Immunomodulation

Question 1

Describe immunomodulation.

Answer 1

use of agents to improve/suppress the IR
1. Immunosuppression
-nonspecific
-selective
2. Immunopotentiation
-stim IS

Question 2

Describe nonspecific immunosuppresion.

Answer 2

1. Radiation
2. Corticosteroids
3. Cytotoxic drugs
   >Alkylating agents = cyclophosphamide
   >Folic acid antagonists = methotrexate
   >DNA synthesis inhibitors = azatiophrine

Question 3

Describe nonspecific immunosuppression - radiation.

Answer 3

-prevents cell division
-DNA damage
>cell cycle arrest (G1/S checkpoint)

Question 4

Describe nonspecific immunosuppression - corticosteroids.

Answer 4

-stim synthesis of IkBa (inhibitor of NF-kB)
-blocks cytokine synthesis & T cell responses
-anti inflammatory & immunosuppressive

Question 5

Describe nonspecific immunosuppression - cytotoxic drugs (alkylating agents = cyclophosphamide).

Answer 5

-cross link DNA preventing cell division
-cyclophosphamide is toxic for resting & dividing cells (esp for dividing immunocompetent cells)
-impaired B & T cell resp
-risk of bone marrow suppression
>leukopenia w predisposition to infection
>thrombocytopenia, anemia

Question 6

Describe nonspecific immunosuppression - cytotoxic drugs (folic acid antagonists = methotrexate).

Answer 6

-blocks prod of tetrahydrofolate needed for thymidine & purine nucleotides syn
-treatment of rheumatoid arthritis
-chemotherapy against cancer

Question 7

Describe nonspecific immunosuppression - cytotoxic drugs (DNA syn inhibitors = azatiophrine).

Answer 7

-suppress lymphocyte activation & mitosis
-inhibit DNA & RNA syn
-anti inflam
-toxic effects:
>bone marrow suppression (leukocytes only)
>acute pancreatitis
>gastroenteritis

Question 8

Describe selective immunosuppresion.

Answer 8

1. Calcineurin inhibitors
   >cyclosporine
   >tacrolimus
2. Rapamycin (sirolimus)
3. JAK (Janus kinase) inhibitors

Question 9

Describe selective immunosuppression calcineurin inhibitors - cyclosporine.

Answer 9

-forms complex w cyclophilin & blocks calcineurin
-inhibits signal transduction & blocks production of IL2 & IFNy by T cells
-block Th1 resp
-indirection suppressive effects on:
>macrophages, B cells, NK cells, neutrophils, eosinophils, mast cells

Question 10

Describe selective immunosuppression calcineurin inhibitors - tacrolimus.

Answer 10

-forms complex w immunophilin & blocks calcineurin
-inhibits IL2, IL3, IL4, IL5, IFNy & TFNFa
-more potent than cyclosporine in inhibiting T & B cell resp

Question 11

Describe selective immunosuppression rapamycin (sirolimus).

Answer 11

-forms complex w immunophilin & blocks mTOR (mechanistic target of rapamycin)
>mTOR = regulate T cell activation by integrating the signals received from antigens, costim receptors, & cytokines & directing the T cell differentiation into effector, regulatory, or memory pathways

Question 12

Describe selective immunosuppression JAK inhibitors.

Answer 12

1. JAK-STAT signaling
   -immunity
   -cell division
   -cell death
2. JAK inhibitors = oclacitnib (Apoquel)
   -inhibits JAK1
   -treatment for atopic dermatitis
   -JAK1 dependent cytokines:
   >IL2, IL4, IL6, IL13, IL31

Question 13

Describe the stimulation of the IS.

Answer 13

1. Bacterial products
   -bacille calmette-guerin
   -source of PAMPs, TLR stim, cytokine syn
2. Complex carbohydrates
   -zymosan, glucans, lentinans, aminated polyglucose
   -activate macrophages
3. Vitamins
   -A, D, & E
4. Cytokines
   -IL2, recombinant INFs (a & y)

Question 14

Describe trained immunity.

Answer 14

-BCG vaccine induces enhanced prod of pro-inflam cytokines like IL1B, TNFa, & IL6
-effects accompanied by transcriptional, epi genetic & metabolic reprogramming of myeloid cells in BCG vaccinated individuals