Non-corticosteroid immunosuppressants and immunotherapies

Notes

Assessments
Non-corticosteroid immunosuppressants and immunotherapies

Flashcards

0 / 45 complete

Questions

0 / 1 complete
Flashcards

Non-corticosteroid immunosuppressants and immunotherapies

45 flashcards
Preview

Which gastrointestinal disorder can be treated with infliximab and adalimumab?

Questions

USMLE® Step 1 style questions USMLE

1 questions

USMLE® Step 2 style questions USMLE

1 questions
Preview

A 54-year-old woman presents to her dermatologist with red, round patches on her face and shoulders. Additionally, she reports muscle aches and fever. She has a past medical history significant for asthma, hypertension and rheumatoid arthritis. She does not smoke and wears sunscreen.


Which of the following medications is most likely to account for her rash?

External References
Transcript

Content Reviewers:

Yifan Xiao, MD

Non-corticosteroid immunosuppressants are a class of medications that suppress the immune system and they’re used primarily to reduce the immune response after organ transplantation and inorder to prevent transplant rejection.

Imagine the immune system as an army ready to fight against anything foreign that might cause harm like microorganisms and toxins but without harming the body’s own cells. To make that work, the immune system is trained to distinguish non-self or foreign, from self.

The soldiers of the army are our immune cells which are basically white blood cells.

A specific type of the immune cells are the T cells and there are two main types: cytotoxic T cells and helper T cells.

Cytotoxic T cells kill infected or cancerous cells, whereas T helper cells primarily support other immune cells.

These cells like the generals on the battlefield: they secrete cytokines that coordinate the efforts of all the immune cells and that explains why immunosuppressants primarily act by inhibiting their action.

Okay but first things first. When a T cell is initially formed it’s considered naive but later when that T cell encounters an antigen, it gets activated and turns into an effector T cell. This process requires two signals.

The first signal is the antigen itself, which is usually presented to the helper T cell by an antigen presenting cell like a macrophage.

The second signal is called costimulation, and it’s when a ligand called CD28 on the surface of a T cell binds to a ligand called B7 on the antigen presenting cell.

Once activated, the T helper cell begins making lots of a cytokine called interleukin 2, or IL-2.

At the same time, the T helper cell also upregulates its IL-2 alpha receptor which is found on its surface.

When IL-2 binds to these receptors it activates a signal pathway called the mammalian target of rapamycin, or mTOR, pathway.

The mTOR pathway regulates cell proliferation and so the T cell starts to rapidly undergo DNA replication and cell division - a process called clonal expansion, which means that they massively proliferate. This makes the immune response stronger to fight microorganisms, remove toxins, and destroy tumor cells.

Okay, now imagine getting a kidney transplantation. It comes as no surprise that the immune system army will recognise this new kidney as foreign and attack it, and this will eventually lead to transplant rejection.

The good news is that we can prevent this by using medications that suppress the immune response prior to the transplantation.

Note though that immunosuppressants can also be used in other conditions such as autoimmune disorders like lupus and rheumatoid arthritis.

Okay, let’s start with the calcineurin inhibitors which include cyclosporine and tacrolimus, also known as FK506.

Both of these drugs inhibit a protein called calcineurin.

When a T-cell is activated, calcineurin dephosphorylates a transcription factor called “nuclear factor of activated T cells” or NFAT.

NFAT travels to the nucleus and induces the production of cytokines like interleukin 2.

Okay, so cyclosporine binds to an immunosuppressant protein called cyclophilin and tacrolimus binds to FK506 binding protein, or FKBP.

Both medications form complexes with their respective proteins and these complexes bind to calcineurin and inhibit the activation of NFAT. This means that the activated T cells can’t secrete IL-2 and other cytokines.

Okay moving on to the indications. Apart from the prevention of transplant rejection, cyclosporine is also indicated for the treatment of autoimmune disorders and inflammatory bowel disease.

The bad news is that both cyclosporine and tacrolimus are highly nephrotoxic.

Tacrolimus is more likely to cause electrolyte disturbances like hyperkalemia.

Cyclosporine can cause hypertension, hyperlipidemia, gingival hyperplasia or enlarged gums, hirsutism or excessive hair growth, and hyperuricemia or gout.

Okay, now sirolimus which is also known as rapamycin, also binds to FKBP.

However, the complex that forms will inhibit a protein called mTOR, or Mammalian Target Of Rapamycin. This protein form a complex that’s a part of the signaling pathway for cell proliferation and metabolism. When this pathway is inhibited the T cell proliferation stops.

Sirolimus is used specifically for the prophylaxis against kidney transplant rejection. It’s also used in coating on cardiac stents to prevent stenosis after coronary angioplasty.

Sources
  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Organ transplantation and drug eluting stents: Perioperative challenges" World Journal of Transplantation (2016)
  5. "Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation" Clinical Pharmacokinetics (2017)
  6. "Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer’s Disease: Understanding the Therapeutics Strategies" Molecular Neurobiology (2014)