Immunosuppressants

Intentional suppression of the immune system to prevent a harmful immune response, but ↑ susceptibility to infection and malignancy.

The nomenclature used here distinguishes between immunosuppression (iatrogenic use of medication to dampen an immune response) versus immunocompromise, an umbrella term for both iatrogenic and pathological (e.g. diabetes, HIV/AIDS causes.

Indications

• Normalise hyper-active immune system
  • Autoimmune disease
• Suppress normal immune system
  • Prevent allograft rejection in organ transplantation

Contraindications

Principles

Key Terms

• Induction immunosuppression
  Immediate use of high-intensity immunosuppression after transplantation.
• Maintenance immunosuppression
• Cytokine release syndrome
  Occurs due to initial T-cell activation and is characterised by fever, hypotension, and pulmonary oedema.
• Fusion protein
  Created by joining genes that initially coded for different proteins.

Medications

Comparison of Immunosuppressants

Immunosuppressive drug	Class of Drug	Mechanism of Action	Considerations
Antithymocyte globulin	Polyclonal antibody	Animal immunoglobulin targeted to human T-cells, which block T-cell membrane proteins modulating their homing and cytotoxic function.	Indicated for induction immunosuppression and steroid-resistant rejection Cytokine-release syndrome Persistent, profound lymphopenia ↑ Post-transplant lymphoma Rabbit ATG preferred to horse ATG due to ↓ rejection and ↑ tolerability
Alemtuzumab (CAMPATH-1H)	Monoclonal antibody	Humanised rat IgG1 anti-CD52 antibody, depleting: T-cells B-cells NK cells Monocytes	Indicated for induction immunosuppression and steroid-resistant rejection Cytokine-release syndrome Autoimmune disease Persistent, profound lymphopenia
Rituximab	Monoclonal antibody	Anti-CD20 antibody, causing: B-cell depletion ↓ T-cell proliferation	Induction immunosuppression Infusion-related reactions
Basiliximab	Non-depleting monoclonal antibody	Chimeric human-mouse monoclonal anti-CD25 antibody, causing: ↓ IL-2-induced T-cell proliferation But not depletion.	Hypersensitivity reactions
Belatacept	Fusion protein	Blocks co-stimulation by binding to CD80 and CD86 receptors on APCs and prevents binding to CD28 on the T-cell	Post-transplant lymphoproliferative disease Only in EBV negative, so should be restricted to EPB positive patients. Bone marrow suppression Hypertension Dyslipidemia
Azathioprine	Antimetabolite or antiproliferative	↓ Purine synthesis, which ↓ T-cell proliferation	Leukopenia and thrombocytopenia Nausea and vomiting Hepatotoxicity Malignancy
Mycophenolate mofetil	Antimetabolite or antiproliferative	Inhibits inosine monophosphate dehydrogenase, ↓ T and B-cell proliferation	Maintenance immunosuppression More selective than azathioprine Neutropenia Anorexia, abdominal pain, gastritis and diarrhea Opportunistic infections Teratogenic
Cyclosporine	Calcineurin inhibitor	Inhibits calcineurin by binding cyclophilin, causing: ↓ T-cell proliferation ↓ Cytokine production	Maintenance immunosuppression Acute and chronic nephrotoxicity Diabetes Hypomagnesemia and hyperkalemia Neurotoxicity Malignancy
Tacrolimus	Calcineurin inhibitor	Inhibits calcineurin by binding FK506-binding protein 12, causing: ↓ Cytokine production ↓ T-cell proliferation	As cyclosporine except: ↓ Incidence of hyperlipidemia, hypertension, hirsutism, and gingival hyperplasia ↑ Incidence of: diabetes, neurotoxicity Better outcomes than cyclosporine for transplantation
Sirolimus, everolimus	Mammalian target of rapamycin (mTOR) inhibitor	Inhibits mTOR by binding FK506-binding protein 12, causing ↓ T-cell proliferation	Maintenance immunosuppression Alternative to calcineurin inhibitors in the setting of: Neurotoxicity SCC or Karposi’s sarcoma Anti-tumour properties. Delayed wound healing Leukopenia and thrombocytopenia Increased risk of infections Anaphylaxis and hypersensitivity reactions
Prednisolone, methylprednisolone	Corticosteroid	Broad array of effects by: Direct genomic ↓ Prostaglandin synthesis ↑ Anti-inflammatory protein synthesis ↓ Inflammatory protein synthesis Indirect genomic ↓ Prostaglandin synthesis Non-genomic ↑ NO synthetase	Induction and maintenance immunosuppression ↓ Wound healing Opportunistic infections Sleep disturbances and mood changes Cushing syndrome ↑ BSL HTN Dyslipidaemia Osteoporosis

Practice

Complications

Key Studies

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References

1. Claeys E, Vermeire K. Immunosuppressive drugs in organ transplantation to prevent allograft rejection: Mode of action and side effects. Journal of Immunological Sciences. 2019;3(4). Accessed July 13, 2023. https://www.immunologyresearchjournal.com/articles/immunosuppressive-drugs-in-organ-transplantation-to-prevent-allograft-rejection-mode-of-action-and-side-effects.html
2. Pilch NA, Bowman LJ, Taber DJ. Immunosuppression trends in solid organ transplantation: The future of individualization, monitoring, and management. Pharmacotherapy. 2021;41(1):119-131. doi:10.1002/phar.2481