• Clinical science

Immunosuppressants

Abstract

Immunosuppressants use heterogeneous mechanisms of action to suppress the body's cell-mediated and humoral immune response. They may be used as transplant rejection prophylaxis or to treat autoimmune disorders such as lupus, psoriasis, and rheumatoid arthritis. Commonly used immunosuppressants include cyclosporine A, tacrolimus, glucocorticoids, methotrexate, and biological agents (like rituximab). A common side effect of immunosuppressants is an increased susceptibility to infection and malignancy.

Glucocorticoids are discussed in detail in another learning card.

Overview

Immunosuppressant class Common drugs Mechanism of action Suppression of cell-mediated immune response Suppression of humoral immune response Main clinical uses
Glucocorticoids Prednisolone
  • Inhibition of intracellular NF-κB → Multiple inflammatory and immune mediators are inhibited.
  • Acute effect (occurs within minutes) → While the mechanism is not entirely clear, a membrane stabilizing effect is hypothesized.
  • Long-term effects (in hours) → direct influence on gene expression
✓ ✓
  • Transplant rejection prophylaxis
  • To suppress various allergic, inflammatory, and autoimmune reactions

Calcineurin inhibitors (calcineurin = calcium- and calmodulin-dependent serine-threonine phosphatase)

Cyclosporine A
  • Immunosuppression: binds cyclophilin → inhibition of calcineurin → inhibition of NFAT activation → ↓ IL-2 transcription → ↓ activation of T cells
  • Cytostatic action: binding to multidrug resistance glycoprotein P-170
✓ –
Tacrolimus (also FK-506 or fujimycin)
  • Binding to FK506 binding protein (FKBP) → inhibition of calcineurin → inhibition of NFAT activation → ↓ IL-2 transcription → ↓ activation of T cells
✓ –
Pimecrolimus
mTOR inhibitors Sirolimus (also known as rapamycin)
  • Binds to FKBP → inhibition of mTOR kinase→ inhibition of the IL-2-mediated cell cycle → prevents response to IL-2 → blocks T-cell activation and B-cell differentiation → ↓ IgM, IgG, and IgA production
 ✓ (✓)
Everolimus
Purine analog

Azathioprine (mercaptopurine)

 ✓ (✓)
Protein drugs Antibodies
  • Specific binding to relevant structure in the immune cascade (detailed explanation below)
 ✓ ✓
Other biological proteins
IMDH/IMPDH inhibitors Mycophenolate mofetil ✓ ✓
Other cytostatic and antiproliferative agents Methotrexate ✓ ✓
Cyclophosphamide (✓) ✓

✓ = Definite suppression

(✓) = Probable suppression (inconclusive research currently)

– = No suppression

References:[1][2][3][4][5][6]

Biological agents used in immunotherapy

  • Biological agents are recombinant proteins that intervene in immunological processes.
  • Used in autoimmune diseases and malignancies
  • Although complex and costly, they can significantly improve the success of treatment in some cases.
Antibody Type Target Indication

Infliximab

 Chimeric TNF-α inhibition

Adalimumab

 Humanized
Etanercept Fusion protein

Golimumab

Humanized

Certolizumab

Humanized
Rituximab Chimeric CD20
Cetuximab Chimeric Epidermal growth factor receptor (EGFR inhibitor)
Alemtuzumab Humanized CD52
Natalizumab Humanized Alpha-4 integrin
Omalizumab Humanized IgE
Abciximab Humanized Antagonist of IIb/IIIa receptors
Muromonab-CD3 Mouse antibody CD3 from T cells
Basiliximab Chimeric Alpha chain (CD25 antigen) of the IL-2 receptor of T cells
Daclizumab Humanized
Trastuzumab Humanized HER2/neu
Bevacizumab Humanized VEGF
Eculizumab Humanized Complement protein C5

Side effects

Calcineurin inhibitors

Cyclosporine A

  • Toxicity:
    • Nephrotoxic
    • Neurotoxic
  • Tremors
  • Hypertension
  • Gingival hyperplasia
  • Hypertrichosis and hirsutism
  • Hyperkalemia
  • Nausea and diarrhea
  • Diabetogenic effect (particularly after organ transplantation). This can lead to:
  • Increase in malignancies and infectious diseases (e.g., increase in the risk of squamous cell carcinoma by 50% in patients who are on simultaneous treatment with PUVA during psoriasis treatment)

Tacrolimus

Many side effects of tacrolimus are similar to cyclosporine A, but tacrolimus does not cause gingival hyperplasia or hypertrichosis!

Tacrolimus and cyclosporine A should not be combined because together they could have nephro- and neurotoxic effects!

IMDH inhibitors (Azathioprine/Mercaptopurine)

  • Pancytopenia (leukopenia, macrocytic anemia, thrombocytopenia)
    • Increased by interaction with allopurinol
    • There are patients with genetic polymorphisms (decreased thiopurine methyltransferase) that may impede degradation and thereby result in azathioprine toxicity. As testing is not possible before treatment, it is recommended that it be performed before starting treatment in patients who would require high doses of the drug.
      •
  • Infection (e.g., pancreatitis)
  • Hepatotoxicity
  • Malignancies: e.g., cervical cancer, lymphoma, squamous cell carcinoma, melanoma (rare)
  • Nausea, vomiting, and dose-related diarrhea

mTOR inhibitors (Sirolimus, Everolimus)

Mycophenolate mofetil

Methotrexate

Salvage therapy (leucovorin rescue therapy)

Biologics (e.g., daclizumab)

Both calcineurin inhibitors (cyclosporine and tacrolimus) are highly nephrotoxic.

To rule out latent tuberculosis or activation, testing should be performed before initiating treatment!
Allopurinol causes toxic accumulation of azathioprine! In cases in which concomitant treatment is unavoidable, ∼ 1/4 of the normal dose of azathioprine should be given and the drug must be carefully adjusted!
References:[5][7][8][6][9][10][11][12][13][14][15][16][17][18][19]

We list the most important adverse effects. The selection is not exhaustive.