Transplant rejection explained: hyperacute, acute, chronic and GVHD
Is the host attacking the graft, or the graft attacking the host? How to tell the three types of transplant rejection and graft-versus-host disease apart by timing and immune mechanism.
Distinguish hyperacute, acute and chronic transplant rejection and graft-versus-host disease (GVHD) by timing and immune mechanism.
The short version
- Donor HLA (MHC) is the target: the greater the mismatch, the worse the long-term graft survival.
- Hyperacute rejection takes minutes to hours and is caused by preformed antibody; it cannot be treated, only prevented by ABO matching and a crossmatch.
- Acute rejection takes days to months, mostly in the first year, and is mostly T-cell mediated (direct pathway); the other form is antibody-mediated.
- Chronic rejection takes months to years and leaves progressive fibrosis and vasculopathy (indirect pathway).
- In rejection the host attacks the graft; in graft-versus-host disease, donor T cells attack the host's skin, gut and liver.
Transplant rejection: three transplants, three different failures
Picture three patients. In the first, a kidney is sewn in and the clamps come off, and within minutes the surgeons watch the new kidney fail. In the second, a kidney works for a few months and then starts to fail. In the third, a marrow graft takes, then attacks its new owner.
Each of the three stories is a different failure. The first is over almost at once, the second unfolds over months, and the third is not a failure of the graft at all but an attack by it. The rest of this page sorts them by when they happen, what drives them and what the biopsy shows.
Same immune system, different mistakes. Transplant rejection is not one process: the types differ in timing and in mechanism, and graft-versus-host disease (GVHD) turns the arrow around entirely.
HLA mismatch and direct versus indirect allorecognition
Our HLA molecules, the MHC, tell T cells “this is self”. A donor organ carries the donor's HLA, which looks foreign, and the greater the mismatch, the worse the long-term graft survival.[1][2]
The recipient's T cells can recognise the graft in two ways.[1][2]
| Pathway | What the recipient T cell sees | Character |
|---|---|---|
| Direct | Intact donor MHC on donor antigen-presenting cells carried in the graft | Strong and fast; chiefly drives acute rejection |
| Indirect | Donor proteins picked up by the recipient's own antigen-presenting cells and shown as peptides on the recipient's MHC | Slower but persistent; drives chronic rejection |
Hyperacute rejection: preformed antibody
Hyperacute rejection happens within minutes to hours. It is caused by antibodies that were already in the recipient before the transplant.[1][2][3]
- Natural anti-A or anti-B antibodies.
- Anti-HLA antibodies from a transfusion, a pregnancy or an earlier transplant.
These antibodies bind the lining of the graft's blood vessels and activate complement, and the vessels clot.[1]
Acute rejection: T-cell mediated and antibody-mediated
Acute rejection appears days to months after transplant, mostly in the first year; about 10–20% of patients have an episode in that first year.[1]
| Form | Mechanism | Kidney biopsy |
|---|---|---|
| T-cell mediated (most common) | Driven chiefly by the direct pathway | Lymphocytes, inflammation between the tubules, and tubulitis (lymphocytes inside the tubules) |
| Antibody-mediated | New donor-specific antibodies and complement | C4d staining in capillaries |
A steroid, a calcineurin inhibitor and an antimetabolite are the foundation of keeping a graft alive.[1][9]
Chronic rejection: fibrosis and vasculopathy
Chronic rejection develops over months to years. Antibodies and T cells both contribute, and the indirect pathway drives it.[1][2][3]
Unlike hyperacute rejection, there is no single dramatic event here: the damage accumulates slowly, which is why the picture is dominated by scarring rather than clotting.
Slow injury and repair leave progressive fibrosis and vasculopathy: scarring, thickened artery linings and, eventually, graft loss.[1][3]
Worked example: three biopsies
Match each biopsy to its type using timing and histology. Timing gives the first answer, and the histology confirms the mechanism: capillary thrombi point to preformed antibody, lymphocytes in the tubules point to T cells, and fibrosis with a thick artery lining points to long-running injury and repair.
- Ten minutes after the clamps come off: thrombi in the capillaries and fibrinoid necrosis → hyperacute rejection, from preformed antibody.
- Four months out, creatinine up from 1.1 to 1.8 mg/dL, lymphocytes in the tubules → acute rejection, T-cell mediated.
- Six years out, creatinine creeping up, fibrosis and a thick artery lining → chronic rejection.
Graft-versus-host disease: turning the arrow around
In graft-versus-host disease the arrow points the other way. A stem cell graft carries immunocompetent donor T cells. They see the recipient's tissues as foreign, and the immunosuppressed recipient cannot stop them.[2][4][10][11]
| Timing | Features | |
|---|---|---|
| Acute | Classically within 100 days | Skin: maculopapular rash. Gut: watery diarrhoea. Liver: jaundice.[5][7] |
| Chronic | Classically after 100 days | Skin fibrosis, dry eyes and mouth, and cholestatic liver disease.[6][8] |
The 100-day split is the classic exam convention; current criteria classify acute and chronic GVHD by their clinical features, so acute GVHD can appear after day 100.[5][6][7]
Practice question
Original · USMLE styleA 41-year-old woman had a matched unrelated donor stem cell transplant for leukaemia 24 days ago. She now has a maculopapular rash on her palms and trunk, profuse watery diarrhoea and jaundice. Total bilirubin is 4.6 mg/dL. Stool cultures are negative.
Common questions
What are the types of transplant rejection?
Hyperacute (minutes to hours, preformed antibody), acute (days to months, mostly T-cell mediated, with an antibody-mediated form) and chronic (months to years, fibrosis and vasculopathy).
What causes hyperacute rejection?
Antibodies already present in the recipient: natural anti-A or anti-B, or anti-HLA antibodies from a transfusion, pregnancy or earlier transplant. They bind the graft's vessel lining, activate complement and the vessels clot.
What is the difference between direct and indirect allorecognition?
In the direct pathway recipient T cells see intact donor MHC on donor antigen-presenting cells. In the indirect pathway the recipient's own antigen-presenting cells show donor peptides on the recipient's MHC; it is slower but persistent.
What is the difference between rejection and graft-versus-host disease?
In rejection the host immune system attacks the graft. In graft-versus-host disease, immunocompetent donor T cells in the graft attack the immunosuppressed host.
Which organs does acute GVHD affect?
Skin (maculopapular rash), gut (watery diarrhoea) and liver (jaundice), classically within 100 days of transplant.
Transcript
Read the full narration, by chapter681 words
0:00Three transplants, three different failures
A kidney is sewn in, and the clamps come off. Within minutes, the surgeons watch the new kidney fail, and nothing can save it. A second kidney works for a few months, then starts to fail. A third patient's marrow graft takes, then attacks its new owner. Same immune system, different mistakes.
0:20The goal, and HLA as the target
Today: tell hyperacute, acute and chronic rejection and graft-versus-host disease apart by timing and mechanism. Our HLA molecules, the MHC, tell T cells "this is self". A donor organ carries the donor's HLA, which looks foreign, and the more the mismatch, the worse the long-term graft survival.
0:43Direct and indirect allorecognition
The recipient's T cells can recognise it in two ways. Direct: they see intact donor MHC on donor antigen-presenting cells carried in the graft. That response is strong and fast. Indirect: the recipient's own antigen-presenting cells pick up donor proteins and show them as peptides on the recipient's MHC. That is slower but persistent.
1:09Hyperacute rejection: preformed antibody, prevented by ABO match and crossmatch
Hyperacute rejection: minutes to hours, caused by antibodies that were already in the recipient before the transplant. Natural anti-A or anti-B antibodies, or anti HLA antibodies from a transfusion, pregnancy or earlier transplant. They bind the graft's blood vessel lining, activate complement, and the vessels clot. It cannot be treated, only prevented: match ABO and do a crossmatch before the operation.
1:39Acute rejection: T-cell mediated and antibody-mediated
Acute rejection: days to months, mostly in the first year, in about 10 to 20% of patients. Mostly it is T-cell mediated, driven chiefly by the direct pathway: biopsy shows lymphocytes, inflammation between the tubules, and tubulitis, lymphocytes inside them. The other form is antibody-mediated: new donor-specific antibodies, complement, and C4d staining in capillaries. A steroid, a calcineurin inhibitor and an antimetabolite are the foundation of keeping a graft alive.
2:15Chronic rejection: fibrosis and vasculopathy
Chronic rejection: months to years. Antibodies and T cells both contribute, and the indirect pathway drives it. Slow injury and repair leave progressive fibrosis and vasculopathy: scarring, thickened artery linings, graft loss.
2:32Worked example: three biopsies
Three biopsies. Ten minutes after the clamps come off: thrombi in the capillaries and fibrinoid necrosis. Hyperacute, from preformed antibody. Four months out, creatinine up from 1.1 to 1.8, lymphocytes in the tubules. Acute, T-cell mediated. Six years out, creatinine creeping up, fibrosis and a thick artery lining.
2:58Graft-versus-host disease: acute and chronic
Chronic. Now turn the arrow around: graft-versus-host disease. A stem cell graft carries immunocompetent donor T cells. They see the recipient's tissues as foreign, and the immunosuppressed recipient cannot stop them. Acute disease, classically within a 100 days, hits three organs: skin with a maculopapular rash, gut with watery diarrhoea, liver with jaundice. Chronic disease, classically after a 100 days, brings skin fibrosis, dry eyes and mouth, and cholestatic liver disease.
3:34Your turn: a practice question
Your turn. A 41-year-old woman had a matched unrelated donor stem cell transplant for leukaemia 24 days ago. She now has a maculopapular rash on her palms and trunk, profuse watery diarrhoea, and jaundice, with a total bilirubin of 4.6 milligrams per decilitre. Stool cultures are negative. Which of the following best explains her illness? A, preformed recipient antibodies against donor endothelial antigens. B, recipient T cells recognising intact donor MHC on graft cells. C, donor T cells recognising recipient tissue as foreign. D, recipient antigen-presenting cells showing processed donor peptides. E, newly formed recipient antibodies against donor HLA molecules. Pause here and decide.
4:33The answer, one option at a time
A is out: preformed antibody means hyperacute rejection, within minutes to hours of surgery. B is out: that is acute rejection, the recipient attacking the graft. Our arrow points the other way. D is out: the indirect pathway is a recipient response to the graft, driving chronic rejection. E is out: new antibodies against donor HLA are antibody-mediated acute rejection, again aimed at the graft.
5:04So the answer is C
So the answer is C. Rash, diarrhoea and jaundice after a stem cell graft: acute graft-versus-host disease, donor T cells attacking skin, gut and liver.
5:17Recap pocket card
Three things to keep. One: hyperacute is minutes, preformed antibody; acute is months, mostly T cells; chronic is years, fibrosis and vasculopathy. Two: in rejection, the host attacks the graft. Three: in graft-versus-host disease, donor T cells attack the host's skin, gut and liver. Next, vaccines: live, inactivated, subunit and messenger RNA.
Sources
Numbers in the text, e.g. [1], point here- Graft rejection across solid organ transplants: mechanisms, monitoring, and immunosuppressive therapeutics (2026). europepmc.org/article/PMC/PMC13136141
- The HLA system: genetics, immunology, clinical testing, and clinical implications (2007). europepmc.org/article/PMC/PMC2628004
- Diagnosis and management of antibody-mediated rejection: current status and novel approaches (2014). europepmc.org/article/PMC/PMC4285166
- New insights into the basic biology of acute graft-versus-host-disease (2020). europepmc.org/article/PMC/PMC7604569
- Treatment and unmet needs in steroid-refractory acute graft-versus-host disease (2020). europepmc.org/article/PMC/PMC7192843
- The pathophysiology of chronic graft-versus-host disease: the unveiling of an enigma (2011). europepmc.org/article/PMC/PMC3128905
- Intestinal involvement in graft versus host disease in children: ESPGHAN overview (2025). europepmc.org/article/PMC/PMC12314575
- The Pathophysiology and Treatment of Graft-versus-Host Disease: Lessons Learnt From Animal Models (2021). europepmc.org/article/PMC/PMC8417310
- Management of kidney transplant recipients for primary care practitioners (2024). europepmc.org/article/PMC/PMC10946132
- Pathophysiology of GvHD and Other HSCT-Related Major Complications (2017). europepmc.org/article/PMC/PMC5357769
- Current Preventions and Treatments of aGVHD (2020). europepmc.org/article/PMC/PMC7773902
The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.
Image credits. Illustrations: NIAID NIH BioArt Source (bioart.niaid.nih.gov), public domain, recoloured and outlined: kidney, bone marrow, T cell, dendritic cell, antibody, complement. Servier Medical Art (smart.servier.com), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), adapted (recoloured, outlined, resized): cut blood vessel, skin, intestine, liver. Syringe icon: Health Icons (healthicons.org), CC0. The timelines, graphs, tubules, biopsy fields, figures, cards and all handwriting are drawn in code (original). No AI-generated teaching images.
Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-IMM-012.
For exam study only, not medical advice. Read the medical disclaimer.
In this series
Playlist on YouTube- EP 01MHC I vs MHC II: how antigen presentation works5:03
- EP 02T-cell activation: the two-signal model4:58
- EP 03Th1, Th2, Th17 and Treg: helper T-cell subsets5:13
- EP 04Antibody isotypes and class switching5:13
- EP 05Central vs peripheral tolerance: how lymphocytes learn self-tolerance5:26
- EP 06Complement system explained: three pathways, one ending5:24
- EP 07Complement deficiencies: C1q, C3, C5–C9 and C1 inhibitor5:15
- EP 08Hypersensitivity types I to IV: the four effectors5:20
- EP 09B-cell vs T-cell immunodeficiency: predict the infections5:24
- EP 10Hyper IgM syndrome: CD40 ligand and class switching5:19
- EP 11Chronic granulomatous disease: NADPH oxidase and the respiratory burst5:20
- EP 12Leukocyte adhesion deficiency: CD18 and neutrophil extravasation5:01
- EP 13Transplant rejection explained: hyperacute, acute, chronic and GVHD5:51
- EP 14Vaccine types explained: live, inactivated, conjugate and mRNA5:41