Flashcards in Immuno-Suppressants Deck (90):
What are the seven mechanisms of action for the immunosuppressant drugs ?
1. Inhibition of Gene Expression
2. Selective attack against clonal expanding cell populations
3. Inhibition of intracellular signaling
4. Neutralization of cytokines and receptor required for T cell activation
5. Selective depletion of T cells or other immune cells
6. Inhibition of co-stimulants by APC's
7. Inhibition of lymphocyte target interaction
What would be an important cytokine target to slow down T cell proliferation ?
IL-2 or a drug that simply targets a T cell surface receptor that will mark it for degradation
What are the three critical aspects of immunosuppressive regimens for organ transplant ?
Induction- intesse prolonged use prohibitively toxic
Maintenance- lower potency and tolerable in chronic use
Rescue- Intense, applied in response to a rejection
Could the body tolerate the doses required for induction and rescue in a long term setting ?
No these dosages would not be well tolerated
What are some of the potential obstacles that will need to be overcome to determine the regimen for induction of immunosupressant dosages
A careful examination of previous medical conditions including
-Type of tissue being transplanted
What characterizes the maintenance therapy of the immunosuppressant regimen
Maintenance generally consists of triple drug therapy using agents that work at different levels of the inflammatory cascade.
an example would be a calcineruin inhibitor, anti-proliferative, and steroid
What factors will cause variation in the maintenance regimen
Medication related toxicities
What is a drug target that will impair the function of the T cell receptor, and what will this cause ?
CD-3 Which will block T cell activation and CD 28 which will block the secondary signal associated with T cell activation
What is Calcineurin ?
This is responsable for controlling access to a transcriptional factor known as nuclear factor of activated transcription ( NFAT )
What will inhibition of calcineurin do ?
**Same as the function of NFAT
Inhibition of calcineurin will prevent the up regulation of IL-2, This process is dependent on NFAT.
What will glucocorticoids do inside the nucleus ?
Within the nucleus glucocorticoids will inhibit the transcriptional regulation or pro-inflammatory genes which will diminish the ability of the T cell to produce and release IL-2
What do monoclonal antibodies that bind to CD-25 do ?
These will inhibit the activity of IL-2 and prevent clonal expansion of the T cells
When released from the T cell what does IL-2 interact with ?
IL-2 interacts with CD-25 ( the IL-2 receptor ) this will stimulate T cell proliferation
In the T cell what will binding of IL-2 to CD-25 actually do ?
IL-2 will activate mTOR and the initiation of cell cycling critical to clonal expansion.
What will the inhibition of mTOR do ?
by inhibition of mTOR the IL-2 will have no effect on the proliferation of T cells
What is the CD-52 receptor ?
It is a cell surface receptor on mature lymphocytes.
How can CD-52 be a target for drugs to degrade a T cell
if a monoclonal antibody binds to CD-52 the cell will be target for lysis by both antibodies and complement mediated cytotoxicity
How could you target the T cell bor destruction in a very general way.
Polyclonal IgG from horses ( Atgam ) or rabbits ( Thymoglobin ) Lymphocyte depletion will occur
What is a calcineurin inhibitor ?
What are two drugs that inhibit mTOR ?
Sirolimus (Life Threatening Hepatotoxicity) and Everolimus
What is a drug that is a glucocorticoid that will inhibit the transcription of the IL-2 gene ?
What are the two drugs that inhibit mTOR ?
Sirolimus and Everolimus
What antibody blocks CD-25 and what will this cause ?
Anti-CD-25 mAb - This will prevent IL-2 from binding and stimulating the T cell to proliferate
What drug will block the activation of CD-3
What transcription factor does calceneurin regulate
Nuclear Factor of Activated Transcription ( NFAT )
What will Anti-CD-52 mAb do to the T cell
This will cause antibody mediated degradation as well as Complement Mediated Cytotoxicity
What will polyclonal IgG do to T lymphocytes
It will cause Opsonization of the entire T cell
What are the 4 types of antibody drugs ?
Murine, Chimeric, Humanized, Human
What are the 4 possible effects of antibody drugs ?
Antagonism, Signaling, CDC, ADCC
Will a monoclonial antibody binding to IL-2 cause lymphocyte deletion ?
No it will just halt monoclonal expansion
What is a CDR ?
A complementary determining region
What composes the Fc region of the antibody ?
The hinge and the constant heavy chain domains of the antibody. This region is responsible for complement fixation and binding to the Fc receptors
What controls the functions of mAb's
Functions of mAb's are controlled by antagonism and signaling are controlled by specific CDR's within the Fab region
What are the functions of mAb's used in modulation of the immune system and dictated by the Fc region ?
Complement Mediated Cytotoxicity, Antibody Dependent Cytotoxicity and antibody dependent
What are common antigenic targets of mAb's
CD-3 IL-2 CD-52, and CD-80
What drugs bind to CD-80 ?
Belatecpt which will induce lymphocyte depletion
What drug binds to CD-52 ?
Alemtuzumab, which is lymphocyte depleting
What drugs bind to IL-2 ?
Daclizumab and Basiliximab, **Remember that IL-2 binding drugs will not cause depletion of the lymphocyte
What is the major risk associated with taking immunosuppressant drugs ?
Opportunistic infections, so you would want to give the patient prophylactic antibiotics in hope of preventing the infection
Other than opportunistic infections what other risks will immunosuppressants carry with them ?
There is a high risk of secondary malignancies (Lymphoma and skin cancer)
What drug requires that patients be EBV zero-positive to reduce the likelihood of progressive multifocal leukoencephalopathy and post transplant lymphoproliferative disorder
What causes lymphoma and lymphoproliferative disorder ?
B cell mutation s
What are the major risks for Muronomab ?
Angioedema, pulmonary edema, and seizures
What are the common Calcineurin Inhibitors ?
Cyclosporine, Tacrolimus, and Picolimeus
What do calcineurin inhibitors do ?
Inhibit the first phase of T cell activation
How is calcineurin activated ?
When an APC binds to a T cell there is an increase of Ca levels in the nucleus which will activate Calcineurin which will allow NFAT transcription factor into the cell and activate transcription of IL-2 genes
What will inhibiting Calcineruin do ?
It will inhibit the first phase of T cell activation by inhibiting the production of IL-2
What is a risk of calcineurin ?
Nephrotoxicity by inducing renal vasoconstriction ( thromboxane, prostaglandins, angiotensin 2 and endothelium PAF )
What is ironic about calcineurin adminsitration with renal transplant ?
It is hard to distinguish between transplant rejection and the side effects of the drug
How do corticosteroids actually work ?
Cytosolic glucocorticoid receptors (GR) bind to corticosteroids and the receptor ligand complex translocate to the nucleus and bind to the co activators to inhibit Histone Acetyl Transferase
What is the target in the nucleus for corticosteroids ?
Histone Acetyl Transferase- when bound to the glucocorticoid receptor and corticosteroid it is inhibited which prevents deacetylation of the
What are the two ways that corticosteroids inhibit the normal function of HAT
1. They recruit histone deacetylase which reverses histone acetylation which will suppress the activated inflammatory genes.
2. Increase Neutrophil production, monocytopenia, eosinopenia and decrease production and differentiation
What are some of the adverse effects of corticosteroids ?
Hypercorticism (Cushings syndrome) menstral irregularity, hypercholesterolemia, aggravation of DM.
What is the most common combination of drugs given in an innumo-suppressant Maintenance regimen
Calcuneurin Inhibitor, anti-proliferative, steroid
What is the mTOR inhibitor you should know ?
Sirolimus and Tacrolimeus
How do mTOR inhibitors actually work ?
They Bind to FKBP12 but inhibits activation of mammalian target of Rapamycin. It inhibits second phase of activation: Signal transduction and clonal proliferation of T cells ( G1 arrest )
What are mTOR's synergistic with ?
Cyclosporine in vivo and vitro
What is the end effect of mTOR's ?
Inhibition of B cell terminal differentiation into plasma cells. You will have a decrease in IgM, IgG, and IgA
What is a danger of Sarcolimus ?
The binding target that inhibits B cell proliferation is expressed on other cells in the body
What are the major adverse reactions of Sirolimus ?
Hyperlipidemia and Hepatotoxicity
What are the cell cycle disruptors ?
Azathioprine and Mycophenolate Mofetil
What is a huge concern when giving Azathioprine ?
It is a class D for birth defects
What are the adverse reactions associated with Sirolimus ?
Dose related Hyperlipidema.
Hepatotoxicity that could include fatal hepatic necrosis. Anemia, Leukopenia, Thrombocytopenia, Hypokalemia, Fever and diarrhea
Thrombophelibitis and Thromboembolism
What is the mechanism of Mycophenolate Mofetil ?
Inhibits the T and B lymphocyte Cell cycle in the S phase by inhibiting Purine Synthesis. It inhibits Inosine Monophosphate Dehydrogenase
What are the advantages of cell cycle disruptors (MM specifically ) ?
1. Blocks the secondary antibody responses mediated by memory B cells
2. Selective Effect on Lymphocyte Proliferation
3. No Chromosomal Breaks
What are the side effects of T cell cycle inhibitors (MM specifically ) ?
GI related, Constipation Diahrrhea, Dyspnea, nausea and vomiting, Myelosupressant
What is necessary before Cyclophosphoamide can work correctly ?
Metaboic activation, This is an alkylating agent that produces DNA cross links (inhibiting transcription) and mainly effects B cells.
What are the draqbacks of Cyclophosphoamide ?
It has significant Heart toxicity (Hemhorragic Cystitis by conversion to acrolein)
**Fibrosis of the bladder
Fertility problems if on the drug long term
What are the significant Drug-Drug Toxicities associated with Azathioprine ?
Allopurinol, Warfarin, Sulfas
What is the main function of Azathioprine ?
It is converted to a number of active metabolites. Two of which are significant.
*6-Thioguanine Triphosphate- Blocks co-stimulation of T cels and wipes out Memory T cells. It is also a puring atagonist which will be incorporated into DNA and cause Cell cycle arrest.
What are the toxicities of azathioprine ?
Category D for Birth Defects. Since it is converted to many different metabolites you have to be aware that blockage of any of these pathways will increase the Aza levels in the blood. It will also cause an increase in liver enzymes which needs to be monitored.
What is Cyclophosphoamide ?
An Alkylating agent producing DNA cross links. It is a lymphocytic drug which affects T cells much more than B cells.
What is a toxic product of Cyclophosphoamide ?
Acrolein which will cause Hemhorrhagic cystitis.
The drug will also cause Fibrosis of the Lungs and bladder
Can Azathioprine cause secondary malignancies ?
Yes it will place the patient at high risk for skin cancer and the patient should avoid direct sunlight.
What are the main uses of methotrexate ?
Anticancer and immune suppression in conjunction with arthritic conditions
What is the class of Methotrexate ?
Dihydrofolate Reductase Inhibitor
How is methotrexate taken into the cell ?
The folate pathway and can be effluxed by ABC transporters
What is Methotrexate converted into once inside the cell ?
What do MPXTG's do ?
1. Impede the formation of bioactive forms of Folate
2. Inhibit Pyrimidine Synthesis and cause accumulation of products of Purine Synthesis (AICAR)
3. The ACIR generated from step two will inhibit ADA and AMP deaminase causing the accumulation of adenosine which has the anti-inflammatory activity
In a nut shell what does Methotrexate do for the immuno-supressant application of the drug
It causes the accumulation of Adenosine
Who has Adenosine Receptors ?
APC's ---> starting to see where were going here
What happens when adenosine binds to the adenosine receptors on APC's
Down regulation of TNF and IL-12
Upregulation of IL-10 (anti-inflammatory) and VEFG.
What is the ultimate effect of methotrexate in immunosupression ?
Decreased TH1 vs TH2 cell development
What stage of the cell cycle will methotrexate interrupt ?
S phase so tissues that are actively dividing are the target.
What are the toxicities of methotrexate ?
N&V which is lessened with premedication of corticosteroids
Hematologic toxicity (anemia, leukopenia neutropenia and thrombocytopenia )
**Use contraception for 3 months post treatment
Do different races have different conc.'s of immuno suppressant ?
Sirolimus is increased in Blacks
Cyclosporine and Tacrolimus are decreased in blacks
What antiimmune drug is used in coronary Stents ?
Should you breast feed while on immunosupressants ?
No it is risky
What are the immunosuppressants that you can not give to pregnant women ?
All except Methotrexate and Cyclophosphoamide