Non-corticosteroid immunosuppressants and immunotherapies

Definitions & Key takeaways

Non-corticosteroid immunosuppressants are a class of medications that suppress the immune system. They're used primarily to reduce the immune response after organ transplantation and to prevent transplant rejection, or to treat autoimmune disorders. Examples include cyclosporine and tacrolimus are calcineurin inhibitors.

On the other hand, immunotherapies are used to boost or restore the immune system. They can upregulate or downregulate the immune system to achieve certain therapeutic effects. Conditions treated with immunotherapy include inflammatory disorders, malignancies, and infectious diseases. Common immunotherapies include cytokines, immunizations, and monoclonal antibodies.

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Introduction0:00–0:14

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.

Physiology0:14–2:15

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.

Pathology2:15–2:43

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.

Calcineurin Inhibitors2:43–4:09

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.

Sirolimus4:09–5:08

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.
Cardiac stents are foreign bodies inside our vessels and so they trigger an immune response which can be suppressed by immunosuppressants like sirolimus.
Unlike the calcineurin inhibitors, sirolimus is not nephrotoxic but side effects of sirolimus include insulin resistance which causes diabetes-like symptoms, hepatotoxicity, hyperlipidemia, and pancytopenia.
Alright, now let’s move on to basiliximab and daclizumab. Their names have the suffix -mab which means that they’re monoclonal antibodies.

Basiliximab and Dacilzumab5:08–6:32

Going back to the T helper cell. Let’s zoom a bit more in the interleukin 2 receptor.
It has three protein components - alpha, beta, and gamma. Okay so basiliximab and daclizumab bind to the alpha chain of the IL-2 receptor and block IL-2 from binding to its receptor.
So they suppress the immune response by inhibiting the activity of interleukin 2. They’re used specifically to prevent rejection in kidney transplantation.
Side effects include edema or swelling, hypertension, and tremor. Okay, now azathioprine and mycophenolate mofetil suppress the immune system by blocking DNA replication especially in actively replicating cells like the immune cells and thus, blocking cell division and clonal expansion.
PRPP amidotransferase and IMP dehydrogenase are two enzymes involved in purine synthesis. Now mycophenolate mofetil inhibits IMP dehydrogenase and azathioprine is a prodrug that gets converted into 6-mercaptopurine, or 6-MP, which then inhibits PRPP amidotransferase.
So they both block purine and DNA synthesis. Alright, azathioprine is also indicated for the management of autoimmune disorders like inflammatory bowel disorders and systemic lupus erythematosus.

Azathioprine6:32–7:18

Note also that allopurinol, which is an antigout medication, inhibits xanthine oxidase which is the enzyme that metabolizes mercaptopurine and thus, when azathioprine and allopurinol are used together, mercaptopurine increases to toxic levels.
Side effects of azathioprine and mycophenolate mofetil include gastrointestinal disturbances, like nausea and vomiting, pancreatitis, and pancytopenia.
Also the use of mycophenolate mofetil has been associated with invasive cytomegalovirus, or CMV, infection. Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts.

Memory Palace7:18–10:30

Since the non-corticosteroid immunosuppressants are used for organ transplants, let’s go to the lab of a mad scientist who likes to mix and match the organs of different species.
For his “patients,” one is a cyclist wearing sports wear, for cyclosporine. The other is an American football player who’s an offensive tackle, for tacrolimus.
Since both these drugs inhibit calci-neurin, let’s say the scientist is about to transplant the brain of a milk cow into his patients.
For side effects, both drugs are nephrotoxic so let’s remove the two athletes’ kidneys and put them in a cooler between them.
Tacrolimus causes hyperkalemia so let’s have the football player eating a large banana. The cyclist is chewing gum and blowing a big bubble, for gum hypertrophy.
He’s also got a large mustache for hirsutism. There are uric acid crystals growing from his toe to remind you of gout, and he’s got a large blood pressure cuff around his fat tummy to help you remember hypertension and hyperlipidemia.
Moving on to the mTOR inhibitors, like sirolimus. The scientist is going to have the rest of the cow for dinner, so he’s cooking a big sirloin steak, for sirolimus.
He’s doing the cooking with a blow Torch for mTOR, the target of this drug. Nearby, there’s a heart with a metal straw coming out of it to remind you sirolimus can also be used during cardiac stenting.
For side effects, let’s put a large candy bar on the table for diabetes-like symptoms. There’s a half eaten liver with a slice of butter on it for hepatotoxicity and hyperlipidemia, and finally there’s a frying pan with some dead blood cells and platelets in it for pancytopenia.
Okay, for the monoclonal antibodies that block IL-2 receptors, let’s have the scientist set up an illegal underground arena where he pits 2 of his crazy creations against one another.
So first, we got a rooster-lizard hybrid, also known as a basilisk, and it represents basiliximab. The other one is a dachshund-lizard mutant for daclizumab.
For the side effects, an earthquake split the ground between the two, which represents tremors. Inside the crack, there’s a blood pressure cuff for hypertension and a water balloon for edema.
Moving on to the final experiment! The mad scientist has been messing around with genetics as can be seen by a large DNA molecule on his lab table.
This is where we’ll put the drugs that inhibit DNA replication like azathioprine, represented by a regal looking zebra who received the genes of a prince, and mycophenolate mofetil, which is a Michael Jackson clone whose genes have been combined with a phoenix.
Okay, in terms of the side effects, let’s put a frying pan that’s on fire between the two for pancreatitis. There are some dead blood cells and platelets in the pan for pancytopenia.
They ate what’s in the pan and it caused them to vomit, so these drugs can cause GI disturbances. Finally owl’s eye inclusion bodies are pathognomonic for cytomegalovirus, so let’s put a little owl on Michal-phoenix's head to help you remember mycophenolate increased risk for this type of infection.

Review10:30–11:04

All right, as a quick recap. Non-corticosteroid immunosuppressants are a diverse class of medications used to prevent rejection in organ transplantation and can sometimes be used in the treatment of autoimmune disorders.
Cyclosporine and tacrolimus are calcineurin inhibitors. Sirolimus inhibits the mTOR signaling pathway.
Basiliximab and daclizumab are monoclonal antibodies that act as IL-2 receptor antagonists. Finally, azathioprine and mycophenolate mofetil block purine synthesis.
But wait, there’s more: Here’s a mind map with all of the mnemonics. Go ahead and pause the video so you can test yourself to see what you remember.

Mind Map11:04–11:17

Stay tuned for the answers after the credits.