Organ transplantation: HLA matching, rejection immunology, and the Murray-Calne Nobel revolution

Intuition Beginner

Organ transplantation is the surgical replacement of a failing organ with a healthy one from a donor. The first successful kidney transplant was performed on December 23, 1954, between identical twins, so the recipient's body did not reject the new organ. The central problem of transplantation was born the moment surgeons tried the same operation on people who were not identical twins: the recipient's immune system sees the new organ as foreign and attacks it. This attack is called rejection, and for decades it was an unsolved barrier.

The body tells self from non-self by molecular markers called HLA (human leukocyte antigens) on the surface of every cell. Close HLA matching between donor and recipient lowers the chance of rejection but does not eliminate it. Joseph Murray, who led the 1954 kidney transplant, won the 1990 Nobel Prize for this work. Thomas Starzl pioneered the liver transplant in 1963, and Christiaan Barnard performed the first heart transplant in Cape Town in 1967.

Modern transplant medicine relies on immunosuppressive drugs such as cyclosporine and tacrolimus, which block the activation of T cells without destroying the immune system as a whole. Recipients take these drugs for life. About 40,000 transplants are performed each year in the United States, and roughly 100,000 people sit on waiting lists. The bottleneck is the supply of donor organs, which is why xenotransplantation (pig organs) and tolerance induction are active frontiers.

Visual Beginner

The timeline below marks the discoveries and operations that built modern transplantation, from the vascular-suture technique that made organ reattachment possible, through the immunology that explained rejection, to the drugs and operations that made transplantation routine.

Read left to right, the timeline splits into three strands. The surgical strand (Carrel, Starzl, Barnard, Cooper) solved the mechanical problem of removing, plumbing in, and reperfusing an organ. The immunology strand (Medawar, Dausset, Snell, Benacerraf) explained why non-identical grafts fail. The pharmacology strand (Calne, Borel) supplied the drugs that bridged the two by holding rejection at bay long enough for the graft to survive.

Worked example Beginner

On December 23, 1954, at the Peter Bent Brigham Hospital in Boston, a 23-year-old man named Ronald Herrick donated one of his kidneys to his identical twin brother Richard, who was dying of end-stage renal disease caused by chronic glomerulonephritis. The surgeon was Joseph Murray. The case is the first successful solid-organ transplant in a human, and it succeeded for one specific reason: because the brothers were identical twins, their HLA markers matched exactly, so Richard's immune system did not recognise the new kidney as foreign.

Step 1 — Confirm identical twinship. The team exchanged skin grafts between the brothers beforehand. A graft from a non-identical donor would be rejected in one to two weeks; Ronald's skin on Richard healed and stayed, proving immunological identity.

Step 2 — Remove the donor kidney. Ronald's left kidney was removed. A single healthy kidney is enough to sustain life, so Ronald went on to live a normal lifespan with one kidney.

Step 3 — Implant and re-plumb. Murray's team sewed the renal artery, renal vein, and ureter of the donor kidney into Richard's pelvis using Carrel's vascular-anastomosis technique. Blood flowed through the new kidney within minutes, and it produced urine the same day.

Richard Herrick lived eight more years, married, and fathered two children. He died in 1963 of recurrent kidney disease in the transplanted organ, not of rejection. Murray went on to develop the immunosuppressive protocols that made non-twin transplants possible and received the 1990 Nobel Prize. What this tells us: the 1954 operation proved transplantation was technically possible, and the subsequent three decades solved the immunological problem of rejection.

Check your understanding Beginner

Formal definition Intermediate+

Organ transplantation is the transfer of a functional organ (or vascularised tissue) from a donor to a recipient, with surgical re-establishment of blood flow, such that the graft is intended to sustain physiological function in the recipient over months to years. Two immunological objects govern its outcome: the HLA system and the T-cell activation cascade.

The human leukocyte antigen (HLA) system is the human major histocompatibility complex (MHC), encoded on chromosome 6. It is the most polymorphic gene family in the human genome, with more than 10,000 alleles at some loci. Class I molecules (HLA-A, HLA-B, HLA-C) are expressed on all nucleated cells and present endogenous peptides to CD8 cytotoxic T cells. Class II molecules (HLA-DR, HLA-DQ, HLA-DP) are expressed on antigen-presenting cells (dendritic cells, macrophages, B cells) and present exogenous peptides to CD4 helper T cells. For kidney transplantation, the operational match is the six-antigen match: identity at both alleles of HLA-A, HLA-B, and HLA-DR predicts the lowest rejection rate, although modern immunosuppression has reduced but not erased the survival gap between matched and mismatched grafts.

Rejection is classified into three temporal patterns. Hyperacute rejection (minutes to hours) is mediated by preformed antibodies against donor ABO blood-group antigens or HLA, for example from prior sensitisation by transfusion, pregnancy, or a previous transplant; complement activation destroys the graft before the operation is over, and it is prevented by ABO matching and a negative crossmatch. Acute rejection (days to weeks, most often within the first six months) is primarily T-cell mediated: recipient CD4 and CD8 T cells recognise donor HLA and mount a cellular attack on the graft, often reversible with high-dose corticosteroids and adjustment of maintenance immunosuppression. Chronic rejection (months to years) manifests as progressive vascular intimal thickening, fibrosis, and gradual loss of function; it is multifactorial, only partly immunological, and not reversible by current drugs.

Immunosuppression is organised in three phases around the transplant event. Induction (at transplantation) uses potent agents such as anti-thymocyte globulin (ATG) or the anti-CD25 monoclonal antibody basiliximab to deactivate T cells at the moment of antigen exposure. Maintenance (lifelong) rests on a backbone of three drug classes: a calcineurin inhibitor (tacrolimus, or cyclosporine), an antimetabolite (mycophenolate mofetil, or azathioprine), and a corticosteroid (prednisone). Rescue (for acute rejection episodes) uses high-dose methylprednisolone, antibody therapy, or escalation of maintenance dosing. The mTOR inhibitors (sirolimus, everolimus) and costimulatory blockers (belatacept) are alternative or adjunct agents.

Counterexamples to common slips

• Identical twins are always needed. False. Modern HLA matching combined with calcineurin-inhibitor-based immunosuppression allows transplant between completely unrelated donors and recipients, which is the normal case in deceased-donor kidney transplantation.
• A transplant cures the disease. False for most organs. The original disease (for example recurrent glomerulonephritis, hepatitis C, or autoimmune hepatitis) can recur in the graft, and most recipients need lifelong immunosuppression with its infection and cancer risks.
• HLA matching is essential for every organ. Partly false. Kidney grafts benefit measurably from HLA matching, but liver grafts are relatively tolerogenic and ABO plus crossmatch compatibility often suffices; heart and lung outcomes depend more on donor quality and ischaemic time than on HLA identity.
• Rejection is always an acute, treatable event. False. Chronic rejection, in particular chronic lung allograft dysfunction and transplant glomerulopathy, is the leading cause of long-term graft loss and is not preventable with current drugs.
• More donor organs would solve everything. Partly true for access, false for outcomes. Even with unlimited organs, recipients would still need lifelong immunosuppression, with its attendant risks, unless immunological tolerance were achieved.

Key mechanism: calcineurin-NFAT-IL-2 axis and immunosuppression Intermediate+

The central immunological barrier to organ transplantation is T-cell-mediated rejection, and modern maintenance immunosuppression is built to interrupt the calcineurin-NFAT-IL-2 axis of T-cell activation. When a recipient T cell encounters donor HLA on an antigen-presenting cell, the T-cell receptor (signal 1) together with costimulation (signal 2) triggers a calcium influx into the T cell. Calcium binds calmodulin, and the calcium-calmodulin complex activates calcineurin, a serine-threonine phosphatase. Active calcineurin dephosphorylates NFAT (nuclear factor of activated T cells), allowing NFAT to enter the nucleus and transcribe interleukin-2 (IL-2). IL-2 is the autocrine growth factor that drives T-cell clonal proliferation: it binds the IL-2 receptor on the same and neighbouring T cells, activating mTOR and the cell cycle. Block IL-2 transcription and the T-cell clone cannot expand; without clonal expansion, rejection cannot be mounted.

$$\underset{\text{signal 1}}{\underbrace{\text{TCR}+\text{HLA}}}\stackrel{{\text{Ca}}^{2+}}{\to }\text{calcineurin}\stackrel{\text{dephosphorylate}}{\to }{\text{NFAT}}_{\text{nuclear}}\stackrel{\text{transcribe}}{\to }\text{IL-2}\stackrel{\text{mTOR}}{\to }\text{T-cell proliferation}.$$

Each drug class in the maintenance regimen targets one arrow of this cascade. Calcineurin inhibitors (cyclosporine, isolated by Borel in 1972 from the soil fungus Tolypocladium inflatum; tacrolimus / FK506, discovered 1987) bind their respective immunophilins (cyclophilin for cyclosporine, FKBP-12 for tacrolimus) and the resulting complex inhibits calcineurin, blocking NFAT dephosphorylation and IL-2 transcription. mTOR inhibitors (sirolimus / rapamycin) block the IL-2 receptor's downstream proliferation signal, arresting the cell cycle without preventing IL-2 production. Antimetabolites (azathioprine, developed by Calne in the early 1960s from 6-mercaptopurine; mycophenolate mofetil) inhibit purine synthesis, starving proliferating T cells of nucleotide building blocks. Corticosteroids dampen cytokine transcription and inflammation broadly. Biologics (basiliximab anti-CD25, the IL-2 receptor alpha chain; alemtuzumab anti-CD52) deplete or block specific lymphocyte populations. The combination is designed so that no single agent's toxicity — nephrotoxicity from calcineurin inhibitors, myelosuppression from antimetabolites, metabolic and infectious burden from steroids — reaches its ceiling while the aggregate suppresses the rejection cascade at every stage.

Key result: the cyclosporine revolution in graft survival

The empirical proof that this axis is the load-bearing target is the survival revolution that followed cyclosporine's clinical introduction in 1978-1980. Before cyclosporine, one-year kidney-graft survival for deceased-donor transplants hovered near 50 percent under azathioprine-and-steroid protocols; within five years of cyclosporine's adoption it exceeded 80 percent, and heart and liver transplantation moved from experimental to routine. The transition from cyclosporine to tacrolimus in the 1990s, and the addition of mycophenolate and induction antibodies, pushed one-year kidney-graft survival above 95 percent and five-year survival to roughly 85 percent today, with heart at about 80 percent five-year survival, liver about 75 percent, and lung about 55 percent. These numbers are the clinical fingerprint of the calcineurin-NFAT-IL-2 axis: when it is blocked, T cells cannot proliferate, acute rejection rates fall, and grafts last.

Bridge. The calcineurin-NFAT-IL-2 mechanism builds toward 17.10.01 innate immunity and 18.10.04 vaccines and immunological memory, where the same T-cell activation cascade is the target of stimulation rather than inhibition. The foundational reason transplantation immunology and vaccine immunology are mirror images is that both turn the same molecular knob in opposite directions, and this is exactly the structure that identifies the calcineurin axis as the central control point of adaptive immunity. The central insight generalises from solid-organ rejection to autoimmune disease and to checkpoint-inhibitor cancer immunotherapy, where releasing the brakes on the same cascade produces graft-versus-host-like autoimmunity as the price of tumour rejection. Putting these together, the bridge is from the molecular pharmacology of cyclosporine to the population-level graft-survival statistics that define modern transplantation.

Exercises Intermediate+

Advanced results Master

Result 1: the HLA polymorphism and the six-antigen match

The HLA loci are the most polymorphic in the human genome: the IMGT/HLA database lists more than 10,000 alleles at HLA-B alone. This polymorphism is maintained by balancing selection from infectious pressure over millions of years, and it is the quantitative reason unrelated-donor HLA identity is rare. The six-antigen match (zero mismatch at HLA-A, -B, -DR) was shown in the Collaborative Transplant Study era to predict one-year kidney-graft survival roughly 8 to 12 percentage points above fully mismatched grafts under azathioprine-based protocols; under modern tacrolimus-based immunosuppression the gap narrows but does not vanish, especially at HLA-DR. The current allocation system weights HLA matching alongside waiting time, donor age, paediatric priority, and sensitisation status.

Result 2: the three temporal patterns of rejection

Rejection partitions cleanly by timescale and mechanism. Hyperacute rejection (minutes) is antibody-complement injury to the graft endothelium, prevented by ABO compatibility and a negative crossmatch; it is now rare because of mandatory pre-transplant antibody screening. Acute cellular rejection (days to weeks) is predominantly CD8 T-cell mediated, occurs in 10 to 20 percent of kidney recipients under modern regimens, and is usually reversible with methylprednisolone. Acute antibody-mediated rejection, mediated by donor-specific anti-HLA antibodies and complement (C4d staining on biopsy), is more damaging and requires plasmapheresis, intravenous immunoglobulin, and rituximab. Chronic rejection (months to years) produces vascular intimal thickening, interstitial fibrosis, and tubular atrophy; it is the dominant cause of long-term graft loss and is not reversible by current drugs, although tacrolimus-based regimens delay it.

Result 3: the calcineurin-NFAT-IL-2 axis as the load-bearing pharmacological target

The molecular identification of the calcineurin-NFAT-IL-2 cascade as the central control point of T-cell activation is what makes modern transplantation possible. Cyclosporine (Borel 1972, from Tolypocladium inflatum) and tacrolimus (FK506, 1987) each bind an immunophilin and the resulting complex inhibits calcineurin's phosphatase activity; without calcineurin, NFAT cannot dephosphorylate, cannot enter the nucleus, and cannot transcribe IL-2. The downstream consequence is that the antigen-stimulated T-cell clone cannot proliferate, which halts rejection. The clinical fingerprint is the doubling of one-year kidney-graft survival between 1978 and 1984 as cyclosporine entered practice, and the further rise of heart and liver transplantation from experimental to routine over the same interval.

Result 4: the major solid-organ transplant programs and their survival statistics

Each organ has a distinct survival profile that reflects its immunogenicity, its tolerance of ischaemia, and the disease being replaced. Kidney transplantation (about 22,000 per year in the United States, live or deceased donor) achieves five-year graft survival near 85 percent and restores survival relative to dialysis. Liver transplantation (Starzl 1963; about 9,000 per year) achieves five-year survival near 75 percent and is notable for the liver's regenerative capacity and relative tolerogenicity. Heart transplantation (Barnard 1967; about 2,500 per year) achieves five-year survival near 80 percent. Lung transplantation (Cooper 1983; about 2,000 per year) has the worst long-term outcome at about 55 percent five-year survival, dominated by chronic lung allograft dysfunction. Pancreas transplantation is usually combined with kidney for diabetic renal failure; intestinal transplantation remains rare and high-complication.

Result 5: islet, composite-tissue, and xenotransplant frontiers

Beyond the solid organs, three frontiers extend the field. Islet-cell transplantation (the Edmonton Protocol, Shapiro 2000) infuses isolated pancreatic islets into the liver via the portal vein and produces insulin independence in about 50 percent of type-1 diabetic recipients at five years, with the remainder still benefiting from reduced hypoglycaemia. Composite-tissue allotransplantation (face, Dubernard 2005; hand, Lyons 1998) transfers immunogenic non-life-saving tissues and therefore exposes recipients to lifelong immunosuppression for quality-of-life indications, with about 45 face transplants performed worldwide to date. Xenotransplantation, using genetically modified pigs with the alpha-Gal antigen knocked out and human complement regulators added, produced the first pig-to-human heart transplant (Maryland, January 2022, two-month survival limited by porcine cytomegalovirus) and pig-to-human kidney transplants (2024), opening a possible route to expanding the donor supply.

Result 6: tolerance induction as the unsolved central problem

The durable goal of transplantation is donor-specific tolerance: a state in which the recipient accepts the graft without generalised immunosuppression. The principal achieved route is mixed chimerism (recipient receives both an organ and haematopoietic stem cells from the same donor, producing a chimeric immune system with central deletion of donor-reactive clones), demonstrated in some HLA-mismatched kidney recipients. Regulatory T-cell expansion, co-stimulatory blockade (CTLA4-Ig / belatacept), and antigen-specific tolerising protocols are active research fronts. No protocol yet reliably induces tolerance across arbitrary donor-recipient pairs, which is why lifelong calcineurin-inhibitor-based immunosuppression remains the clinical standard.

Synthesis. Putting these together, the seventy-year arc from Carrel's vascular suture to the Maryland pig-heart transplant is the foundational reason transplantation is the canonical case of applied immunology: the surgical problem was solved by 1902, the immunological barrier was identified by Medawar in 1944, and the pharmacological bridge was built by Calne and Borel between 1960 and 1980. The central insight is that T-cell-mediated rejection, channelled through the calcineurin-NFAT-IL-2 axis, is the single molecular target that all maintenance regimens attack, and this is exactly why cyclosporine's clinical arrival in 1978 doubled graft survival within five years and turned heart and liver transplantation from experimental to routine. The pattern recurs across every solid-organ program: each organ's survival curve is a fingerprint of how completely its T-cell infiltration is held in check, and the bridge is between the molecular pharmacology of a single fungal metabolite and the population-level survival of hundreds of thousands of graft recipients worldwide. This framework generalises from solid organs to islet, composite-tissue, and xenotransplant frontiers, and identifies tolerance induction — the controlled release of the same calcineurin brake — as the remaining open problem whose solution would eliminate the lifelong trade-off between rejection and over-suppression.

Full proof set Master

Proposition 1 (probability of a zero-mismatch six-antigen match under balanced polymorphism)

Consider a single HLA locus with $n$ equally frequent alleles in Hardy-Weinberg equilibrium. Two unrelated individuals are drawn at random. The probability that they share the same genotype (and therefore match at both alleles) is

$$P(\text{genotype match at one locus})=\frac{1}{n^2}+\frac{2(n-1)}{n^2}\cdot \frac{1}{n^2}=\frac{n^2+2(n-1)}{n^4}.$$

In particular, as $n\to \infty$ this probability tends to $1/n^2$, dominated by the homozygous-match term.

Proof. Let individual 1 have genotype $(X_1,X_2)$ and individual 2 have genotype $(Y_1,Y_2)$, where each allele is drawn independently and uniformly from $\{1,\dots ,n\}$. The probability that individual 1 is homozygous is $P(X_1=X_2)={\sum }_{i}P(X_1=X_2=i)=n\cdot (1/n{)}^2=1/n$, and conditional on $X_1=X_2=i$, the probability that individual 2 is also homozygous for $i$ is $(1/n{)}^2=1/n^2$. Summed over the $n$ possible shared homozygous genotypes, this contributes $n\cdot (1/n)\cdot (1/n^2)=1/n^2$.

For the heterozygous match, individual 1 is heterozygous with probability $1-1/n=(n-1)/n$, and conditional on being heterozygous his genotype is some unordered pair $\{i,j\}$ with $i\ne j$. Individual 2 matches this unordered pair with probability $2\cdot (1/n{)}^2=2/n^2$ (either ordered draw $(i,j)$ or $(j,i)$). Summed, the heterozygous-match contribution is $((n-1)/n)\cdot (2/n^2)=2(n-1)/n^3$.

Combining and putting over a common denominator,

$$P(\text{match})=\frac{1}{n^2}+\frac{2(n-1)}{n^3}=\frac{n+2(n-1)}{n^3}=\frac{3n-2}{n^3},$$

which is asymptotic to $3/n^2$ for large $n$, and the homozygous contribution $1/n^2$ is exactly one-third of the leading term. The exact form for a single locus is $(3n-2)/n^3$. For a six-antigen match across HLA-A, HLA-B, HLA-DR (treated as three independent loci with $n_A,n_B,n_{DR}$ common alleles), the probability is the product ${\prod }_L(3n_L-2)/n_L^3$, which is vanishingly small for the thousands of alleles present at each locus, the quantitative reason unrelated zero-mismatch donors are rare and national registries exist to find them. $\square$

Proposition 2 (steady-state trough concentration under twice-daily dosing)

A patient receives a maintenance immunosuppressant (for example tacrolimus) as an oral dose $D$ every $\tau$ hours. The drug is eliminated by first-order kinetics with elimination rate constant $k$, and has oral bioavailability $F$ and volume of distribution $V$. At steady state, the peak-to-trough fluctuation and the average trough concentration $C_{\min ,\text{ss}}$ are

$$C_{\min ,\text{ss}}=\frac{FD}{V}\cdot \frac{1}{e^{k\tau }-1}.$$

Proof. After each dose the concentration jumps by $\Delta C=FD/V$ (the bioavailable dose divided by the volume of distribution) and then decays exponentially as $C(t)=C_0{e}^{-kt}$. At steady state under periodic dosing with period $\tau$, the concentration immediately before the next dose (the trough) satisfies the fixed-point relation $C_{\min ,\text{ss}}=(C_{\min ,\text{ss}}+\Delta C)e^{-k\tau }$, because the post-dose concentration $C_{\min ,\text{ss}}+\Delta C$ decays for time $\tau$ to become the next trough. Solving,

$$C_{\min ,\text{ss}}(e^{k\tau }-1)=\Delta C{e}^{-k\tau }\cdot e^{k\tau }=\Delta C,C_{\min ,\text{ss}}=\frac{\Delta C}{e^{k\tau }-1}=\frac{FD}{V(e^{k\tau }-1)}.$$

Equivalently, writing $t_{1/2}=(\ln 2)/k$ for the half-life, $k\tau =\tau \ln 2/t_{1/2}$, and the trough falls as the dosing interval grows or the half-life shortens. For tacrolimus with $t_{1/2}\approx 12$ h dosed every $\tau =12$ h, $k\tau =\ln 2$, giving $C_{\min ,\text{ss}}=FD/V\cdot 1/(\ln 2\cdot \dots )$ in the limit; clinically the trough is monitored by blood test and the dose adjusted to keep it within the narrow window (typically 5 to 15 ng/mL for kidney recipients) that minimises both rejection and nephrotoxicity. $\square$

Connections Master

• Surgery and emergency medicine 35.10.01. This unit is the transplantation chapter anchored to the surgery survey, which supplies the three-phase perioperative care model, the ASA classification, sterile technique, and the oxygen-delivery framework that govern every transplant operation. The transplantation-specific content here — HLA matching, the rejection cascade, calcineurin-inhibitor pharmacology — slots into the operative and perioperative structure that the survey establishes, and every transplant recipient's intraoperative and postoperative course is governed by the hemodynamic and infection-control principles developed there.

• Vaccines and immunological memory 18.10.04. Transplant immunosuppression is the inverse operation of vaccination: both act on the same calcineurin-NFAT-IL-2 axis of T-cell activation, vaccination to stimulate clonal expansion and memory, immunosuppression to prevent it. Live vaccines are contraindicated in transplant recipients precisely because the suppressed T-cell system cannot contain a replicating attenuated pathogen; inactivated vaccines are given but mount a blunted response, which is why transplant candidates are vaccinated before immunosuppression begins.

• HIV/AIDS, retroviral biology, and pandemic response 35.02.05. HIV was a defining opportunistic-infection threat in early transplantation because the same T-cell depletion that defines AIDS is iatrogenically produced by calcineurin inhibitors. The pharmacokinetic interaction is also direct: ritonavir's inhibition of CYP3A4 (treated in the HIV and pharmacology units) dramatically raises tacrolimus levels, and co-management of HIV and transplant immunosuppression requires careful dose adjustment to avoid both rejection and over-suppression.

• Innate immunity at the molecular level 17.10.01. Rejection is an adaptive-immune phenomenon, but its earliest effector phase — complement deposition, neutrophil infiltration, and cytokine release on the graft endothelium — is mediated by the innate system. Hyperacute rejection in particular is pure innate-immune complement injury driven by preformed antibody, and the TLR and NF-kB signalling pathways of innate immunity supply the costimulatory signals that licence the adaptive T-cell response this unit's drugs target.

Historical & philosophical context Master

The lineage of organ transplantation weaves together three strands that matured separately. Alexis Carrel, working in Lyon, developed the triangulation technique for vascular anastomosis in 1902 ^{[Carrel 1902]}, which made it surgically possible to remove an organ, re-plumb its vessels, and restore blood flow; he received the 1912 Nobel Prize for this and related work on suturing and transplantation. The immunological strand opened when Peter Medawar, working with burn patients during the Second World War, observed that a second skin graft from the same donor was rejected faster than the first, and concluded in 1944 that rejection is an immune phenomenon with memory ^{[Medawar 1944]}; he shared the 1960 Nobel Prize with Macfarlane Burnet. The genetic strand was the identification of the mouse H-2 system by George Snell from 1948 and the discovery of the first human HLA antigen (Mac) by Jean Dausset in 1958, with Baruj Benacerraf's immune-response genes of the 1960s completing the picture; the three shared the 1980 Nobel Prize.

The clinical synthesis began with Joseph Murray's transplant of a kidney from Ronald Herrick to his identical-twin brother Richard on December 23, 1954 at the Peter Bent Brigham Hospital ^{[Murray 1955]}, which proved transplantation technically viable in humans and earned Murray the 1990 Nobel Prize. Roy Calne, working in the early 1960s, demonstrated that 6-mercaptopurine and then azathioprine could prevent rejection in dogs, opening the era of chemical immunosuppression ^{[Calne 1960]}; Jean-François Borel's isolation of cyclosporine from Tolypocladium inflatum in 1972 and its clinical introduction in 1978 ^{[Borel 1976]} produced the graft-survival revolution that turned heart and liver transplantation from experimental to routine. Thomas Starzl performed the first human liver transplant in 1963 and led the tacrolimus era of the late 1980s; Christiaan Barnard performed the first human heart transplant in Cape Town on December 3, 1967 ^{[Barnard 1967]}; Joel Cooper performed the first successful single-lung transplant in 1983.

Bibliography Master

Primary sources

• Carrel, A. (1902). "La chirurgie expérimentale des anastomoses vasculaires et la transplantation des viscères." Lyon Médical 99: 340-344. ^{[Carrel 1902]}
• Medawar, P.B. (1944). "The behaviour and fate of skin autografts and skin homografts in rabbits." Journal of Anatomy 79: 157-176. ^{[Medawar 1944]}
• Dausset, J. (1958). "Iso-leuco-anticorps." Acta Haematologica 20: 156-166.
• Snell, G.D. (1948-1960s). Methods for the study of histocompatibility in the mouse (the H-2 system).
• Murray, J.E., Merrill, J.P., Harrison, J.H. (1955). "Renal homotransplantations in identical twins." Surgical Forum 6: 432-436. ^{[Murray 1955]}
• Calne, R.Y. (1960). "The rejection of renal homografts: inhibition in dogs by 6-mercaptopurine." The Lancet 276: 417-418. ^{[Calne 1960]}
• Starzl, T.E. et al. (1963). "Homotransplantation of the liver in humans." Surgery, Gynecology & Obstetrics 117: 659-676.
• Barnard, C.N. (1967). "A human cardiac transplant: an interim report of a successful operation performed at Groote Schuur Hospital, Cape Town." South African Medical Journal 41: 1271-1274. ^{[Barnard 1967]}
• Borel, J.F. et al. (1976). "Biological effects of cyclosporin A: a new antilymphocytic agent." Agents and Actions 6: 468-475. ^{[Borel 1976]}
• Shapiro, A.M. et al. (2000). "Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen." New England Journal of Medicine 343: 230-238.

Bibtex

@article{carrel1902,
  author  = {Carrel, Alexis},
  title   = {La chirurgie exp{\'e}rimentale des anastomoses vasculaires et la transplantation des visc{\`e}res},
  journal = {Lyon M{\'e}dical},
  volume  = {99},
  pages   = {340--344},
  year    = {1902}
}
@article{medawar1944,
  author  = {Medawar, Peter B.},
  title   = {The behaviour and fate of skin autografts and skin homografts in rabbits},
  journal = {Journal of Anatomy},
  volume  = {79},
  pages   = {157--176},
  year    = {1944}
}
@article{dausset1958,
  author  = {Dausset, Jean},
  title   = {Iso-leuco-anticorps},
  journal = {Acta Haematologica},
  volume  = {20},
  pages   = {156--166},
  year    = {1958}
}
@article{murray1955,
  author  = {Murray, Joseph E. and Merrill, John P. and Harrison, J. Hartwell},
  title   = {Renal homotransplantations in identical twins},
  journal = {Surgical Forum},
  volume  = {6},
  pages   = {432--436},
  year    = {1955}
}
@article{calne1960,
  author  = {Calne, Roy Y.},
  title   = {The rejection of renal homografts: inhibition in dogs by 6-mercaptopurine},
  journal = {The Lancet},
  volume  = {276},
  pages   = {417--418},
  year    = {1960}
}
@article{starzl1963,
  author  = {Starzl, Thomas E. and others},
  title   = {Homotransplantation of the liver in humans},
  journal = {Surgery, Gynecology \& Obstetrics},
  volume  = {117},
  pages   = {659--676},
  year    = {1963}
}
@article{barnard1967,
  author  = {Barnard, Christiaan N.},
  title   = {A human cardiac transplant: an interim report of a successful operation performed at Groote Schuur Hospital, Cape Town},
  journal = {South African Medical Journal},
  volume  = {41},
  pages   = {1271--1274},
  year    = {1967}
}
@article{borel1976,
  author  = {Borel, Jean F. and Feurer, C. and Gubler, H. U. and St{\"a}helin, H.},
  title   = {Biological effects of cyclosporin {A}: a new antilymphocytic agent},
  journal = {Agents and Actions},
  volume  = {6},
  pages   = {468--475},
  year    = {1976}
}
@article{shapiro2000,
  author  = {Shapiro, A. M. James and Lakey, Jonathan R. T. and Ryan, Edmond A. and others},
  title   = {Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen},
  journal = {New England Journal of Medicine},
  volume  = {343},
  pages   = {230--238},
  year    = {2000}
}
@book{starzl1992,
  author    = {Starzl, Thomas E.},
  title     = {The Puzzle People: Memoirs of a Transplant Surgeon},
  publisher = {University of Pittsburgh Press},
  year      = {1992}
}
@book{morris-knechtle2014,
  author    = {Morris, Peter J. and Knechtle, Stuart J.},
  title     = {Kidney Transplantation: Principles and Practice},
  edition   = {7},
  publisher = {Saunders/Elsevier},
  year      = {2014}
}