Transplant Rejection & Immunosuppressants
From hyperacute thrombosis to calcineurin blockade
Overview: rejection runs on a clock
Three tempos plus a reversal. Graft rejection is classified by timing, and timing points to mechanism: hyperacute rejection occurs within minutes (preformed antibodies), acute rejection over weeks to months (new cellular and humoral responses), and chronic rejection over months to years (irreversible vascular fibrosis). Graft-versus-host disease (GVHD) is the reverse: donor lymphocytes attacking the host.
Why the graft looks foreign. Recipient T cells recognize donor MHC (HLA) molecules, either directly on donor antigen-presenting cells or as donor peptides displayed by recipient APCs, while recipient antibodies bind donor HLA and ABO antigens on graft endothelium.
| Feature | Hyperacute | Acute | Chronic |
|---|---|---|---|
| Timing | Minutes, at reperfusion | Weeks to months | Months to years |
| Mechanism | Preformed recipient antibodies to donor ABO/HLA (type II) | Cellular (CD8 and CD4 T cells vs donor MHC) and humoral (new antidonor antibodies) | Ongoing recipient T-cell and antibody response to donor MHC |
| Pathology | Complement fixation, vessel thrombosis, ischemic necrosis | Lymphocytic interstitial infiltrate (tubulitis); C4d in capillaries | Vascular wall thickening, fibrosis, parenchymal atrophy |
| Outcome | Graft lost; must be removed | Reversible with more immunosuppression | Irreversible |
Hyperacute, acute, and chronic rejection
Hyperacute rejection. Within minutes of reperfusion, preformed recipient antibodies against donor ABO or HLA antigens bind graft endothelium, fix complement, and thrombose graft vessels, a type II hypersensitivity reaction. A kidney turns mottled and cyanotic on the table and undergoes ischemic necrosis. Prevention relies on ABO matching and a pretransplant crossmatch; preformed anti-HLA antibodies typically come from prior transfusions, pregnancies, or transplants.
Acute rejection. Weeks to months after transplant. In cellular rejection, recipient CD8 and CD4 T cells attack donor MHC, producing a lymphocytic interstitial infiltrate (tubulitis in the kidney). In humoral rejection, antidonor antibodies formed after transplant activate complement and leave C4d deposits in capillaries. Both usually respond to increased immunosuppression.
Chronic rejection. Over months to years, recipient T cells and antibodies continue to react to donor MHC, and their cytokines drive vascular wall thickening, smooth muscle proliferation, and fibrosis. It is irreversible. Organ-specific patterns:
- Heart: accelerated atherosclerosis; cardiac allograft vasculopathy is the signature lesion.
- Lung: bronchiolitis obliterans.
- Liver: vanishing bile ducts.
- Kidney: chronic allograft nephropathy.
Graft-versus-host disease
The graft attacks the host. In GVHD, immunocompetent donor T cells recognize the tissues of an immunocompromised host as foreign, a type IV reaction. It follows lymphocyte-rich grafts, classically allogeneic bone marrow transplant and occasionally liver transplant. Donor T cells target skin, liver, and gut, producing a maculopapular rash, jaundice, and watery diarrhea, which can appear within weeks of the transplant.
The upside. The same alloreactivity produces a graft-versus-tumor effect that can help clear residual leukemia.
Irradiating cellular blood products for severely immunocompromised recipients inactivates donor lymphocytes and prevents transfusion-associated GVHD.
How the immunosuppressants work
Blocking T-cell activation. Most transplant drugs interrupt the chain from antigen recognition to clonal expansion:
- TCR signal → calcineurin → NFATBlocked by cyclosporine and tacrolimus
- IL-2 transcribed and secretedThe T-cell growth signal
- IL-2 binds its receptor (CD25)Blocked by basiliximab
- IL-2 receptor signals through mTORG1→S progression; blocked by sirolimus
- Clonal proliferation needs purinesBlocked by mycophenolate and azathioprine
Calcineurin inhibitors. Cyclosporine binds cyclophilin and tacrolimus (FK506) binds FKBP; each complex inhibits calcineurin, so NFAT is not activated, IL-2 is not transcribed, and T cells are not activated. Both are nephrotoxic (afferent arteriolar vasoconstriction), neurotoxic, and hypertensive; both are CYP3A4 substrates with narrow therapeutic windows, so drug levels are monitored. Tacrolimus is more potent than cyclosporine.
Cyclosporine vs tacrolimus. Cyclosporine adds hyperlipidemia and the distinctive gingival hyperplasia and hirsutism. Tacrolimus lacks gingival hyperplasia and hirsutism but is more diabetogenic, causing hyperglycemia and new-onset diabetes.
Sirolimus (rapamycin). Sirolimus also binds FKBP, but the complex inhibits mTOR instead of calcineurin, so T cells cannot respond to IL-2 and arrest at the G1→S transition. Toxicities: pancytopenia, hyperlipidemia, insulin resistance, and impaired wound healing. It is notably not nephrotoxic, which makes it useful when renal function is a concern, and its antiproliferative effect is exploited on drug-eluting stents.
Antimetabolites. Mycophenolate mofetil (MMF) inhibits IMP dehydrogenase, blocking de novo guanine (purine) synthesis, on which lymphocytes depend. It causes GI upset/diarrhea, bone marrow suppression, and invasive CMV infection, and it is also used for lupus nephritis. Azathioprine is converted to 6-mercaptopurine (6-MP), a purine analog that inhibits purine synthesis; its main toxicity is myelosuppression.
Corticosteroids. Prednisone and other glucocorticoids inhibit NF-κB, broadly suppressing cytokine transcription and inflammation. Chronic use is Cushingoid: hyperglycemia, osteoporosis, avascular necrosis, cataracts, hypertension, weight gain, psychosis, and adrenal suppression. Neutrophil demargination also raises the WBC count.
Toxicities and interactions
| Drug | Target | Hallmark toxicity |
|---|---|---|
| Cyclosporine | Calcineurin (via cyclophilin) | Nephrotoxicity, hypertension, hyperlipidemia, neurotoxicity, gingival hyperplasia, hirsutism |
| Tacrolimus | Calcineurin (via FKBP) | Nephrotoxicity, neurotoxicity, hypertension, new-onset diabetes |
| Sirolimus | mTOR (via FKBP) | Pancytopenia, hyperlipidemia, insulin resistance, poor wound healing; not nephrotoxic |
| Mycophenolate | IMP dehydrogenase | GI upset, marrow suppression, invasive CMV |
| Azathioprine | Purine synthesis (via 6-MP) | Myelosuppression, amplified by allopurinol |
| Corticosteroids | NF-κB | Cushingoid effects, avascular necrosis, adrenal suppression |
Azathioprine plus allopurinol: xanthine oxidase normally inactivates 6-MP, so allopurinol (or febuxostat) raises active drug levels and causes profound pancytopenia. Reduce the azathioprine dose. Low TPMT activity similarly increases thiopurine toxicity.
Gingival hyperplasia trio: cyclosporine, phenytoin, and calcium channel blockers.
Clock recap: cyanotic, thrombosed graft within minutes → hyperacute; lymphocytic infiltrate at weeks to months → acute; progressive vascular fibrosis over years → chronic; rash, diarrhea, and jaundice after marrow transplant → GVHD.