Immunosuppressants Flashcards
Major classes of immunosuppressants
- Corticosteroids
- Cyclophilin-binding drugs
- Immunosuppressant anti-metabolites
- Antibodies
Most important clinical corticosteroids
- Methylprednisone
- Presdnisolone
- Prednisone
Effects of corticosteroids in various tissues
Complications of chronic corticosteroid use
- Bone loss
- Peptic ulcers
- Hypertension
- Infection
- Increased blood glucose
- Osteonecrosis
- Weight gain
- Cataracts
- Striae (stretch marks)
- Muscle atrophy
The hypothalamic-pituitary-adrenal axis
The cyclophilin binding drugs
- Cyclosproine & Tacrolimus: Bind NF-AT
- Sirolimus (Rapamycin) & Everolimus: Bind mTOR
- Both groups serve to impede T cell growth, activation, and mediator production
When do we use cyclophilin binding drugs?
- Most importantly, FOR TRANSPLANTS to prevent rejection
- Also, to treat T cell-mediated diseases: Psoriasis, RA, Crohn’s, atopic dermatitis
Cyclosporine A mechansitic diagram
Complications and toxicities of cyclosporine
- Infection (obviously)
- Cancer (obviously)
- Hypertension
- Renal toxicity
- Hepatic toxicity
- Tremor
Tacrolimus (aka FK506) mechanistic diagram
mTOR
Member of the phosphatidylinositol 3- kinase-related kinase protein family;
it is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, transcription
TCR and IL-2R pathways
Immunosuppressive antimetabolites
- Inhibit cell replication and thus affect immune system because it has the most rapidly dividing natural human cells
- Methotrexate
- Mycophenylate
- Azathioprine
Methotrexate
- First line therapy for RA
- Dose dependent liver fibrosis is a toxicity
- Incompatible with pregnancy
- An antifolate
Azathioprine
- Pro-drug which is converted into 6-mercaptopurine then into thioinosinic acid once inside of cell
- Thioinosinic acid inhibits DNA synthesis
Mycophenylate
- Converted into mycophenylic acid
- Inhibits inosine monophosphate dehydrogenase, an ezyme involved in nucleotide biosynthesis
- Fairly selective action at inhibiting T and B cell proliferation
alemtuzumab
Anti-CD52
Depletes both T and B cells
Main concern with anti-TNFs
Infection! Many possible infections (viral, bacterial, fungal, etc etc)
But not so much cancer
Anti-cytokine antibodies associated with infection risk
- TNFa
- IL-2
Anti-cytokine antibodies associated with relatively normal risk of infection
- IL-6
- IL-17
- IL-23
- IL-4
Anti-Th17-cytokines
- Ustekinumab - anti-IL-23R
- secukinumab, ixekizumab - anti-IL-17A
- brodalumab - anti-IL-17R
Major cytokine-depleting antibody diagram
At what stages are B cells CD20+?
Antithymocyte globulin
- Polyclonal antibodies produced by immunizing orthologous species against human lymphoid tissue and harvesting the resultant sera
- Approved for treatment of acute cellular rejection and used as induction agent
Antibiotics with immunosuppressive effects
- Low dose doxycycline
- tetracycline
- minocycline
Antimalarials with immunosuppressive effects
- Hydroxychloroquine
- Chloroquine
- Quinacrine
Jak/STAT inhibitors
Progressive multifocal leukoencephalopathy (PML)
- rare and usually fatal virally mediated brain inflammation
- John Cunningham virus (JCV), human polyomavirus
- Latent virus present in GI tract in healthy controls, viral shedding occurs, suppressed by immune system
- Observed in immunocompromised (HIV, lymphoma/leukemia, autoimmune diseases, immunosuppressant Rx)
What do you need to screen for before immunosuppressing someone?
- Watch patients carefully! Report fevers, chills, muscle aches promptly
- Latent TB
- Hepatitis B and C
- HSV
- VZV
- JCV
- Polyomavirus
- Toxoplasma
- Pneumocystis
- Candidiasis
HAART
- Highly active antiretroviral therapy
Cancers associated with T cell immunosuppression
- Mostly virally-mediated cancers
- Kaposi’s sarcoma (Human Herpes virus 8 / HHSV8)
- Oral, cervical, throat and anal squamous cell cancers (human papilloma virus / HPV)
- Lymphomas (Epstein Barr virus / EBV)
- Merkel cell carcinomas (Merkel cell polyomavirus)
- Liver cancer (Hepatitis B, Hepatitis C)
- Non-infectious cancers: lung, kidney cancer, skin squamous cell carcinomas
Oral Kaposi’s sarcoma
Best treatment for Kaposi’s sarcoma
Reduction of dosage of immunosuppression
Best treatment for immunosuppression-associated mucosal squamous cell carcinomas
excision, radiation, chemo
Merkel Cell Carcinoma
Potential infectious causes of lymphoma
- EBV
HIV - Human T cell leukemia virus-1 (HTLV-1)
- Hepatitis C
- HHV8
- H. pylori
Leading cause of death in solid organ transplant patients
Immunosuppression-induced squamous cell carcinoma of the skin
Risk of SSC in transplant patients is associated with
- Sun exposure
- Depth of T cell immunosuppression
- Which T cell immunosuppressant is used (highest risk is with cyclosporine, lowest is with mTOR inhibitors)
Managing risks of SCC for transplant patients
- Strict sun protection and dermatology followups
- Use minimum possible level of immunosuppression
- Switch to mTOR inhibitors if possible and well tolerated
__ + __ = squamous cell carcinoma
sun exposure + cyclosporine = squamous cell carcinoma
People with HIV have too ___ T cell immunity
People with HIV have too little AND too much T cell immunity
In other words, they have too few proinflammatory CD4 T cells for proper protection, and too few Tregs for proper tolerance
