Immunosuppressants

Question 1

Major classes of immunosuppressants

Answer 1

• Corticosteroids
• Cyclophilin-binding drugs
• Immunosuppressant anti-metabolites
• Antibodies

Question 2

Most important clinical corticosteroids

Answer 2

• Methylprednisone
• Presdnisolone
• Prednisone

Question 3

Effects of corticosteroids in various tissues

Answer 3

Question 4

Complications of chronic corticosteroid use

Answer 4

• Bone loss
• Peptic ulcers
• Hypertension
• Infection
• Increased blood glucose
• Osteonecrosis
• Weight gain
• Cataracts
• Striae (stretch marks)
• Muscle atrophy

Question 5

The hypothalamic-pituitary-adrenal axis

Answer 5

Question 6

The cyclophilin binding drugs

Answer 6

• Cyclosproine & Tacrolimus: Bind NF-AT
• Sirolimus (Rapamycin) & Everolimus: Bind mTOR
• Both groups serve to impede T cell growth, activation, and mediator production

Question 7

When do we use cyclophilin binding drugs?

Answer 7

• Most importantly, FOR TRANSPLANTS to prevent rejection
• Also, to treat T cell-mediated diseases: Psoriasis, RA, Crohn’s, atopic dermatitis

Question 8

Cyclosporine A mechansitic diagram

Answer 8

Question 9

Complications and toxicities of cyclosporine

Answer 9

• Infection (obviously)
• Cancer (obviously)
• Hypertension
• Renal toxicity
• Hepatic toxicity
• Tremor

Question 10

Tacrolimus (aka FK506) mechanistic diagram

Answer 10

Question 11

mTOR

Answer 11

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

Question 12

TCR and IL-2R pathways

Answer 12

Question 13

Immunosuppressive antimetabolites

Answer 13

• Inhibit cell replication and thus affect immune system because it has the most rapidly dividing natural human cells
• Methotrexate
• Mycophenylate
• Azathioprine

Question 14

Methotrexate

Answer 14

• First line therapy for RA
• Dose dependent liver fibrosis is a toxicity
• Incompatible with pregnancy
• An antifolate

Question 15

Azathioprine

Answer 15

• Pro-drug which is converted into 6-mercaptopurine then into thioinosinic acid once inside of cell
• Thioinosinic acid inhibits DNA synthesis

Question 16

Mycophenylate

Answer 16

• Converted into mycophenylic acid
• Inhibits inosine monophosphate dehydrogenase, an ezyme involved in nucleotide biosynthesis
• Fairly selective action at inhibiting T and B cell proliferation

Question 17

alemtuzumab

Answer 17

Anti-CD52

Depletes both T and B cells

Question 18

Main concern with anti-TNFs

Answer 18

Infection! Many possible infections (viral, bacterial, fungal, etc etc)

But not so much cancer

Question 19

Anti-cytokine antibodies associated with infection risk

Answer 19

• TNFa
• IL-2

Question 20

Anti-cytokine antibodies associated with relatively normal risk of infection

Answer 20

• IL-6
• IL-17
• IL-23
• IL-4

Question 21

Anti-Th17-cytokines

Answer 21

• Ustekinumab - anti-IL-23R
• secukinumab, ixekizumab - anti-IL-17A
• brodalumab - anti-IL-17R

Question 22

Major cytokine-depleting antibody diagram

Answer 22

Question 23

At what stages are B cells CD20⁺?

Answer 23

Question 24

Antithymocyte globulin

Answer 24

• 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

Question 25

Antibiotics with immunosuppressive effects

Answer 25

* Low dose doxycycline * tetracycline * minocycline

Question 26

Antimalarials with immunosuppressive effects

Answer 26

* Hydroxychloroquine * Chloroquine * Quinacrine

Question 27

Jak/STAT inhibitors

Answer 27

Question 28

Progressive multifocal leukoencephalopathy (PML)

Answer 28

* **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)**

Question 29

What do you need to screen for before immunosuppressing someone?

Answer 29

* **Watch patients carefully! Report fevers, chills, muscle aches promptly** * Latent TB * Hepatitis B and C * HSV * VZV * JCV * Polyomavirus * Toxoplasma * Pneumocystis * Candidiasis

Question 30

HAART

Answer 30

* Highly active antiretroviral therapy

Question 31

Cancers associated with T cell immunosuppression

Answer 31

* 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

Question 32

Answer 32

Oral Kaposi's sarcoma

Question 33

Best treatment for Kaposi's sarcoma

Answer 33

Reduction of dosage of immunosuppression

Question 34

Best treatment for immunosuppression-associated mucosal squamous cell carcinomas

Answer 34

excision, radiation, chemo

Question 35

Answer 35

Merkel Cell Carcinoma

Question 36

Potential infectious causes of lymphoma

Answer 36

* EBV HIV * Human T cell leukemia virus-1 (HTLV-1) * Hepatitis C * HHV8 * *H. pylori*

Question 37

Leading cause of death in solid organ transplant patients

Answer 37

Immunosuppression-induced squamous cell carcinoma of the skin

Question 38

Risk of SSC in transplant patients is associated with

Answer 38

* Sun exposure * Depth of T cell immunosuppression * Which T cell immunosuppressant is used (highest risk is with cyclosporine, lowest is with mTOR inhibitors)

Question 39

Managing risks of SCC for transplant patients

Answer 39

* Strict sun protection and dermatology followups * Use minimum possible level of immunosuppression * Switch to mTOR inhibitors if possible and well tolerated

Question 40

\_\_ + __ = squamous cell carcinoma

Answer 40

**sun exposure** + **cyclosporine** = squamous cell carcinoma

Question 41

People with HIV have too ___ T cell immunity

Answer 41

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**