Immunomodulation Therapy Flashcards
What are the main uses of immunosuppressive drugs?
- Transplant rejection
- Graft VS Host Response
- Autoimmunity
Hyperacute Rejection
Occurs within minutes of transplant
Caused by pre‐existing reactive antibodies - avoided via crossmatching before the operation
Acute Rejection
6‐12 months post transplant
T cell‐mediated
Chronic Rejection
Months to years
Due to fibrosis causing damage to the graft blood vessels
What type of rejection is immunosuppression aimed towards preventing?
Immunosuppressive therapy aimed at preventing acute rejection and prolonging graft survival
What is the use of multi-tiered drugs in immunosuppression?
It allows for the targeting of multiple aspects of the immune system as well as allowing for lower doses
What are some examples of the adrenocortical steroids (glucocorticoids)?
- Prednisone (prodrug)
- Prednisolone
What are the effects of prednisone/prednisolone?
• non‐specific inhibitor of the immune system and/or immune system genes (e.g. cytokines)
• inhibits expression of critical pro‐inflammatory CH3
• decreases the numbers of circulating leukocytes
MOA of Prednisone/Prednisolone
- Glucocorticoids diffuse into cells and bind their receptors in the cytoplasm
- Promote receptor dimerization & nuclear translocation
- Active receptors bind to target genes and influence their expression - either increase or decrease
- Inhibition of critical immunoregulatory genes inhibits the immune response
Indications of Prednisone/Prednisolone
• Commonly used in combination with other agents in standard immunosuppressive therapy regimens to prevent organ graft rejection
• High dose IV pulses of steroids additionally used to combat:
‐ Acute rejection episodes
‐ GvHD in BMT
‐ Treatment of Cytokine‐Release Syndrome (cytokine storm)
• Autoimmune and Inflammatory Diseases: rheumatoid arthritis, lupus, multiple sclerosis, psoriasis, inflammatory bowel disease, skin diseases, eye diseases, asthma
Prednisone/Prednisolone SE
‐ Hyperglycemia, Hypertension, Hyperlipidemia, Obesity
‐ Increased risk of exacerbating pre‐existing diabetes and/or developing diabetes
‐ Osteopenia
‐ Cataracts
‐ Growth retardation in children
‐ Poor wound healing
What is typically done with glucocorticoids in order to minimize SE?
The doses are slowly tapered over the first month - do NOT abruptly withdraw though due to possibility of acute adrenal crisis
What are the drugs of the proliferation inhibitors/anti-metabolites?
- Azathioprine (prodrug of 6-mercaptopurine)
* Mycophenolate mofetil
Why is azathioprine used of 6-mercaptopurine?
It has a high oral bioavailability and it will then be converted to 6-mercaptopurine
MOA of Azathioprine
It is converted to 6-mercaptopurine and then 6-TIMP which inhibits de novo purine synthesis.
A further metabolite, 6-TGTP inhibits CD28/Rac1 T cell costrimulation as well as the induction of apoptosis via DNA damage.
All of this prevents lymphocyte proliferation.
Indications of Azathioprine
- Prophylactic prevention of graft rejection following organ transplantation
- Autoimmune diseases and other immune‐mediated diseases
• Rheumatoid arthritis
• Crohn’s
• Multiple sclerosis
Azathioprine SE
a) Diarrhea, nausea & vomiting
b) Leukopenia & thrombocytopenia
c) Hepatotoxicity
d) Increased risk of infections
e) Increased risk of malignancy
What are the drug interactions of azathioprine?
Allopurinol and Febuxostat - xanthine oxidase inhibitors will lead to the build-up of 6-mercaptopurine which can be toxic.
Xanthine oxidase normally also metabolized 6-mercaptopurine
What is mycophenolate mofetil a prodrug of?
Mycophenolic Acid
MOA of Mycophenolate Mofetil
Mycophenolic acid (MPA) is a non‐competitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II ‐ the rate‐limiting enzyme in the de novo synthesis of purine nucleotides
Indications of Mycophenolate Mofetil
- To prevent graft rejection following organ transplantation
- Some autoimmune diseases and immune‐mediated disorders
Mycophenolate Mofetil SE
a) Diarrhea, nausea & vomiting
b) Leukopenia & anemia
c) Embryo/fetal toxicity‐ risk of first trimester loss and congenital abnormalities d) Increased risk of infections – bacteria, viruses (esp. CMV), fungi & parasites
e) Increased risk of malignancies (lymphoma/skin)
f) Progressive multifocal leukoencephalopathy (RARE, but potentially fatal)
Contraindications of Mycophenolate Mofetil
Pregnancy, women of child bearing age who wish to become pregnant, and men who wish to become fathers – due to the teratogenicity ‐ azathioprine is preferred in these patients
Why are lymphocytes specifically affected by mycophenolate mofetil?
Lymphocytes are more dependent on de novo purine biosynthesis than are other cell types because there is no Salvage pathway - IMPDH II is also selectively expressed in lymphocytes
Methotrexate MOA
Inhibition of dihydrofolate reductase indirectly inhibits purine/pyrimidine synthesis
Methotrexate Indications
Autoimmune diseases (especially Rheumatoid arthritis)
Methotrexate SE
Renal, hepatic & GI toxicity, lung damage, BM suppression, neurotoxicity, increased risk of malignancy, teratogenic
Methotrexate Contraindications
Pregnancy
Cyclophosphamide MOA
Nitrogen mustard alkylating agent crosslinks DNA, RNA and proteins
Cyclophosphamide SE
Bone marrow suppression, GI issues, increased risk of cancer, risk of infertility (both male and female)
Cyclophosphamide Indications
Prevention of acute graft rejection and GvHD ‐ Reserved for most severe disease
Cyclophosphamide Contraindications
Pregnancy & men who wish to become fathers
Chlorambucil MOA
Nitrogen mustard alkylating agent crosslinks DNA, RNA and proteins
Chlorambucil SE
Bone marrow suppression, Fertility, Secondary cancers, GI issues
Chlorambucil Indications
Certain autoimmune diseases
Chlorambucil Contraindications
Pregnancy & men who wish to become fathers
What are the inhibitors of T-cell signaling?
Calcineurin inhibitors: Cyclosporin and Tacrolimus
mTOR inhibitors: Sirolimus and Everolimus
What are the calcineurin inhibitors?
Cyclosporin and Tacrolimus
Indications of Cyclosporin and Tacrolimus
- Prevention of solid organ rejection: Heart, kidney, liver, lungs
- Prevention of Graft‐versus‐Host disease in bone marrow transplantation
- Treatment of a number of autoimmune diseases:
What is unique about the classification of Cyclosporin and Tacrolimus?
They can also be referred to as antibiotics
MOA of Cyclosporin and Tacrolimus
- Cylcosporin binds to cyclophilin
- Tacrolimus (FK506) binds to FKBP (FK506‐binding protein)
Instead the complexes of cyclosporine/cyclophilin and tacrolimus/FKBP form inhibitory complexes that bind and inhibit the activity of CALCINEURIN‐ a critical signaling enzyme in T cell activation involved in the activation of the NFAT transcription factor responsible for the expression of numerous genes including the T cell growth factor Interleukin‐2 (IL‐2).
- Cyclosporine and tacrolimus therefore inhibit signal 1 of T cell activation and prevent T cell proliferation by inhibiting the production of IL‐2
What is unique about the MOA of cyclosporin and tacrolimus?
Both cyclophilin and FKBP catalyze cis/trans isomerization of peptide bonds containing proline residues - cyclosporin and tacrolimus and inhibit their peptidylprolyl isomerase activity which is unrelated to the MOA
What is calcineurin and its normal function?
Calcineurin is a calcium‐regulated phosphatase activated in response to T cell receptor‐induced increases in intracellular calcium - the activation of calcineurin induces the dephosphorylation of the NFAT transcription factor and its translocation from the cytoplasm to the nucleus, where it induces the expression of numerous genes including the T cell growth factor IL‐2
What is the metabolism of cyclosporin and tacrolimus?
They are both metabolized by CYP450 3A4
Cyclosporin and Tacrolimus SE
a) Nephrotoxicity*
b) Hypertension*
c) Neurotoxicity/tremor
d) Glucose intolerance (T>C)
e) Hyperlipidemia (C>T)
What drugs can increase the concentration of cyclosporin and tacrolimus in the plasma and how do they work?
Grapefruit juice, Azole antifungals, Erythromycin/Clarithromycin, Verapamil, Dilitazem
Inhibit CYP 3A4
What drugs can decrease the concentration of cyclosporin and tacrolimus in the plasma and how do they work?
Rifampin, Carbamazepine, Phenobarbital, Phenytoin, St. John’s wort
Induce CYP 3A4
What drugs can enhance the nephrotoxicity of cyclosporine and tacrolimus?
NSAIDs - have inherent nephrotoxicity
What are the mTOR inhibitors?
- Sirolimus
- Everolimus
What is the difference between Sirolimus and Everolimus?
Everolimus has a shorter half life
Sirolimus and Everolimus MOA
Unlike FKBP/tacrolimus, FKBP/sirolimus
does not bind to calcineurin, but instead
binds and inhibits the mTOR kinase complex - mTOR kinase regulates protein synthesis, cell proliferation and survival.
- Inhibition of mTOR by sirolimus inhibits IL‐2 mediated signals in T cells (Signal 2), thereby inhibiting T cell proliferation
Sirolimus and Everolimus Indications
• Prophylactic prevention of graft rejection
NOT RECOMMENDED for: Liver transplants (increased risk hepatic artery thrombosis) and Lung transplants (increased risk anastomotic dehiscence)
- Prevention of Graft‐versus‐Host Disease following bone marrow transplantation
- Included in coronary stents to inhibit restenosis by preventing cell proliferation
Sirolimus and Everolimus SE
a) Hypertriglyceridemia/Hypercholesterolemia
b) Pulmonary edema/Lung disease
c) Increased risk new onset diabetes
d) Hematologic‐ anemia, thrombocytopenia and leukopenia e) Decreased wound healing
f) Increased risk of infection
g) Increased risk of malignancy
h) Teratogenic effects
Sirolimus and Everolimus Contraindications
- Pregnancy‐ (should be discontinued > 12 weeks prior to attempted conception)
- Liver and Lung transplant immunotherapy
What are some drug interactions of Sirolimus and Everolimus?
Metabolized by CYP3A4‐ similar interactions as cyclosporine and tacrolimus
Induction Therapy
“Induction therapy” involves use of anti‐lymphocyte antibodies to acutely inhibit T cell responses in the recipient at the time of transplantation
What are the two classes of induction therapy?
- Lymphocyte Depleting Ab
- Functional Inhibition Ab
Rabit Anti‐thymoycyte Globulins (rTAG) MOA
- Anti‐T cell antisera generated from rabbits immunized with human lymphocytes
- Reacts with proteins expressed on lymphocyte surface‐ CD2, CD3, CD4, CD8, CD11a etc
- Actively depletes lymphocytes from the blood and lymphoid organs ‐ Fc receptor‐mediated/complement‐dependent lysis and opsonization
- Recovery of the immune system takes several months
Rabit Anti‐thymoycyte Globulins (rTAG) SE
Cytokine release syndrome (Ab activates T cell and induces cytokines) ‐ leukopenia and increased infections
Alemtuzumab MOA
- Humanized anti‐CD52 (expressed on T and B cells, macrophages, NK cells and granulocytes)
- Triggers antibody‐mediated lysis of lymphocyte
Alemtuzumab SE
Cytokine release syndrome ‐ prolonged lymphopenia‐ increased infections
Basiliximab MOA
- Humanized antibody that binds CD25
- Acts as an IL‐2R antagonist that inhibits T cell proliferation
- Not as effective as depleting antibodies
- Well tolerated, although more rejection than with depleting agents
What is the triple immunosuppressive regimen?
Glucocorticoid + either cyclosporin or tacrolimus + an anti‐proliferative drug
Fingolimod MOA
Structural analogue of sphingosine activates the Sphingosine‐1 phosphate receptor expressed on lymphocytes, sequestering lymphocytes in the lymph node thereby preventing them from accessing the CNS
Fingolimod SE
- Risk of bradyarrhythmia and atrioventricular block (potentially fatal)
- Increased risk varicella zorster virus infection (potentially fatal)
- Increased risk of malignancy
Natalizumab MOA
Anti‐alpha4 integrin antibody blocks entry of lymphocytes into the CNS
Natalizumab SE
Increased risk of PML - progressive multifocal leukoencephalopathy
Interferon Beta MOA
Reduce the entry of inflammatory cells into the CNS and reduce T cell activation
Glatiramer acetate MOA
Mixture of polymers of 4 amino found in myelin basic protein MBP ‐ promotes production of specific suppressor T cells that migrate to the brain and produce bystander suppression at sites of inflammation
IGIV
Intravenous Immunoglobulin
• Purified human immunoglobulin from pooled human plasma
• Used to prophylactically to provide passive immunity to individuals with underlying
immunodeficiency diseases e.g. hypogammaglobulinemia
• Immunity last for weeks‐months
Hyperimmune Ig
• Similar to IGIV, except purified from individuals with high titers against a specific antigen or organism
i.e. - Hepatitis B, CMV, Rabies, tetanus toxin, botulism, diphtheria, varicella‐zoster snake and scorpion toxins
Rho(D) Immune globulin
- Antibodies specific for the Rh (D) antigen on red blood cells
- Used to prevent hemolytic disease of the newborn in Rh‐negative women ‐ administered at 28 weeks of pregnancy to Rh‐negative women where the father is Rh+
Ipilimumab MOA and Indications
USED IN CANCER IMMUNOTHERAPY
mAb specific for the CTLA4 protein expressed on activated T cells:
- prevents CTLA4 from binding to CD80/86 prevents CTLA4 from delivering a negative signal
- leaves CD28 co‐stimulation intact
‐ leading to enhanced T cell activation
Pembrolizumab and Nivolumab MOA
• Pembrolizumab and Nivolumab are antibodies specific for the negative regulatory PD1 protein expressed on T cells ‐ stimulation of PD1 by its ligand PD‐L1 inhibits T cell activation
• PD‐L1, is expressed on a variety of cell types including cancer cells
‐ believed to be a mechanism by which cancer cells evade the immune system
• Pembrolizumab & Nivolumab block PD1/PD‐L1 interactions thereby preventing PD1 negative signaling and leading to enhanced T cell immune responses against the cancer cell
