Pharm 3: Immunosuppressant Mechanisms Flashcards
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)
