Immunomodulatory, Anti-inflammatory and DMARDs

Question 0

BCG (Immucyst)

Answer 0

Live attenuated bacillus calmette-guerin
Interacts with PRR (APCs) > Increased APC activity
Use: bladder cancer
SE: systemic inflammatory response (direct activation of macros) and septic shock (fatal)

Question 1

Immunostimulant Overview

Answer 1

use normal agonist of immune system
Lack specificity
SE: systemic inflammatory reaction, flu-like symptoms
Applications: vaccination response (adjuvant), chronic infectious disease, immunodeficiency disorders

Question 2

IL-2 (Aldesleukin, Proleukin)

Answer 2

Lacks specificity, Increased proliferation of activated T cells > IFN-gamma production and increased Tc activity
Use: metastatic melanoma and renal cell carcinoma
SE: capillary leak syndrome, hypotension, reduced organ perfusion (fetal)

Question 3

IFN-gamma (Actimmune)

Answer 3

Stimulates cell mediated cytotoxic immune response

Use: Treat severe recurrent infections

Question 4

Immunosuppressant Overview

Answer 4

All have SE: increased risk of infection, cancer with chronic use (PTLD)
Drug in class often combined together with differing SEs

Question 5

Calcineurin inhibitor SE

Answer 5

nephrotoxicity

Question 6

glucocorticosteroids SEs

Answer 6

metabolic effects of hypertension and diabetes

Question 7

Anti-metabolites, sirolimus

Answer 7

myelosuppression and anemia

Question 8

Cyclophosphamide (Cytoxan)

Answer 8

Alkylating agent (bischolorethylamine)
Action: crosslinking DNA/killing prol. cells > prevent clonal expansion + healthy cells
Uses: auto-immune diseases, bone marrow transplant
SE: myelosuppression, nausea, vomiting, infertility

Question 9

Azathioprine (Imuran)

Answer 9

Metabolized to anti-metabolites 6-MP and 6-TG (purine antagonists)
DNA damage and inhibit purine synthesis
Inactivated by xanthine oxidase
Uses: renal and tissue trasplantation, autoimmune disorders (lupus,RA)
SE: myelosuppression, nausea and vomiting

Question 10

Mycophenolate mofetil (Cell-Cept)

Answer 10

Hydrolyzed into mycophenolic acid > inhibits inosine monophosphate dehydrogenase > prevent purine synthesis
Use: solid organ transplant, auto-immune diseases
SE: myelosuppression, nausea, vomiting

Question 11

methotrexate

Answer 11

Antimetabolite > inhibits dihydrofolate reducatse (DHFR) > prevent thymidine + purine nucleotide synthesis
uses: Main drug for rheumatoid arthritis, auto-immune diseases
SE: nausea, mucosal ulcers, modest hepatotoxicity, myelosuppression

Question 12

leflunomide

Answer 12

metabolized to A77-1726 > inhibits dihydroorotate dehydrogenase > decreased pyrimidine synthesis
19 day half-life + enterohepatic recirculation
Use: rheumatoid arthritis, auto-immune
SE: diarrhea, modest hepatotoxicity, myelosuppression

Question 13

Glucocorticosteroids Overview

Answer 13

Naturally synthesized in adrenal cortex, anti-infla+immunosuppressive
Induce transcription > annexins > inhibit PLA2 + lipid mediator synthes
Repress transc > IL-2 + IFN-g > reduce Th resp, B cell Ab prod, cyto
Cyclooxygenase, NO synthase, PLA2 > reduce mediator release
IL-8 > reduced recruitment of leukocytes (decreased prostaglandins + leukotrienes)

Question 14

Prednisone

Answer 14

Glucocorticoid-Immunosuppressive: first line immunosuppresant for solid organ + hematopoietic stem cell transplant
Manage autoimmune, asthma, allergic rections, systemic inflammation
SE: more than 2 weeks of daily use > Cushing’s syndrome, glucose intolerance, ocular disturbance, osteoprosis, hypertens, psych, GI
(Can combine with anti-metabolites)

Question 15

Calcineurin

Answer 15

calcium dependent phosphatase that dephosphorylates NF-AT > Active NF-AT > drive transcriptoin > IL-2,3,4, FasL, IFN-g, GM-CSF

Activated by TCR > PTKs > PLC > IP3 > increased [Ca2+]

Question 16

Cyclosporine

Answer 16

Usually combined with other immuno-suppressants/agents
Binds to the immunofilin (proline isomerase) cyclphilin > binds to calcineurin > prvents phosphatase activity = no NF-AT activation
Use: kidney, liver, cardiac transplants, autoimmune disorders (RA), IBD
SE: *nephrotoxicity, hypertension, hyperglycemia, liver dys

Question 17

Tacrolimus (FK506)

Answer 17

Binds to FKBP12 > binds to calcineurin > prevents NF-AT activation
10X more potent than cyclosporine
Use: Kidney, liver, cardiac transplant, autoimmune (RA)
SE: nephrotoxicity, hypertension, hyperglycemia, liver dys

Question 18

Sirolimus (rapamycin, Rapamune)

Answer 18

Binds to FKBP12 to prevent mTOR kinase activity > prevent IL-2 activated phosphorylation
Uses: preserve solid organ transplants, steroid-resistant graft vs host disease in hematopoietic stem cell transplants
SE: myelosuppression (potently), hyperlipidemia, hypertension, edema, hepatotoxicity
Antagonizes with tacrolimus (FKB12) but synergize with cyclosporine

Question 19

Antibody Overview

Answer 19

All require parenteral administration but have long half-lives = weekly-monthly doeses
Uses: neutralize/opsonize antigens, passive immunity, target specific Ag, immunosuppresoin

Question 20

Rh(D) immune globulin (BayRho-D, WinRho SDF)

Answer 20

human IgG with high titer of Rh(D) Abs > prevents maternal immune response to fetal Rh antigen
Via: opsonization + clearance of D antigens, inhibit activation of maternal naive Rh reactive B cells

Question 21

Belatocept (Nulojix)

Answer 21

fusion protein that binds to high affinity B7 ligand (CTLA4 mimic, normally found on T cell) with IgG Fc domain > prevents B7 (APC) and CD28 (T cell) interation > anergy of T cell if binds to Ag without costimulation > death
SE: Anemia, neutropenia, peripheral adema, increased infection/cancer
Similiar to calcineurin inhibitors in preventing transplant rejection

Question 22

Anti-T cell globulin (ATG)

Answer 22

purified IgG (polyclonal animal Ab) against TCR > opsonization of T cells > T cell depletoin (more than a year)
SE: Serum sickness, anaphylaxis (repeat usage), cytokine release syndrome (fever, chills, headache, nausea, can be reduced via acetaminophen + antihistamine prior to admin)

Question 23

CD52

Answer 23

Surface protein on T and B cells, monocytes, macrophages, NK cells

Question 24

Alemtuzumab (Campath)

Answer 24

Humanized anti-CD52 Ab > depletes broad variety of cells (B, T, Macro, NK (innate + adaptive cells)) > prolonged depletion of cells (1 year)
SE: myelosuppression, flu-like symptoms

Question 25

Basiliximab (Simulect)

Answer 25

Humanized anti-IL-2 Ab > blocks and opsonizes IL-2 receptor (CD25) on ACTIVATED T cells > Depletes only Ag activated > less robust immuno suppression
SE: Well tolerated
Reduced risk of infection than normal immunosuppressants, good for patients with low-to-moderate risk of rejection

Question 26

Disease-modifying antirheumatic drugs (DMARDs)

Answer 26

Target the cytokines that promote/amplify the inflammation response = IL-l, IL-6 + TNF-alpha

Question 27

Infliximab (Remicade)

Answer 27

DMARD: humanized Ab to TNF-alpha > binds > prevents interaction with receptor + reduce systemic/local concentrations
Uses: Rheumatoid arthritis (in combo with methotrexate), Crohn’s disease (in combo with azathioprine)
SE: increased frequency of infections (upper resp, urinary)

Question 28

Other anti-TNFa agents than infliximab

Answer 28

Adalimumb (Humira): human Ab
Etanercept (Enbrel): fusion protein
Same uses/SE
All DMARD

Question 29

Anakinra (Kineret)

Answer 29

DMARD: Competitive IL-1 receptor antagonsist (IL-1a analog)
Short half-life requires daily injections
Use: Rheumatoid arthritis
SE: susceptibility to infection

Question 30

Tofacitinib (Xeljanz)

Answer 30

general Jak kinase inhibitor (enteral) > inhibits all activity of adaptive cytokines (IL-2, IL-4), inflam cyto (IL-6), used for second line therapy following methotrexate (Rheumatoid arthritis)
SE: current dosage is low but higher dose > immunosuppressoin + normal SE = anemia, neutropenia, myelosuppression, increase risk of infection (Herpes zoster)