Immunosuppression in transplantation

Immunosuppression in transplantation is the use of medications to suppress the recipient's immune response and prevent or treat rejection of a transplanted organ.[1][2] Because the immune system recognizes donor HLA and other antigens as foreign, recipients of solid-organ allografts require lifelong immunosuppression; the central clinical challenge is balancing enough suppression to prevent rejection against the infectious, malignant, and metabolic complications of over-suppression.[1][2][3] Regimens are conventionally divided into induction (intense suppression at the time of transplant) and maintenance (long-term suppression), supplemented by short courses of intensified therapy to treat acute rejection.[1][2] Drug selection, dosing, and target levels are individualized clinical decisions made by the transplant team.

Goals and general principles

Immunosuppression aims to blunt the alloimmune response, particularly T-cell activation and the generation of donor-specific antibodies, without abolishing protective immunity.[1][2] Several principles are common across programs: combining agents from different drug classes to act on complementary targets while limiting the toxicity of any one drug; using more intense suppression early (when rejection risk is highest) and tapering over time; and tailoring intensity to the recipient's immunologic risk (for example, degree of HLA mismatch and sensitization) and to organ-specific and infectious considerations.[1][2][3] Most maintenance regimens combine a calcineurin inhibitor, an antiproliferative agent, and (often) a corticosteroid.[2][3]

Induction therapy

Induction is intense immunosuppression given perioperatively to lower early rejection risk and, in some protocols, to permit reduced or delayed maintenance dosing.[1][2] Agents are antibody-based and fall into two categories:

• Depleting antibodies, which deplete lymphocytes. Antithymocyte globulin (ATG) is a polyclonal preparation that depletes T cells; alemtuzumab is an anti-CD52 monoclonal that depletes both T and B cells.[2][4] These provide potent induction and are favored for higher-immunologic-risk recipients but increase infection risk.[2][4]
• Non-depleting (immunomodulatory) antibodies. Basiliximab is an anti-CD25 (interleukin-2 receptor) monoclonal that blocks T-cell proliferation without depletion; it is generally used in lower-risk recipients and has a favorable safety profile.[2][4]

Maintenance therapy

Maintenance immunosuppression is continued long-term and typically draws from four drug classes.[2][3]

Calcineurin inhibitors (CNIs)

Calcineurin inhibitors, tacrolimus and ciclosporin (cyclosporine), are the backbone of most modern maintenance regimens.[2][5] They bind intracellular immunophilins (tacrolimus binds FKBP12; ciclosporin binds cyclophilin) to inhibit calcineurin, blocking the transcription factor NFAT and thereby suppressing interleukin-2 production and T-cell activation.[2][5] Tacrolimus is more commonly used than ciclosporin in contemporary practice.[5] CNIs have a narrow therapeutic index and require therapeutic drug monitoring of blood levels.[2][5] Their principal dose-limiting toxicity is nephrotoxicity (both acute, hemodynamic and vasoconstrictive, and chronic, with characteristic structural injury), and they also cause neurotoxicity (tremor), hypertension, electrolyte disturbances, and, especially tacrolimus, diabetogenicity.[2][5]

Antiproliferative (antimetabolite) agents

These inhibit lymphocyte proliferation. Mycophenolate (mycophenolate mofetil or mycophenolate sodium) inhibits inosine monophosphate dehydrogenase, the rate-limiting enzyme of de novo purine synthesis on which lymphocytes depend, and has largely replaced the older agent azathioprine in most regimens.[2][6] Common toxicities are gastrointestinal (diarrhea) and hematologic (leukopenia); mycophenolate is teratogenic and contraindicated in pregnancy.[2][6]

mTOR inhibitors

Mechanistic target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, bind FKBP12 and inhibit mTOR, blocking the cytokine-driven proliferation of lymphocytes.[2][7] They are used as alternatives or adjuncts to CNIs, including in CNI-minimization strategies to spare the kidney, and have antiproliferative properties of interest in certain malignancies.[2][7] Characteristic adverse effects include impaired wound healing, mouth ulcers, hyperlipidemia, proteinuria, cytopenias, and pneumonitis.[2][7]

Corticosteroids

Corticosteroids (such as prednisone and methylprednisolone) are broad anti-inflammatory and immunosuppressive agents used at high doses for induction and for treating acute cellular rejection, and at low doses for maintenance.[2][8] Their many long-term toxicities, including hyperglycemia, osteoporosis, weight gain, hypertension, cataracts, and mood and skin effects, motivate steroid-minimization or steroid-avoidance protocols in selected lower-risk recipients.[2][8]

Costimulation blockade

Belatacept, a CTLA-4-immunoglobulin fusion protein, blocks T-cell costimulation (the CD28-B7 pathway) and is used as a CNI-sparing maintenance agent in selected kidney recipients to avoid CNI nephrotoxicity; it is associated with a higher risk of post-transplant lymphoproliferative disorder in Epstein-Barr virus-seronegative recipients, in whom it is contraindicated.[2][9]

Complications of immunosuppression

The collective effect of immunosuppression is increased susceptibility to infection and malignancy, alongside drug-specific toxicities.[1][3]

• Infection. Suppressed cellular immunity predisposes to opportunistic infections. Cytomegalovirus (CMV) is among the most important; programs use risk-stratified prophylaxis (commonly valganciclovir) or preemptive monitoring based on donor/recipient CMV serostatus.[1][3] BK polyomavirus can cause BK virus-associated nephropathy in kidney recipients, managed chiefly by reducing immunosuppression.[1][3] Other concerns include Pneumocystis pneumonia (routinely prevented with trimethoprim-sulfamethoxazole prophylaxis) and reactivation of latent infections.[1][3]
• Post-transplant lymphoproliferative disorder (PTLD). A spectrum of lymphoid proliferations, most often Epstein-Barr virus-driven, arising under chronic immunosuppression; the risk rises with the intensity and duration of suppression, and the mainstay of management is reduction of immunosuppression, with rituximab and chemotherapy as needed.[10] Recipients also face elevated rates of skin cancers and other malignancies.[1][3]
• Nephrotoxicity. CNI-related kidney injury is a major source of chronic morbidity, including in non-kidney transplant recipients, and drives interest in CNI-sparing regimens.[2][5]
• New-onset diabetes after transplantation (NODAT/PTDM). Hyperglycemia and new diabetes are common, driven especially by corticosteroids and calcineurin inhibitors (tacrolimus more than ciclosporin), and contribute to cardiovascular risk.[5][11]
• Cardiovascular and metabolic toxicity. Hypertension, dyslipidemia, and weight gain are frequent and reflect the combined effects of steroids, CNIs, and mTOR inhibitors.[2][3]

The clinical art of transplantation lies substantially in titrating these agents against each individual recipient's rejection and complication risks; specific regimens are not described here as guidance and are determined by the treating team.[1][2]

See also

• Transplant rejection
• Transplant immunology
• Donor-specific antibodies (DSA)
• Transplant tolerance and mixed chimerism
• The transplant recipient journey

References

• Justiz Vargas AN, Sharma S, et al. Transplantation Immunology. StatPearls. NBK538218. https://www.ncbi.nlm.nih.gov/books/NBK538218/
• Holt CD. Overview of Immunosuppressive Therapy in Solid Organ Transplantation. Anesthesiol Clin. 2017;35(3):365-380. PMID:28784214. https://pubmed.ncbi.nlm.nih.gov/28784214/
• Claeys E, Vermeire K. Immunosuppressive drugs in organ transplantation to prevent allograft rejection: Mode of action and side effects. J Immunol Sci. 2019;3(4):14-21. https://pmc.ncbi.nlm.nih.gov/articles/PMC7430534/
• Hardinger KL, Brennan DC. Novel immunosuppressive agents in kidney transplantation. World J Transplant. 2013;3(4):68-77. PMID:24392310. https://pmc.ncbi.nlm.nih.gov/articles/PMC3879524/
• Farouk SS, Rein JL. The Many Faces of Calcineurin Inhibitor Toxicity, What the FK? Adv Chronic Kidney Dis. 2020;27(1):56-66. PMID:32147003. https://pubmed.ncbi.nlm.nih.gov/32147003/
• Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 2000;47(2-3):85-118. PMID:10878285. https://pubmed.ncbi.nlm.nih.gov/10878285/
• Saunders RN, Metcalfe MS, Nicholson ML. Rapamycin in transplantation: a review of the evidence. Kidney Int. 2001;59(1):3-16. PMID:11135051. https://pubmed.ncbi.nlm.nih.gov/11135051/
• Tacrolimus. StatPearls. NBK544318. https://www.ncbi.nlm.nih.gov/books/NBK544318/
• Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and Long-Term Outcomes in Kidney Transplantation. N Engl J Med. 2016;374(4):333-343. PMID:26816011. https://pubmed.ncbi.nlm.nih.gov/26816011/
• Posttransplant Lymphoproliferative Disorders. StatPearls. NBK513249. https://www.ncbi.nlm.nih.gov/books/NBK513249/
• Sharif A, Cohney S. Post-transplantation diabetes, state of the art. Lancet Diabetes Endocrinol. 2016;4(4):337-349. PMID:26632668. https://pubmed.ncbi.nlm.nih.gov/26632668/