Transplant rejection

Why must a person given a life-saving organ stay deliberately vulnerable to infection?

A surgeon replaces a failing kidney with a working one, and the operation succeeds. Then the patient begins a course of drugs that will not end, whose declared purpose is to make them worse at fighting infection and worse at suppressing new cancers — for the rest of their life.

It is worth refusing to accept that as obviously necessary. Why can we not suppress only the response to the graft? We ask drugs for far finer discriminations than that every day. What is it about this particular target that makes precision unavailable?

Begin with what is being recognised. Every nucleated cell in a body displays HLA molecules — the most variable set of genes in the human genome. Two unrelated people almost certainly differ in them, and a donated kidney arrives covered in a version of a self-molecule that the recipient's immune system has never had to tolerate.

Now the size of the response, because it is not what intuition suggests. For a typical foreign peptide — a fragment of a virus, say — the fraction of a naive T cell repertoire able to respond is somewhere around one in a hundred thousand to one in a million. For a given foreign HLA molecule, the fraction is on the order of one to ten per cent (both recalled figures, and the second is a standard teaching estimate rather than a precise one). That is a difference of roughly ten thousand to a hundred thousand fold.

Sit with what that means. The folk picture is that a transplant is like a splinter — a foreign object the body will eventually get used to. It is the reverse. The graft provokes a response larger than any infection the patient will meet, and unlike an infection the antigen never clears, because it is the organ.

So why not just aim the drugs at that response? Here is the crux, and it is structural rather than technological. Immune specificity is not written into a pathway. It is generated by random recombination inside each individual lymphocyte as it develops, and it lives in that one cell's receptor. A T cell that recognises the donor kidney and a T cell that recognises cytomegalovirus are, in every respect a drug can read, identical: the same receptor architecture, the same costimulation through CD28, the same calcineurin signal, the same interleukin-2 to drive proliferation. There is no molecular label reading "anti-graft". Every drug we have — calcineurin inhibitors, antimetabolites, corticosteroids, mTOR inhibitors — acts on the shared machinery, and therefore on the whole repertoire at once.

That gives a test with a known answer. If the response is to inherited polymorphic molecules, then a graft between people who share none should need no suppression at all, and a graft between people who share the major ones should need less but not none. Both hold: identical twins require no immunosuppression, and HLA-identical siblings still do, because they differ in minor histocompatibility antigens — ordinary self-proteins whose sequences vary between individuals. The prediction survives, and the residual case tells us the molecular difference goes all the way down.

Two refinements and then the place where my own account fails.

First, the vulnerability is not uniform. It is a dial, and it is turned highest in the early months when the alloresponse is largest, then eased. The cost is real and measurable: long-term recipients carry a risk of squamous cell skin cancer many tens of times the general population's — a recalled figure whose commonly quoted multiplier varies widely between studies, and the softest number in this piece. I have deliberately quoted no graft-survival percentage, because those depend on organ, era, registry definition and how failure is counted, and would look like a fact while behaving like a convention.

Second, the neighbouring piece on Autoimmunity in this collection ends by naming exactly this trade — suppressing a misdirected immune response at the price of the infections that response was preventing. The difference in this case is that autoimmunity has a wrong target to be corrected, whereas the transplant response is perfectly correct: the organ genuinely is foreign. Nothing here is a malfunction, which is why nothing here can be repaired.

Now the failure. My argument says specificity is unaddressable, so blanket suppression is the only option. If that were the whole truth, graft-specific tolerance would be impossible — and it is not. A minority of liver recipients can be weaned off drugs entirely and keep the organ. More pointedly, protocols that give donor bone marrow alongside the organ have produced patients holding functioning grafts with no immunosuppression at all. So tolerance is achievable; we simply cannot induce it reliably or safely on demand. What covers the gap is that these approaches do not inhibit a pathway. They edit the repertoire — letting donor-derived cells sit in the recipient's thymus so that developing T cells reactive to the donor are deleted as they arise. The specificity becomes addressable only at the point where it is created, which is precisely what my account predicts.

• Why chronic rejection continues slowly for years despite adequate suppression of the acute response.
• What separates the liver, which is unusually tolerated, from the kidney and heart, which are not.

Every term the collection defines is gathered in the glossary.