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In this lecture we are gonna cover the pharmacology of immunosuppressants, so let's get right

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into it.

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The immune system is a complex network of cells and proteins that work together to defend

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the body against substances it sees as harmful or foreign.

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Now the human immune system has two levels of immunity, innate and adaptive.

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The innate immunity is nonspecific and fast-acting, and serves as the primary line of protection

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against pathogen invasion.

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Numerous cells are involved in the innate immune response, including natural killer

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cells, mast cells and granulocytes, as well as the phagocytic cells such as macrophages,

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dendritic cells and monocytes, that utilize phagocytosis and are equipped with receptors

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which recognize a variety of microbial products known as antigens, resulting in activation

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of the slower-acting, but more specific, adaptive immune system.

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Now the adaptive immune system consists of highly specialized systemic cells and processes

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that are separated into two main components, the humoral and cellular.

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The humoral immunity is mediated by activated B cells that produce and secrete antibodies

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against a specific antigen.

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On the other hand, the cellular immunity is mediated by T lymphocytes, also called T cells.

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Now T cells circulate throughout the body until they recognize a specific antigen they

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are programmed for, on the surface of antigen-presenting cells, such as dendritic cells.

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The T cell receptor on both CD4-positive helper T cells and CD8-positive cytotoxic T cells

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binds to the antigen as it is held in a structure called the Major Histocompatibility Complex

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– MHC for short – in order to discriminate for and from self-antigens and initiate adaptive

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immune responses.

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This sets off a signaling cascade that allows T cells to replicate, differentiate, and secrete

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signaling proteins called cytokines, which in turn activate more cells of the immune

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system.

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Now depending on the type of T cell, either the core receptor CD8 or CD4 binds to the

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MHC molecule.

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The signal transduction is then carried through CD3 that is physically associated with a T

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cell receptor.

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However this initial signal is not sufficient for T cell activation, therefore a secondary

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signal is required.

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This secondary signal, also referred to as costimulation, occurs when CD28 receptor expressed

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on T cells binds CD80 and CD86 molecules that are expressed on antigen-presenting cells,

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thereby triggering a calcium-mediated signaling cascade.

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Basically a rise in intracellular calcium levels leads to a stepwise activation of the

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phosphatase calcine urine, an enzyme that dephosphorylates nuclear factor of activated

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T cells – NFAT for short – which in turn allows it to translocate from the cytoplasm

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into the nucleus.

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Inside the nucleus, NFAT proteins bind DNA target sequences in cooperation with partnering

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transcription factors, leading to activation of genes encoding cytokines, one of which

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is a major growth factor called interleukin-2, IL-2 for short.

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Now generated interleukin-2 binds to the interleukin-2 receptors on the surface of T cells activating

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a signaling protein called a mammalian target of rapamycin, mTOR for short, thereby allowing

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the cell to progress through the cell cycle, promoting cell proliferation of antigen-prime

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T cells, which subsequently produce more interleukin-2, as well as other pro-inflammatory cytokines

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activating natural killer cells, macrophages, and cytotoxic T cells.

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Alright, so the immune system is critical to survival in an environment full of pathogenic

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microbes.

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However, this vital system is not always protective, as deregulation of immune responses can lead

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to chronic inflammatory diseases such as autoimmunity or cancer.

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Moreover, the immune system serves as a barrier for the transplantation of certain beneficial

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organs and tissues.

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Therefore, a continuous use of immunosuppressive drugs is the standard of care for managing

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autoimmunity and transplant rejection.

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Now immunosuppressive drug therapy usually consists of two or more agents with different

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mechanisms of action that disrupt various levels of T cell activation.

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So let's discuss these one by one, starting with calcine urine inhibitors.

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Drugs in this group work by binding to intracellular proteins called immunophilins.

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Immunophilins consist of two protein families, known as cyclophilins and FK-binding proteins,

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and are the major receptors for the immunosuppressive drugs cyclosporine and tacrolimus, respectively.

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These complexes then bind to and inhibit calcine urine, thereby preventing nuclear factor of

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activated T cells from moving to the nucleus, which ultimately impairs transcription of

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the genes encoding interleukin-2 that is necessary for activation of T cells.

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Alright, moving on to the next group of immunosuppressants, that is costimulation blockers.

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Drugs in this group include belatacept and abatacept, which work by selectively binding

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to CD80 and CD86 on antigen-presenting cells, thereby blocking interaction with CD28 on

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T cells.

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This in turn prevents complete T cell activation, reduces T cell proliferation and interleukin-2

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production.

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That being said, it's important to remember here that belatacept was designed to bind

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to CD80 and CD86 more strongly than abatacept and thus has been shown to be more effective

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in the immunosuppression necessary for transplant rejection.

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Now moving on to our third group of immunosuppressants, that is mTOR inhibitors.

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Drugs in this group include sirolimus, also known as rapamycin, and everolimus, which

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work by binding to the same intracellular FK-binding protein as tacrolimus, however

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instead of forming a complex with calcine urine, sirolimus and everolimus subsequently

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bind to mTOR, thereby inhibiting its activity.

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This ultimately leads to slowing or arrest of cell cycle progression, as well as inhibition

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of the cellular response to interleukin-2.

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Alright moving on to the next class of drugs that is immunosuppressive antimetabolites.

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The two most commonly used agents in this class are azathioprine and mycophenolate mofetil,

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which have similar but unique mechanism of action.

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So the first one azathioprine is first activated to become 6 mercapto purine, 6MP for short,

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which is then further metabolized to form purine analogs that mimic the structure of

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a building block of DNA.

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These false purines in turn can disrupt the novel pathway of purine synthesis, as well

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as become incorporated into DNA and RNA, thus terminating their synthesis, ultimately inhibiting

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cellular proliferation.

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Now in contrast, the second agent, mycophenolate mofetil, works by inhibiting inosine monophosphate

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dehydrogenase, IMPDH for short, a key enzyme in purine synthesis, which is involved in

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the production of guanosine nucleotides.

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As a result, DNA synthesis, which requires guanosine triphosphate, does not occur and

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cell proliferation is inhibited.

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However, unlike azathioprine, mycophenolate is not incorporated into DNA and does not

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induce chromosome breaks.

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Now another class of drugs that is often used for immunosuppression in both transplantation

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and various autoimmune disorders is corticosteroids.

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Drugs that belong to this class include prednisone, prednisolone, and methylprednisolone.

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So the effects of corticosteroids are diverse and are likely controlled by several mechanisms.

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One mechanism by which corticosteroids induce immunosuppression is through regulation of

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the T-cell responses.

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Acting directly on T-cells, corticosteroids mediate their effects by binding to the intracellular

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glucocorticoid receptor, resulting in translocation of the complex to the nucleus and subsequent

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inhibition of key transcription factors, such as nuclear factor kappaB and activator

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protein 1, which ultimately alters gene transcription and represses pro-inflammatory genes.

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In addition to this, corticosteroids exert non-genomic actions by causing rapid dissociation

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of a T-cell receptor-associated protein complexes, resulting in impaired receptor signaling and

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T-cell activation.

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Finally, moving on to our last class of immunosuppressants, that is, antibodies.

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Now although many different antibody products exist, for the purpose of this lecture we

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are gonna focus here only on the two that are most commonly used to prevent transplant

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rejection.

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The first such product is anti-timocyte globulins, which consists of polyclonal antibodies that

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bind to a wide variety of proteins on the surface of T-cells, leading to cell death

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via complement-mediated cytotoxicity or apoptosis.

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The second antibody product commonly used in transplant is basiliximab, which is a monoclonal

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antibody that binds to interleukin-2 receptor with similar affinity as interleukin-2, thereby

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effectively competing with interleukin-2 and subsequently inhibiting interleukin-2-driven

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T-cell proliferation.

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And with that I wanted to thank you for watching, I hope you enjoyed this video, and as always

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stay tuned for more!