Immunomodulators Flashcards
What are the 7 classes of immunosuppressant drugs?
1) glucocorticoids/steroids
2) proliferation inhibitors and anti-metabolites
3) immunophilin-binding drugs (inhibitors of T cell signaling pathways)
4) antibodies for induction immunosuppression
5) misc drugs to treat relapsing remitting MS
6) passive immunization Ig
7) immune checkpoint inhibitors
Define hyperacute rejection
cause by pre-existing reactive antibodies
occurs within minutes of transplant
Define acute rejection
6-12 months post transplant
T cell mediated
Define chronic rejection
months to years
due to fibrosis causing damage to graft blood vessels
What type of rejection is targeted by immunosuppressants?
acute
What are the two things that need to be matched prior to transplant?
1) ABO blood type compatible
2) HLA matched
What are the 4 principles of transplantation?
1) appropriate patient and donor prep and selection
2) multi-tiered approach to immunosuppression
3) potential initial immunosuppression (decreases potential toxicity of immunosuppressants)
4) drugs should be reduced or withdrawn if toxicity exceeds benefits
What is the MOA of steroids?
glucocorticoids bind to receptors in the cytoplasm and translocate to the nucleus to bind to target genes and influence their expression (INHIBIT critical immunoregulatory genes to inhibit immune response)
When are steroids indicated?
- standard immunosuppressive therapy to prevent organ graft rejection (along with others)
- high dose IV to combat acute rejection episodes and treatment of cytokine release syndrome
- treats autoimmune diseases (RA, lupus, MS, IBD, asthma, psoriasis)
What are the side effects of steroids?
hyperglycemia, hyperlipidemia, obesity developing diabetes osteopenia cataracts poor wound healing mania and psychosis
Why do steroids need to be tapered?
to avoid adrenal crisis (need to teach the adrenals how to make steroids again)
What percentage of transplant patients stay on steroids after 1 year post transplant?
80%
What are the 2 proliferation inhibitors and anti-metabolites?
azathioprine
mycophenolate mofetil
What does azathioprine do?
inhibit lymphocyte proliferation
What activates azathioprine?
glutathione (converts it from prodrug to 6-mercaptopurine)
What 3 things can azathioprine affect?
1) inhibits de novo purine biosynth
2) leads to apoptosis
3) inhibits T cell and CD28/Rac1 costimulation
What are 2 indications for azathioprine?
1) prophylactic prevention of graft rejection post organ transplant
2) autoimmune diseases (RA, Crohn’s, MS)
What are the adverse effects of azathioprine
diarrhea, leukopenia, hepatotox
What are the important drug interactions for azathioprine?
allopurinol and febuxostat (xanthine oxidase inhibitors used to treat gout)
due to increased levels of 6-MP
What is the MOA of mycophenolate mofetil (MMF)?
reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II which is used to make purine nucleotides
IMPDH is selectively expressed in lymphocytes so MMF selectively blocks lymphocyte prolif
What are the indications of MMF?
on label: prevent graft rejection
off label: autoimmune disorders
What is a potentially very dangerous adverse effect of MMF?
progressive multifocal leukoencephalopathy (caused by reactivation of JC virus)
What are the contraindications of MMF?
pregnancy or fertile patients
In addition to MMF and azathioprine, what are 3 other anti proliferative drugs for immunosuppression?
1) methotrexate (treat RA)
2) cyclophosphamide (treat most severe diseases)
3) chlorambucil
What are the immunophilin binding drugs/inhibitors of T cell signaling pathways?
calcineurin inhibitors (cyclosporin and tacrolimus)
mTOR inhibitors (sirolimus and everolimus)
What are 3 indications of calcineurin inhibitors?
1) prevent solid organ rejection (heart, kidney, liver, lungs)
2) prevent graft vs host in bone marrow transplant
3) treat autoimmune disease (severe psoriasis, severe RA, SLE, IBD, nephrotic syndrome)
What is the MOA of immunophilins? cyclosporin binds to _________ while tacrolimus binds to _________
cyclophilin
FKBP
What are cyclophilin and FKBP?
peptidyleprolyl isomerases but the biologic activity of these drugs is independent of that activity
instead the drug enzyme complex binds and inhibits calcineurin
What does calcineurin do?
helps activate NFAT which is a TF responsible for expression of many genes including T cell growth factor IL2
Cyclosporine inhibits or activates NFAT?
INHIBITS
How are cyclosporine and tacrolimus metabolized?
extensively via CYP450 (strongly affected by drugs that inhibit or induce CYP3A4)
What are the major adverse effects of cyclosporine and tacrolimus?
nephrotoxicity
hypertension
What effects do CYP3A4 drugs have on graft rejection?
inducers = increase likelihood inhibitors = decrease likelihood
What are the mTOR inhibitors?
Sirolimus and Everolimus
What do sirolimus and everolimus bind to?
FKBP (inhibit mTOR kinase complex downstream cytokine and growth factor receptors like the IL2 receptor)
what does mTOR do?
regulates protein synthesis, cell proliferation and survival
Which drug is NOT recommended for liver and lung transplants?
sirolimus and tacrolimus (increases risk of hepatic artery thrombosis and anastomatic dehiscence)
Which drugs are used in coronary stenting to inhibit restenosis by preventing cell proliferation?
sirolimus and everolimus
What are contraindications for siroliumus and everolimus?
pregnancy
What is the goal of induction therapy?
use of anti-lymphocyte antibodies to acutely inhibit T cell responses in the recipient at time of transplant
Name 3 antibody induction reagents
1) rabbit anti-thymocyte globulin
2) alemtuzmab
3) basiliximab
What is the best tolerated antibody induction reagent?
basiliximab
What is the typical triple drug regimen started post-op after organ transplants?
glucocorticoid
cyclosporin and tacrolimus
an anti-proliferative drug
What are 3 common risks of immunosuppression?
1) increased risk of infection
2) increased risk of malignancy
3) post-transplant lymphoproliferative disorder (ex: B cell hyperplasia caused by EBV that can develop into lymphoma)
What are 4 drugs used in treatment of relapsing-remitting MS?
1) fingolimod (sequesters lymphocytes in lymph node preventing them from accessing CNS - risk of fatal bradycardia)
2) natalizumab (increased risk of PML)
3) Interferon beta
4) glatiramer acetate
What is the goal of MS immunotherapy?
to prevent immune cells from accessing the CNS
What are 3 forms of passive immunization?
1) IVIG (can treat pts with underlying immunodeficiency disorders)
2) Hyperimmune Ig (purified from individuals with high titers against a specific antigen like hepatitis B)
3) Rho(D) Ig (used to prevent hemolytic disease of newborn in Rh-neg women)
What kind of drug is ipilimumab?
mAb specific for CTLA4 protein on activated T cells (prevents it from delivering negative signal to T cells keeping them functional and protecting them from conversion to TREGs)
What are some indications in ipilimumab?
late stage melanoma
What are adverse effects of ipilimumab?
over immune activation (like inflammation of skin, GI tract, liver, nerves, and adrenals)
What are Pembrolizumab and nivolumab?
antibodies specific for negative regulatory PD1 expressed on T cells
(when PD1 is stimulated by its ligand PD-L1, it inhibits T cell activation)
What is the goal of pemrolizumab and nivolumab?
block PD1/PD-L1 interactions preventing PD1 negative signaling leading to enhanced T cell immune response against the cancer cell
