In this lecture we’re gonna cover the pharmacology of immunosuppressants, so let’s get right
into it. The immune system is a complex network of cells and proteins that work together to
defend the body against substances it sees as harmful or foreign. Now, the human immune
system has two levels of immunity: innate and adaptive. The innate immunity is non-specific
and fast acting, and serves as the primary line of protection against pathogen invasion.
Numerous cells are involved in the innate immune response including natural killer cells, mast
cells, and granulocytes as well as the phagocytic cells such as macrophages, dendritic cells
and monocytes that utilize phagocytosis and are equipped with receptors, which recognize
a variety of microbial products know as antigens resulting in activation of the slower-acting
but more specific, adaptive immune system. Now, the adaptive immune system consists of
highly specialized systemic cells and processes that are separated into two main components:
the humoral and cellular. The humoral immunity is mediated by activated B cells that produce
and secrete antibodies against a specific antigen. On the other hand, the cellular immunity
is mediated by T lymphocytes, also called T cells. Now, T cells circulate throughout
the body until they recognize a specific antigen (they’re programmed for) on the surface
of antigen presenting cells (APCs) such as dendritic cells. The T cell receptor (TCR)
on both CD4+ helper T cells and CD8+ cytotoxic T cells binds to the antigen as it is held
in a structure called the “major histocompatibility complex” (MHC), in order to discriminate
foreign from self-antigens and initiate adaptive immune responses. This sets off a signaling
cascade that allows T-cells to replicate, differentiate and secrete signaling proteins called
cytokines, which in turn activate more cells of the immune system.
Now, depending on the type of T-cell either the co-receptor CD8 or CD4 binds to the MHC
molecule. The signal transduction is then carried through CD3 that is physically associated
with the T cell receptor. However, this initial signal is not sufficient for T-cell activation
therefore a secondary signal is required. This secondary signal also referred to as
costimulation, occurs when CD28 receptor expressed on T cells, binds CD80 and CD86 molecules
that are expressed on antigen-presenting cells (APCs), thereby triggering a calcium-mediated
signaling cascade. Specifically a rise in intracellular calcium levels leads to a stepwise
activation of the phosphatase calcineurin, an enzyme that dephosphorylates nuclear factor
of activated T-cells (NFAT), which in turn allows it to translocate from the cytoplasm
into the nucleus. Inside the nucleus, NFAT proteins bind DNA target sequences in cooperation
with partnering transcription factors (TF) leading to activation of genes encoding cytokines,
one of which is a major growth factor called interleukin 2 (IL-2).
Now, generated IL-2 binds to the IL-2 receptors on the surface of T cells, activating a
signaling protein called the mammalian target of rapamycin (mTOR), thereby allowing the
cell to progress through the cell cycle, promoting cell proliferation of antigen-primed
T cells, which subsequently produce more IL-2, as well as other pro-inflammatory cytokines
activating natural killer cells, macrophages, and cytotoxic T cells.
All right, so the immune system is critical to survival in an environment full of pathogenic
microbes. However, this vital system is not always protective as deregulation of immune
responses can lead to chronic inflammatory diseases such as autoimmunity or cancer. Moreover,
the immune system serves as a barrier for the transplantation of certain beneficial
organs and tissues. Therefore, a continuous use of immunosuppressive drugs is the standard
of care for managing autoimmunity and transplant rejection.
Now, immunosuppressive drug therapy usually consists of two or more agents with different
mechanisms of action that disrupt various levels of T-cell activation. So let’s discuss
these one by one starting with calcineurin inhibitors. Drugs in this group work by binding
to intracellular proteins called immunophilins. Immunophilins consists of two protein families
known as cyclophilins and FK-binding proteins, and are the major receptors for the immunosuppressive
drugs, Cyclosporin and Tacrolimus, respectively. These complexes then bind to and inhibit calcineurin,
thereby preventing nuclear factor of activated T cells (NFAT) from moving to the nucleus,
which ultimately impairs transcription of the genes encoding interleukin-2 (IL-2) that
is necessary for activation of T cells. All right, moving onto to the next group of
immunosuppressants that is costimulation blockers. Drugs in this group include Belatacept and
Abatacept, which work by selectively binding to CD80 and CD86 on antigen-presenting cells
(APC), thereby blocking interaction with CD28 on T cells. This in turn prevents complete
T-cell activation, reduces T-cell proliferation and IL-2 production. That being said, it’s
important to remember here that Belatacept was designed to bind to CD80 and CD86 more
strongly than Abatacept and thus has been shown to be more effective in the immunosuppression necessary
for transplant rejection. Now, moving on to our third group of immunosuppressants
that is mTOR inhibitors. Drugs in this group include Sirolimus also known as Rapamycin,
and Everolimus, which work by binding to the same intracellular FK-binding protein as Tacrolimus,
however instead of forming a complex with calcineurin, Sirolimus and Everolimus subsequently
bind to mTOR thereby inhibiting its activity. This ultimately leads to slowing or arrest
of cell cycle progression as well as inhibition of the cellular response to IL-2.
All right, moving on the next class of drugs that is immunosuppressive antimetabolites.
The two most commonly used agents in this class are Azathioprine and Mycophenolate mofetil,
which have similar but unique mechanism of action. So the first one, Azathioprine is
first activated to become 6-mercaptopurine (6-MP), which is then further metabolized
to form purine analogs that mimic the structure of a building block of DNA. These false purines
in turn can disrupt de novo pathway of purine synthesis as well as become incorporated into
DNA and RNA thus terminating their synthesis ultimately inhibiting cellular proliferation.
Now, in contrast, the second agent, Mycophenolate mofetil works by inhibiting inosine monophosphate
dehydrogenase (IMPDH), a key enzyme in purine synthesis, which is involved in the production of guanosine
nucleotides. As a result, DNA synthesis, which requires guanosine triphosphate (GTP), does
not occur and cell proliferation is inhibited. However, unlike Azathioprine, Mycophenolate
is not incorporated into DNA and does not induce chromosome breaks.
Now another class of drugs that is often used for immunosuppression in both transplantation
and various autoimmune disorders, is corticosteroids. Drugs that belong to this class include Prednisone,
Prednisolone and Methylprednisolone. So, the effects of corticosteroids are diverse and
are likely controlled by several mechanisms. One mechanism by which corticosteroids induce
immunosuppression is through regulation of the T-cell responses. Acting directly on
T cells, corticosteroids mediate their effects by binding to the intracellular glucocorticoid
receptor (GR), resulting in translocation of the complex to the nucleus and subsequent
inhibition of key transcription factors such as nuclear factor-κB (NF-κB) and activator
protein-1 (AP-1), which ultimately alters gene transcription and represses pro-inflammatory
genes. In addition to this, corticosteroids exert non-genomic actions by causing rapid
dissociation of a T-cell-receptor-associated protein complexes, resulting in impaired
receptor signaling and T-cell activation. Finally, moving on to our last class of immunosuppressants
that is Antibodies. Now, although many different antibody products exist, for the purpose of
this lecture we’re gonna focus here only on the two that are most commonly used to
prevent transplant rejection. The first such product is Antithymocyte globulins, which
consist of polyclonal antibodies that bind to a wide variety of proteins on the surface
of T-cells leading to cell death via complement mediated cytotoxicity or apoptosis. The second
antibody product commonly used in transplant is Basiliximab, which is a monoclonal antibody
that binds to IL-2 receptor with similar affinity as IL-2, thereby effectively competing with
IL-2 and subsequently inhibiting IL-2 driven T-cell proliferation.
And with that, I wanted to thank you for watching I hope you enjoyed this video and as always
stay tuned for more.