivity and rejected while they do not.
02The tension
Tolerance is assessed by mixed lymphocyte reactions, chimerism and peripheral cell frequencies. Those measure the circulating compartment, which is where cells pass through rather than where they meet the graft.
03The mechanism
The graft is a site. Regulatory and effector cells traffic into it, and the local balance determines whether the tissue is attacked. A systemic ratio sets the supply, but the balance at the site is set by recruitment and retention, which differ between tissues.
That makes the local ratio the decision variable, and predicts that two grafts in the same animal can have different fates if their microenvironments differ, which is observed in skin versus heart transplants.
The clinical consequence is that tolerance assays should sample the graft or its draining node, which is now feasible with fine-needle biopsy and single-cell sequencing, rather than the blood.
04What this is not
Those measure the circulating compartment. This measures the site, which predicts discordance between assays and outcomes.
05Predictions
- P1Local regulatory-to-effector ratio should predict acceptance better than any blood assay.
- P2Grafts of different tissues in one host should diverge according to local ratios.
- P3Therapies that recruit regulators to the graft should succeed without systemic chimerism.
06Refutation
Acceptance tracking systemic chimerism at controlled local ratio would relocate the decision to the circulation.
07What it changes
It would move tolerance monitoring to the graft and its draining node.