In the previous tutorial we discussed glucocorticoids,
which interact with the immune system. Let’s now generally discuss immunomodulating drugs that go
some distance in establishing harmony during immune system dysregulation. Immunomodulating
drugs can be broadly separated into a dichotomy of immunostimulants and immunosuppressants.
As these names suggest, immune-stimulating drugs work to enhance specific functions of the
immune system, while immunosuppressants inhibit immune function. In this tutorial and the next,
we will survey pharmacological mechanisms and try to understand how these two drug classes
achieve immune system modulation. Let’s start with immunosuppressants. The most
clinically relevant and actively researched class of immunosuppressants are the glucocorticoids,
which we discussed at length in the previous tutorial, so these will not be discussed further
here. However, it is worth emphasising that when it comes to immunosuppression,
glucocorticoids are king. Even still, the other classes of immunosuppressive drugs are certainly
important and sometimes used in conjunction with glucocorticoids, albeit in more specific
and less common medical situations. These include reducing the risk of organ transplant rejection,
and stent stabilization in the case of blood vessel occlusion, to name a few.
There are four main classes of non-glucocorticoid immunosuppressants.
These are immunophilin binding drugs, cytostatic drugs, antilymphocyte antibodies,
and monoclonal antibodies. First, we will cover immunophilin binding drugs.
Immunophilins are cytosolic proteins that catalyze the biochemical reaction of cis-trans
isomerization for the amino acid proline. This isomerization is critical for the correct folding
for many proteins in achieving the right three-dimensional structure.
These proteins have a wide range of isoforms and functions, and are highly conversed in
terms of evolution, existing in eukaryotic and prokaryotic cells alike, but in the context of
immunosuppressants, immunophilins act as the receptor for this class of immunosuppressants.
Cyclosporin and tacrolimus are examples of immunophilin binding drugs. First, after
administration of the drug, it enters the cytosol of T-cells. Here it binds with immunophilin,
and following drug-immunophilin complex formation, the complex binds to another intracellular protein
called calcineurin. In the absence of these drugs, calcineurin usually acts as a transcription factor
to promote the production of interleukin-2. However, following immunophilin-drug complex
binding to calcineurin, the interleukin-2 transcription activity is inhibited.
Since interleukin-2 is a pro-immune chemokine that increases the activity, maturation,
and differentiation of T-cells, reduction in its production predictably leads to immunosuppression.
Another similar immunophilin binding drug worth being aware of is rapamycin. In the
context of immunosuppression, it also leads to the inhibition of interleukin-2 production, but
it does so via inhibition of the mTOR signaling pathway, not from calcineurin inhibition. In fact,
this is how the important mTOR signaling cascade was named: mechanistic target of rapamycin.
These compounds are primarily used for immunosuppression
after organ transplantation and in rare cases to treat some autoimmune diseases.
The second class of drugs are cytostatic drugs, which means they inhibit cell
division. The aim of these drugs is to reduce the proliferation of T and B lymphocytes. This
is achieved by various mechanisms focusing on the rate reduction of cell division
through the inhibition of DNA replication. In a previous tutorial we discussed methotrexate.
This is a commonly used cytostatic drug that achieves immunosuppression by inhibiting the
enzyme dihydrofolate reductase. The consequence of this is inhibition of thymidine synthesis,
a critical deoxy nucleoside for DNA synthesis and replication, hence reducing cell proliferation.
Of course, many other cytostatic drug mechanisms will be elucidated more thoroughly when we discuss
cancer chemotherapy, since disrupting DNA replication and regulation are the main focus
of many cancer chemotherapy drugs which aim to reduce the rate of tumor growth and proliferation.
With this in mind, it is intuitive to see the overlap between overactive immune responses caused
by autoimmune diseases and cancers that increase proliferation of different white blood cells.
To this end, many similar drugs with immunosuppressive qualities
are used to treat both immune system related cancers and autoimmune diseases.
However, from a different perspective, an important concept of pharmacology
is to appreciate that adverse effects in the treatment for a particular pathology
may be therapeutic for a different pathological condition. In this instance,
when treating cancers that don’t increase immune system reactivity, cancer chemotherapy drugs often
have the adverse effect of immunosuppression, but in cases of immune-stimulating cancers,
immunosuppressive qualities are therapeutic. This can be confusing,
but the main aim of pharmacology is to establish equilibrium in pathological dysregulation.
The last two categories of immunosuppressive drugs we will discuss are anti-lymphocyte antibodies and
monoclonal antibodies. An example of an anti-lymphocyte antibody is the drug alemtuzumab.
This drug binds to CD52, a glycoprotein on the surface of mature B and T lymphocytes.
Once it binds to the glycoprotein antigen, it triggers cell apoptosis.
It’s intuitive to understand that by shifting the equilibrium toward increasing apoptosis of
lymphocytic cells, an immunosuppressive effect is achieved, as dead immune cells are unable
to carry out immune function. This drug is used for the autoimmune condition multiple sclerosis,
a condition where the myelin sheath of neurons is destroyed by the immune system. But it is
more commonly used in some leukemias for its anti-cellular prolific effects on B and T cells.
Lastly, let’s mention one immunosuppressive monoclonal antibody. Muromonab binds to the
CD3 protein of the aptly named T cell receptor on T cells. When this antibody binds to CD3,
apoptosis pathways of the T cell are triggered, leading to immunosuppression.
These drugs are often used in acute organ transplant rejection that are glucocorticoid
resistant, as well as some T-cell related cancers such as T-cell acute lymphoblastic leukemia.
So that covers an introduction to immunosuppressants.
Let’s now move forward and examine some drugs that have precisely the opposite effect.