Pharm 3: Immunosuppressant Mechanisms Flashcards Preview

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Brief overview on T cell activation

T cell activation and the proliferation of T cell population relies upon initial antigen presentation by the APC cell with critical secondary signal activation, leading to a fully activated T cell. This cell then synthesizes and releases interleukin 2 (IL-2), which activates adjacent T cells, leading to proliferation and clonal expansion.


When considering the use of immunosuppressive drugs in the context of organ transplant, you will hear the terms induction, maintenance, and rescue used in conjunction with the therapy. What do these terms mean?

Induction therapies are given at the time of transplantation, re relatively intense, and prolonged use is toxic. May include donor specific transfusion or irradiation as drug alternatives

Maintenance therapies are lower potency drugs that are more tolerable in chronic use but not without side effects

Rescue therapies are intense, yet effective. They are chronically intolerable and applied in response to rejection episodes


T or F. There is no single standard regimen for drugs used for induction.

T. Each potential recipient has their own medical history which will dictate the potential severity of rejection, should it occur, and this leads to careful selection of these powerful drugs on a needs-basis.


Typical maintenance therapy usually involves what 3 drugs?

Calcineurin inhibitor, anti-proliferative, steroid. However, variations in each patient drive preferences of different regimens and low-risk patients may receive only 1 or 2 drugs


What is calcineurin?

a phosphatase within a T cell which is responsible for controlling nuclear access of a transcriptional factor known as nuclear factor of activated transcription (NFAT). By inhibiting this factor, the T cell fails to upregulate the production of IL-2.


How is calcineurin activated?

When an antigen-presenting cell interacts with a T cell receptor, there is an increase in the cytoplasmic level of calcium, which activates calcineurin, by binding a regulatory subunit and activating calmodulin binding


How does Calcineurin activate NFAT?

by dephosphorylating it, thus permitting it to enter the nucleus and up regulate transcription of IL-2.


What drugs are Calcineurin inhibitors?

cyclosporine A and Tacrolimus


What does Cyclosporine A do specifically?

associates with cyclophilin, a protein which is essential to the functioning of calcineurin .


What does Tacrolimus do specifically?

associates with FK binding protein 12, a protein that is essential to the functioning of calcineurin .


Which Calcineurin Inhibitor is more effective, Cyclosporine A or Tacrolimus?

Tacrolimus is about 100x more effective


The major problem with calcineurin inhibitors is the development of ____.

renal toxicity, somewhat ironic when these drugs are used in conjunction with renal transplantation.

Differentiating drug nephrotoxicity from graft rejection is difficult and up to 20% of patients may have both

This adverse effect has prompted the search for alternatives in immunosuppression, and to the use of calcineurin inhibitor-free drug regimens.


Calcineurin inhibitors cause what to increase in serum?

Serum creatinine, BUN, K+, and arterial BP rises


What are some other CNI toxicities?

Mild-moderate HTN (50% of renal and most cardiac patients)- renal vasoconstriction with both

Neurotoxicity with tacrolimus- headache, insomnia, tremor, dizziness, paresthesias

Hirsutism (a condition of unwanted, male-pattern hair growth in women) or hypertrichosis (xcessive hair growth over and above the normal for the age, sex and race of an individual, in contrast to hirsutism) with cyclosporine

Gingival hyperplasia (4-16%) with cyclosporine

Secondary malignancies (lymphomas and skin cancers) due to suppressed immune response


Describe the regulation of transcription in T cell inflammatory factors (e.g. cytokines, adhesion molecules, etc.).

Transcriptional coactivators, such as CREB-binding protein (CBP), have intrinsic histone acetyltransferase (HAT) activity. Their action results in acetylation of core histones and consequent increased expression of genes encoding multiple inflammatory proteins.


What do cytosolic glucocorticoid receptors (GR) do?

Cytosolic glucocorticoid receptors (GR) bind corticosteroids; the receptor-ligand complexes translocate to the nucleus and bind to coactivators to inhibit HAT activity in two ways: directly and, more importantly, by recruiting histone deacetylase-2 (HDAC2), which reverses histone acetylation, leading to the suppression of activated inflammatory genes.


What effects do glucocorticoids have on the immune system?

Corticosteroids leads to a number of effects on the immune system over and above the inhibition of T lymphocyte activity. These drugs produce:

1) neutrophilia (via increased production and decreased apoptosis),

2) eosinopenia (via increased apoptosis),

3) monocytopenia (decreased production & differentiation.)


Corticosteroids are one of the most potent classes of anti-inflammatory and immunosuppressive drugs that are available clinically. Unfortunately, chronic/prolonged use of these drugs is associated with a number of adverse metabolic effects as a result of their interaction with transcriptional regulation. Give some examples.

1) protein metabolism dysfunction (myopathy, impaired wound healing, osteoporosis, bone fractures, stunted growth)

2) Increased susceptibility to infection (can reactivate TB)

3) Hypercholesterolemia, atheroslerosis, fat embolism, thrombosis, thromboembolism, and phlebitis (inflammation of a vein-usually leg)

4) Insomnia, depression, anxiety

5) Skin atrophy, impaired wound healing

6) menstrual irregularity, hyperglycemia, hypercorticism (cushing's syndrome)


What drugs are considered mTOR inhibitors?

Sirolimus (Rapamune)


How does Sirolimus work?

Activation by IL-2 leads to activation of mTOR and the initiation of cell cycling critical to clonal expansion. By inhibiting mTOR with Sirolimus, which like its counterpart tacrolimus, binds to FKBP12, the proliferative signal at the IL-2 receptor has no consequence in terms of cell expansion.

Note that the drug target is also expressed in non-immune cells, a fact that can lead to adverse drug effects elsewhere in the body.


T or F. Sirolimus has no effect on calcineurin activity.

T. But it is synergistic with cyclosporine both in vitro and in vivo


In addition to preventing T cell clonal expansion, what does Sirolimus do?

prevents B cell differentiation into antibody-producing cells, decreasing levels of IgM, IgG, and IgA and affects proliferation of cells outside the immune system including non-lymphoid tumor cells, smooth muscle cells, hepatocytes, and fibroblasts


What is Temsirolimus?

a pro-drug for sirolimus, the active metabolic product.


What are some of the possible adverse effects of Sirolimus?

1) Dose-related hyperlipidemia (patient monitoring needed)

2) decreased serum creatinine and GFR (globular filtration rate)

3) increased azotemia (abnormally high levels of nitrogen-containing compounds (such as urea, creatinine, various body waste compounds, and other nitrogen-rich compounds) in the blood)

4) Hypertension

5) Hepatotoxicity including fatal hepatic necrosis

6) Thrombophelbitis, thromboembolism (pumonary, DVT)

As noted before, lack of immune surveillance can give rise to an increased likelihood of opportunistic infections and secondary malignancies.


What is micophenolate mofetil?

A T and B cell cell-cycle disruptor that inhibits inosine monophosphate dehydrogenase (which normally catalyzes conversion of inosine monophosphate to guanosine monophosphate during purine synthesis), thereby interrupting DNA synthesis.


What is the significance of interruption in the supply of guanosine in T and B cells?

T and B lymphocytes are highly dependent on production of this critical building block, lacking as they do the ability to compensate for deficiency via the salvage pathway from guanine.


What are some of the advantages of Micophenolate Mofetil?

1) Blocks the secondary antibody responses mediated by memory B cells

2) Selective effects on lymphocyte proliferation, unlike azathioprine or methotrexate

3) No chromosomal breaks


What are some of the side effects of Micophenolate Mofetil?

1) most common side effects involve GI tract ( because it is lined throughout with a proliferating cell population which is especially sensitive to drugs which inhibit cell cycle)- constipation, diarrhea, vomiting

2) myelosuppresion (neutropenia) occurs infrequently

3) Opportunistic infections, tumor


What is azathioprine?

A cell-cycle disruptor


What happens to azathioprine when it is ingested?

It undergoes extensive metabolic conversion to a number of products, one of which is 6- mercaptopurine (6MP)

The ultimate metabolism of azathioprine leads to the production of 6-thioguanine triphosphate