13.8 — Transplantation

The first successful human organ transplant was a kidney, performed in Boston in 1954 between identical twins. It worked because there was nothing to reject — the donor and recipient were genetically identical, so the immune system saw nothing foreign.

Every transplant since has been an attempt to reproduce that situation between people who are not identical, and the history of the field is the history of getting progressively better at it.

What is being rejected

Primarily the MHC molecules — HLA in humans (Chapter 13.2).

And there is something unusual about how strongly the response is mounted. Normally a T cell only responds to a foreign peptide displayed on your own MHC. In transplantation, T cells respond directly to the donor's MHC molecules themselves, whatever peptide they are carrying.

And an unexpectedly large fraction of your T cells — perhaps 1 to 10 percent — can do this, against any given foreign MHC. Compare that with the roughly one in a million that respond to a typical individual antigen.

Which is why rejection is so vigorous. The frequency of responding cells is thousands of times higher than for an ordinary immune response.

The explanation is that MHC molecules are structurally similar enough to each other that a T cell selected to recognise your own MHC will frequently also bind a foreign version, in a way that looks to it like your MHC carrying a foreign peptide. It is a case of the recognition system's own design producing a strong response to something it was never selected for.

The main HLA loci matched are A, B and DR — with two alleles at each, giving six antigens to match.

ABO compatibility is also required for solid organs, because the antigens are present on the graft's blood vessel lining.

The kinds of rejection

Hyperacute — minutes to hours.

Caused by preformed antibodies against the donor — from previous transfusions, pregnancies or transplants.

The antibodies bind the graft's vessel lining immediately, complement activates, the vessels thrombose, and the organ becomes black and non-functional on the operating table.

It is untreatable and it is essentially never seen now, because cross-matching before transplant detects it. A solved problem, and a reminder that most of transplant safety is prevention rather than treatment.

Acute — days to months.

T cell-mediated, and the commonest form. The recipient's T cells recognise the graft and attack.

It is treatable — usually with high-dose steroids, and with stronger agents if needed — and most episodes are reversed without lasting damage.

Antibody-mediated acute rejection also occurs and is harder to treat, requiring plasma exchange and antibody-directed drugs.

Chronic — months to years.

Progressive fibrosis and narrowing of the graft's blood vessels, leading to gradual loss of function.

And this is the main limitation on long-term graft survival. It is poorly understood and poorly treated, and it involves a mixture of low-grade immune injury and non-immune factors — hypertension, drug toxicity, infection, and the injury the organ sustained during retrieval and storage.

It is the reason a transplanted kidney has a median survival measured in one to two decades rather than a lifetime.

Graft-versus-host disease — the reverse.

Unique to transplants containing donor immune cells, principally bone marrow and stem cell transplants.

Here the donor's T cells attack the recipient. The patient is the graft.

It affects skin (rash), gut (diarrhoea) and liver (jaundice) most characteristically, and it can be fatal.

And there is a genuinely useful twist: a degree of graft-versus-host activity is beneficial in leukaemia. The same donor T cells attacking the recipient also attack any remaining leukaemia cells — the graft-versus-leukaemia effect. Patients with mild GVHD have lower relapse rates.

So the aim is not to abolish it but to control it, which is one of the more delicate balances in medicine.

Immunosuppression

Nearly all solid organ recipients need it for life.

Induction — intense suppression at the time of transplant, using antibodies that deplete or block T cells.

Maintenance — typically three drugs with different mechanisms, so each can be used at a lower dose:

Calcineurin inhibitors — tacrolimus, ciclosporin. These block a signalling step required for T cell activation, and their introduction in the 1980s is what made transplantation routine. Ciclosporin, from a soil fungus (Chapter 3.7), took kidney graft survival at one year from around 50 percent to over 80.

They are also nephrotoxic, which is a genuine irony — the drug preventing rejection of a kidney damages kidneys, including the transplanted one.

Antiproliferative agents — mycophenolate, azathioprine. Block lymphocyte division.

Steroids — broad suppression (Chapter 12.4).

mTOR inhibitors — sirolimus and relatives, sometimes used to avoid calcineurin toxicity.

And the whole approach is broad rather than targeted. It suppresses the entire immune system rather than only the anti-graft response, which is why the complications are what they are.

Infection — including organisms that healthy people control without noticing. CMV, BK virus, Pneumocystis, fungal infections and tuberculosis reactivation. Prophylactic antiviral and antibiotic treatment is standard for the first months.

Cancer — and the increase is substantial and specific.

Skin cancer risk increases 65 to 250-fold, particularly squamous cell carcinoma. Lymphoma risk increases substantially, largely driven by Epstein–Barr virus proliferating unchecked. Kaposi sarcoma and several other virus-driven cancers increase.

The pattern is informative: the cancers that increase are overwhelmingly the ones with a viral cause, which is direct evidence that immune surveillance normally controls those viruses (Chapter 19.1).

Which is why transplant recipients receive rigorous skin cancer advice and annual skin checks, and it is among the most important pieces of long-term guidance they get.

Drug-specific effects — kidney damage, diabetes, hypertension, tremor, gum overgrowth, and increased hair growth with some agents.

The organs, and how they do

Organ	1-year graft survival	Median graft survival
Kidney (living donor)	~97%	15–20 years
Kidney (deceased)	~93%	10–15 years
Liver	~90%	15+ years
Heart	~90%	12–14 years
Lung	~85%	6–8 years
Pancreas	~85%	10+ years

Lung does worst, for reasons that make sense: the lung is continuously exposed to the outside world, so it is under constant immune stimulation, and chronic rejection of the small airways is common.

Liver does unexpectedly well, and is somewhat immunologically privileged — liver transplants tolerate HLA mismatch better than any other organ, and a small proportion of recipients can eventually stop immunosuppression entirely, which is not true of any other solid organ.

And the kidney is the most transplanted organ, because dialysis provides a bridge that does not exist for the heart or liver — which means kidney transplantation can be planned rather than performed as a rescue.

Living donation

Possible for kidney and for part of the liver (Chapters 10.6, 9.4).

Living donor kidneys do substantially better than deceased donor kidneys, for three reasons: the organ is not subjected to the physiological stress of the donor's death, the cold storage time is minutes rather than hours, and the operation is planned.

Donor safety is taken seriously and the figures are worth stating. Operative mortality is around 3 per 10,000. Long-term life expectancy is essentially normal, with a small absolute increase in the lifetime risk of kidney failure — from about 0.3 percent to about 0.9 percent. Donors are assessed independently of the recipient's team, and can withdraw at any point without a reason being given.

Paired exchange solves the incompatibility problem elegantly. If donor A is incompatible with recipient A but compatible with recipient B, and vice versa, the pairs swap. Chains of many pairs are now routinely constructed by algorithm, and non-directed altruistic donors can start chains that produce dozens of transplants.

The supply problem, and the honest position on consent

The limiting factor everywhere is organ availability, and the gap is large: tens of thousands wait, and thousands die waiting each year in most countries.

Consent systems vary.

Opt-in — you must register as a donor. Opt-out (presumed consent) — you are a donor unless you have registered otherwise.

Countries with opt-out generally have higher donation rates, and the relationship is not simple. Spain has the highest rate in the world and had opt-out legislation for a decade before rates rose — the improvement came from a national network of trained transplant coordinators in every hospital, not from the law itself.

And in practice, families are consulted almost everywhere regardless of the legal position, and family refusal is a major limiting factor.

Which produces the single most useful piece of practical advice on this subject: tell your family what you want. Families who know the person's wishes almost always honour them; families who do not know frequently decline, because they are being asked to make a decision at the worst moment of their lives. Registering is helpful; the conversation is what actually determines the outcome.

Donation after brain death provides organs in the best condition, and requires the formal brainstem testing of Chapter 11.4.

Donation after circulatory death — after the heart stops — is increasingly used and provides more organs, though with somewhat poorer outcomes because of the period without perfusion.

Where the field is going

Xenotransplantation — organs from animals, principally pigs, which are anatomically and physiologically suitable.

The obstacles were long considered insurmountable: hyperacute rejection caused by a sugar antigen on pig cells that humans have antibodies against, plus incompatibilities in the clotting system, plus the risk of transmitting pig retroviruses.

Gene editing has addressed all three (Chapter 2.9): the offending sugar genes deleted, human regulatory genes inserted, and the endogenous retroviruses inactivated.

The first pig heart transplant into a human was performed in 2022; the patient survived two months. Pig kidneys have since been transplanted with longer function.

It is genuinely promising and it is not yet a treatment, and the ethical questions — animal welfare, infection risk to the wider population, consent in desperate circumstances — are real and unresolved.

Tolerance induction is the more elegant goal: making the recipient's immune system accept the graft as self, so that no lifelong immunosuppression is needed.

It has been achieved in small numbers of patients, typically by transplanting donor bone marrow alongside the organ so the recipient becomes a chimera with both immune systems. It is not yet reliable or safe enough for routine use, and it would remove the largest single burden of transplantation if it were.

Machine perfusion keeps retrieved organs functioning outside the body rather than merely cold. It extends viable storage time, allows organs to be assessed and even treated before implantation, and has increased the number of usable organs, particularly from marginal donors.

Bioengineered organs — growing an organ from a patient's own cells on a scaffold — has succeeded for simple structures such as the bladder and windpipe and remains distant for solid organs with complex vasculature.

What this Part adds up to

The immune system solves a problem of enormous difficulty: recognise and destroy anything that could harm you, from among an unlimited set of possibilities, while never attacking the trillions of cells that are you.

It does it by generating receptors at random and then deleting the ones that recognise self — which is expensive, discarding 98 percent of the T cells it makes, and it is the only approach that could cover an unpredictable threat.

And its failures are exactly the failures that approach predicts: it occasionally lets a self-reactive cell through (autoimmunity), it occasionally responds to something harmless (allergy), and it can be overwhelmed or removed (immunodeficiency).

The practical summary is short and encouraging.

Vaccination is the single highest-return health decision available, at every age. Keep yours and your children's up to date, and get the ones offered in later life.

Sleep, physical activity and adequate nutrition all measurably support immune function, and none of the supplements marketed to "boost immunity" have evidence approaching theirs. A boosted immune system is not the goal in any case — a well-regulated one is; the boosted version is autoimmunity.

Do not smoke, which impairs mucosal defences directly.

Wash your hands, which remains one of the most effective infection control measures ever identified.

And know your own risks. If you have no spleen, take the precautions in Chapter 7.8. If you are immunosuppressed, treat fever urgently and check your skin. If you have one autoimmune condition, be alert to a second.

What Part 14 does next

The largest organ in the body has been mentioned constantly and never described. Part 14 covers the skin, hair and nails — the barrier, the thermostat, the vitamin D factory, and the organ whose appearance carries more social weight than any other.