Immunomodulatory Drugs Flashcards
What are the three T cell activation signals that are modified with immune modulatory drugs?
- TCR/MHC Activation
- CD28 (Tcell)/B7 (APC) Costimulatin
- Cytokine signalling:
IL-2 from Tcells to Tcell IL-2R for cell activation
What is Graft vs Host Disease?
Undesired immune reaction to organ/cell allogeneic transplantation:
- T cell driven immune response –> Donor-derived T cells recognize recipient tissues as foreign and attack
Direct Allorecognition:
Donor APCs migrate to a local lymph node and stimulate alloreactive recipient T cells
Indirect Allorecognition:
Recipient APCs process proteins and present peptides derived from the graft
What is the signal cascade for TCR/MHC-II activation?
MHC-II (From APC)+Antigen binds to TCR (from Tcell) with CD3+CD4+ complex
–> Binding of TCR with MHC leads to an influx of Ca++
–> Calcium is necesssary for Calcineurin function
–> Calcineurin is typically used to dephosphorylate NFAT, allowing NFAT to enter the nucleus and complex to become a transcription factor of cytokines (i.e. IL-2)
What is Cyclosporine A?
Calcineurin inhibitor
- Binds to cyclophilin and inhibits calcineurin from dephosphorylating NFAT
- Used to prevent acute rejection of solid organs
(kidney, liver, heart, etc.) as well as acute GVHD - Usually used in conjunction with corticosteroids
- Used for treatment of severe rheumatoid arthritis and psoriasis
What are the side effects of Cyclosporine A?
- ***nephrotoxicity**** - most critical
- Renal hypperfusion
- Arteriopathy
- Tubular atrophy
- Interstitial fibrosis
HTN
Hepatotoxicity
Increased risk of:
lymphoma
Infections
Convulsions
What is tacrolimus?
Calcineurin inhibitor
- Binds to FK binding protein, preventing calcineurin activation
- More potent than CsA
- Superior performace in preventing acute rejection of renal, heart-lung, and liver allografts
What are the side effects of tacrolimus?
Nephrotoxicity
Neurotoxicity
HTN
diabetes
malignant lymphoma
What is Sirolimus (rapamycin)?
mTOR inhibitor –> blocks effects of IL-2 on Tcells
- MOA: Inhibits mTOR complex 1, blocks IL-2 induced proteins synthesis
- Used to prevent renal allograft rejection
- *(as effective as cyclosporine A w/o nephrotoxicity)**
- Contraindicated for liver/lung transplant
What are the toxicities of Sirolimus?
anemia
thrombocytopenia
hyperlipidemia
What is the IL-2R signal cascade?
IL-2 binds to IL-2R on the surface of the Tcell
–> TOR is activated
–> Cyclin/CDK is activated
–> Activates cell cycle progression from G1 phase to S phase
What are the immunemodulators that interfere with the TCR cascade?
Cyclosporine A: Calcineurin inhibitor that binds to cyclophilin
_Tacrolimus: _ Calcineurin inhibitor that binds to FK binding protein
What is Mycophenolate Mofetil (MMF)?
Inhibitor of inosine monophosphate dehydrogenase (required for purine biosynthesis)
–> blocks cell cycle progression
- Useful in kidney/liver transplants in combination with CsA or Tacrolimus
- Hydrolyzed by liver esterases to MPA (the active inhibitor of IMD)
What is Azathioprine?
- *Purine analog metabolized to 6-mercaptopurine**
- disrupts de novo purine synthesis and inhibits DNA transcription
- Used in combination therapy (prednisone +/- CsA/Tacrolimus)
Side Effects:
GI distress
leukopenia
increased infections
What are the “1st line” DMARDs for RA?
1. Methotrexate (Same rationale as MMF; stops cell cycle)
Folic acid analogue –> dihydrofolate reductase inhibitor
Blocks nucleoside biosynthesis
2. Leflunamide
Prodrug whose active metabolite inhibits dihydroorate dehydrongenase (an essential enzyme for pyrimidine synthesis)
- *Also:**
- *Chloroquine** (perturbs lysosomal processing and antigen presentation –> decreased Tcell activation)
Penicillamine (metal chelator prevents IL-1 production and collagen maturation)
Sulfasalazine (Scavenger of ROS produced by neutrophils)
What kind of Antibodies end in:
- omab
- ximab
- zumab
- umab
-omab: mouse antibodies
-ximab: chimeric antibodies
-zumab: humanized antibodies
-umab: human antibodies
What anti-CD3 anbitodies are available for treatment of autoimmunities?
Muromonab
- Mouse mAb directed against signaling chaing of TCR
- -> blocks engagement of TCR
- Indicated for reversal of rejection of heart, liver, and kidney transplants
- Never given prophylactically b/c can cause cytokine storm due to non-specific activation of Tcells
- hypersensitivity reactions associated w/formation of anti-mouse Ab
What anti-CD25 anbitodies are available for treatment of autoimmunities?
daclizumab
Basiliximab
- mAbs directed against the a-chain (CD25) of the high-affinity IL-2 receptor –> inhibits IL-2 mediated T cell proliferation
- Reduces risk of acute rejection when used in combination with cyclosporine/asathioprine in kidney and cardiac transplantation
- Hypersensitivity possible with basiliximab
What drugs are used to block CD28/B7 costimulation of T cells?
CTLA4-Ig:
- *Abatacept –** treats RA
- *Belatacept** – prevent renal transplant rejection
- Rec chimera of the extracellular domain of CTLA4 and IgG1 Fc (biologic drug)
- Binds to B7 on APCs to prevent CD28 engagement
- Causes anergy in Tcells
What drugs are used to inhibit IL-1/IL-1R?
Canakinumab
Anakinra (biologic)
Rilanocept (biologic)
What drugs are used to inhibit IL-12?
Ustekinumab
What drugs are used to inhibit TNF?
anti-TNF:
Infliximab
Adalimumab
Golimumab
Certolizumab pegol
Etanercept (biologic)
What drugs are used to inhibit IL-6R?
toclizumab
What are the indications and side effects of anti-TNF mAb?
(i.e. Infliximab, etanercept, adalimumab)
Indications:
Crohn’s
Ulcerative colitis
RA
Psoriatic Arthritis
Plaque psoriasis
Ankylosing spondylitis
Side Effects:
Infections
Malignancy
hepatotoxicity
What are the indications and side effects of anti-IL-6R mAbs?
(i.e. Tocilizumab)
RA
Side Effects:
Increased infections
hypersensitivity
What are the indications and side effects of anti-IL-1R mAbs?
(i.e. anakinra)
RA
Side effects:
Increased risk of serious bacterial infection
What are indications and side effects of anti-CD20 mAbs?
(i.e. rituximab)
RA
Side Effects:
Infection
cytokine release syndrome
–> extremely effective in depleting B cells
What are indications and side effects of anti-BAFF mAb?
(i.e. belimumab)
SLE
Side effects:
Infections
hypersensitivty
What is natalizumab?
Anti-VLA4 mAb
- Blocks T cell migration to site of inflammation
–> used to treat Crohn’s disease and multiple sclerosis
- Significant risk of JC virus-iduced progressive multifocal leukoencephalopathy
What is fingolimod?
- Phosphorylated form binds to Sphingosine-1 phosphate receptors
- Prevents lymphocytes from migrating out of lymph notdes
–> approved to treat multiple sclerosis
- Increased risk of fatal infections
What is Epoetin alfa?
Rec erythropoeitin analogues that stimulate formation of RBCs in anemic patients
darbepoeitin alfa - longer 1/2 life
What is filgrastim?
G-CSF
Stimulates neutrophil proliferation and maturation
Stimulates neutrophil migration
What is GM-CSF?
Granulocyte Macrophage Colony stimulating factor
- stimulator of granulocyte proliferation and maturation
- inhibits neutrophil migration
What is Oprelvekin?
rIL-11
Stimulates proliferation and maturation of megakaryocytes and formation of platelets
What cytokines and growth factors are medically used to boost your immunity?
Epoeitin alfa
Filgrastim (G-CSF)
GM-CSF
Oprelvekin (rIL-11)
What is IVIG?
