2.2 Pharm Exam 5: Immunopharmacology

Front 1

5 general principles of Organ Transplantation

Back 1

1. Match compatible blood type & HLA

2. Multi-drug immunosuppressive tx for synergistic effect (allows lower dose/toxicity for each drug w/ higher efficacy)

3. Intensive induction tx, followed by lower-dose maintenance

4. Monitor for rejection, drug toxicity, & infection

5. Reduce/remove drugs that are causing more problems than benefits

Front 2

Induction therapy typically involves a combination of ..........

Back 2

immunosuppressive + biologics (monoclonal or polyclonal antilymphocytic Abs)

Front 3

Induction therapy w/ biologic agents is used to delay the use of nephrotoxic calcineurin inhibitors & to intesify immunosuppresson in high risk pts?

What pts are at high risk of rejection?

Back 3

repeat transplant pts

broadly presensitized pts

African-American pts

pediatric pts

Front 4

Biologics may be either polyclonal or monoclonal. Which are safer?

Back 4

Monoclonal: anti-CD3 mAb

(muromonab-CD3 or OKTC), anti-IL-2R mAbs (daclizumab, basiliximab)

*monoclonals are made from a single source & have more specificity & less variability in efficacy/toxicity

Front 5

How are Monoclonal Ab's made?

Back 5

Hybridoma technology:

fuse tumor myeloma cell w/ splenic b cell-->

grow in culture media where only fused cells can grow

Front 6

_________ is used as induction therapy tx of acute organ transplant rejection

MOA: binds E chain of CD3 on T cell receptor complex-->

internalization of T cell receptor-->

rapid depletion of T cells

&

prevents remaining T cells from recognizing Ag-->

prevents T cell from producing IL-2-->

reduced T cell function

Back 6

muromonab-CD3

*made using mice

Front 7

Why are repeated txs w/ muromonab-CD3 (or other mouse monoclonal Abs) CONTRAINDICATED?

Back 7

repeat use-->

immunization of pt against mouse determinants of Ab-->

neutralizes immunosuppressive effects

Front 8

Glucocorticoids are administered before injection of muromonab-CD3 to prevent the release of cytokines & reduce first dose rxns.

*also require resuscitation facility

What SEs does muromonab-CD3 toxicity cause?

Back 8

-"cytokine release syndrome" = fever, chills, N/V, malaise, diarrhea, myalgia--> ARDS, PE, CV collapse (rare, but fatal) (reduced w/ glucocorticoids & successive doses)

-Anaphylaxis

-"Rebound" organ rejection (when stopped)

-Inc infection & cancer

Front 9

What cytokines are responsible for "cytokine release syndrome" (30 mins after injection)?

(cytokines are released by activated T cells or monocytes)

Back 9

TNF-alpha

IL-2 & IL-6

IFN-gamma

Front 10

Why are polyclonal Ab's not as safe?

Back 10

polyclonals:

lymphocyte immune globulin (ATGAM)

antithymocyte globulin/ ATG (THYMOGLOBULIN)

are made from multiple sources & efficacy & toxicity varies btwn batches, HOWEVER they have a broader target & are more potent

Front 11

How are polyclonal Ab's made?

Back 11

repeated injections of human thymocytes (ATG) or lymphocytes (antilymphocyte globulin, ALG) into animals-->

then purifying the serum immunoglobulin fraction

Front 12

_____________ can be used in combo w/ monoclonal Abs for induction therapy, initial rejection, & steroid resistant rejection

MOA: act on small, long-lived lymphocytes-->

deplete T cells ("thymus dependent" lymphocytes)

Back 12

ALG (Antilymphocyte Abs)

*obtained from immunization of large animals (horses, etc)

Front 13

What are the SEs of ALG toxicity?

Back 13

Pain & redness around the injection site

Anaphylaxis & serum sickness (type 3 HSN)

Histocytic lymphomas

Inc risk of cancer

*depletion of T cells can also impair DTH & cellular immunity

Front 14

________ is used for induction therapy in acute renal transplant rejection (w/ immunosuppressives) & acute rejection of other organs, & to reduce severity of GVHD after BMT

MOA: deplete circulating lymphocytes by direct cytotoxicity (BOTH complement & cell-mediated) AND block lymphocyte fxn by binding cell surface molecules

Back 14

ATG (antithymocyte Abs)

*purified gamma globulin obtained from immunization of rabbits

Front 15

ATG contains various cytotoxic Abs that bind to what targets?

Back 15

CD2

CD3, CD4, CD8 (T cells)

CD8, CD 11a, CD18

CD 25, CD44, CD45

HLA class I & class II on T cells

Front 16

What are the SEs of ATG toxicity?

Back 16

fever, chills, & hypotension

Serum sickness (type 3 HSN) & glomerulonephritis

Anaphylaxis (rare)

Leukopenia, thrombocytopenia

Inc risk of infection & cancer

Front 17

What are the 2 types of biologics used for induction therapy?

Back 17

1. depeleting agents- destroy host immune cells (lymphocyte immune globulin, antithymocyte globulin, & muromonab-CD3 mAb)

2. immune modulators- prevent action of immune cells (muromonab-CD3mAb, anti-IL-2R mAb (bind to alpha chain of IL-2R & block IL-2 from activating T cells)

Front 18

T/F

muromonab-CD3 mAb is BOTH a depleting agent & an immune modulator

Back 18

TRUE

Front 19

What is the difference btwn chimeric & humanized monoclonal Abs?

Back 19

chimeric = entire variable domains are from mouse, rest of Ab is human

humanized = CDR (complementary determining region) of the variable domains is human, rest of variable domain is mouse

(may be a mix^)

*CDR determines Ag binding specificity for Fab (Fab is formed by the variable domains of the light & heavy chains, coming together at the N-terminal ends)(constant region of heavy chain = Fc portion, determines isotype & fxn (type of Ig))

Front 20

What is the downfall of chimeric monoclonal Abs?

(humanized have longer half-life & are better)

Back 20

recipients eventually develop Ab's to the mouse variable domains & neutralize them-->

inhibits therapeutic effects

(eventually become resistant to meds*)

Front 21

_______ & ________ are IgG1 monoclonal Abs that bind IL-2 receptor alpha chains on activated lymphocytes--->

block IL-2 from binding

*immune modulators (less SE's than depleters*) used in Induction phase (prophylaxis)

Which is humanized & preffered?

Back 21

Daclizumab (zenapax) & Basiliximab (simulect)

*Daclizumab is humanized & preferred over chimeric basiliximab

Front 22

What drugs are used in combo for Maintenance therapy?

(Induction phase is predominantly biologics = Abs)

Back 22

Calcineurin inhibitor + Glucocorticoid + Mycophenolate mofetil (purine metabolism inhibitor)

(usually cut out glucocorticoids in diabetic pts receiving pancreatic transplants)

Front 23

_____________, is used in maintenance therapy*

MOA: targets downstream pathway of T-cell receptor signalling-->

binds cyclophillin-->

inhibiting calcineurin-->

inhibits NFAT production of IL-2, IL-3, IFN-gamma-->

no T cell proliferation/activation (w/o IL-2)

no B cell or granulocyte activity*

Back 23

Calcineuron inhibitor: Cyclosporine

(normally, Ag binds to T cell receptor-->

IP3 pathway activation-->

intracellular influx of Ca2+-->

activates calcineurin (phosphatase)-->

dephosphorylates NFAT-->

NFAT enters nucleus & binds DNA-->

IL-2, IL-3, etc production-->

T cell proliferation (IL-2)

Front 24

__________ can be used for BOTH solid & BMT transplants

*BUT does NOT work on primed T cells (that have already seen Ag), only on naive cells

*causes severe nephrotoxicity!!

Back 24

Cyclosporine

Front 25

__________, is also a calcineuron inhibitor that is used in maintenance therapy*, of SOLID organ transplant

* Targets downstream pathway of T-cell receptor signalling by binding to BOTH cyclophilin & FKBP--> more POTENT effects, but also more toxic*

What SE's does it cause?

Back 25

Calcineurin inhibitor: Tacrolimus

SE's: (2N, 3H)

Nephrotoxicity*

Neurotoxicity

Hyperglycemia

Hypertension

Hyperkalemia

Front 26

________, is also a calcineurin inhibitor, used in maintenance therapy*, of solid or BMT transplant but it DOES NOT cause nephrotoxicity (less potent)

What SE does it cause?

What is the MOA?

Back 26

Calcineurin inhibitor: Sirolimus (Rapamycin)

SE: myelosuppression (thrombocytopenia)

MOA: Targets downstream pathway of IL-2 receptor signalling-->

binds mTOR on FKBP-->

inhibits mTOR (kinase)-->

prevents T cell proliferation

Front 27

T/F

Although Sirolimus (Rapamycin) is considered a calcineuron inhibitor, it DOES NOT inhibit calcineurin OR inhibit production of IL-2

Back 27

TRUE

Front 28

__________, used in maintenance therapy*

MOA: bound to CBG in circulation-->

dissociate & enter cell-->

bind to INTRACELLULAR receptor (GR)-->

induces conformational change-->

causes GB to dissociate from HSP90 & IP-->

enters nucleus w/ GR (as complex)-->

complex binds GRE (on DNA)-->

gene transcription-->

suppress cytokine (IL-1 & IL-6) production

Back 28

Glucocorticoids (corticosteroids)

*decr cytokine production via neg feedback (low cytokines--> decr endogenous cortisol production)

Front 29

How do corticosteroids downregulate inflammatory responses (anti-inflammatory effects)?

(*inhibit cellular immunity)

Back 29

1. inhibition of inflammatory mediators- downregulation of IL-1 & IL-6, T cells inhibited from making IL-2 & proliferating

2. inhibition of inflammatory cell migration- interfere w/ neutrophil & monocyte activity

3. promotion of lymphocyte apoptosis- via increased IkB--> decr NFKB & activation of endonucleases

Front 30

Glucocorticoid (corticosteroid) uses?

SE: growth retardation in children, hyperglycemia, cataracts, osteopenia, avascular necrosis of bone, inc risk of infection

Back 30

Uses:

-maintenance therapy for BOTH solid organ transplants & BMT

-autoimmune dz (flares)

-asthma (inhalant w/ beta agonist, avoids systemic SEs)

(try to avoid in diabetics if possible*)

Front 31

____________is an antimetabolite used for maintenance therapy* post-solid organ transplant & post-BMT, lupus, & RA

MOA:

Inhibits monophosphate dehydrogenase-->

inhibits purine synthesis-->

Inhibits T & B cell production

What is the active metabolite that this drug is hydrolyzed to?

Back 31

Mycophenolate mofetil

hydrolyzed to mycophenolic acid

Front 32

_________ is a cytotoxic antimetabolite used for kidney transplants* (renally excreted!)

MOA:

converted to 6-mercaptopurine-->

the to 6-thioinosinic acid-->

inhibits inosinic acid-->

Inhibits purine synthesis-->

inhibits DNA replication & lymphocyte proliferation

Back 32

Azathioprine

*used in anything involving immunosuppression of kidney*

Front 33

Azathioprine degradation (via xanthine oxidase & renal excretion is inhibited by _____________

*requires dose lowering of azathioprine

Back 33

Allopurinol

Front 34

_________ is an alkylating agent-->

destroys proliferating lymphoid cells

*used in SLE, MS, Wegener's granulomatosis

*may cause hemorrhagic cystitis!

Back 34

Cyclophosphamide

Front 35

_______ is the DOC* for RA & GVHD (post-BMT)

MOA:
inhibits pyrimidine synthesis (ONLY ONE!)-->

inhibits DNA synthesis-->

prevents lymphocyte proliferation

Back 35

Methotrexate

Front 36

What drugs are used to tx transplant rejection?

Back 36

high dose PULSATILE glucocorticoids

polyclonal antilymphocyte Abs (ALG)

muromonab-CD3 mAbs

(biologics (polyclonal & monoclonal) are the MOST potent agents!!)

Front 37

If rejection is d/t high levels of anti-HLA Abs (anti-alloantigen Abs), what can you do to decrease these?

Back 37

plasmapheresis (remove the Abs)

IVIG (competitive inhibition, IVIG binds Ags)

*can be used in any disorder where pt is creating Abs to something in body (alloantigens or autoantigens (attacked by autoimmune abs)

Front 38

_________ is the DOC for ITP, Autoimmune hemolytic anemia, & Acute Glomerulonephritis (AGN)

Back 38

prednisone (glucocorticoid)

Front 39

Autoreactive tissue disorders (SLE, RA, MS, IBD) are initially tx w/ DMARDs (prednisone, cyclophosphamide, methotrexate, etc), if these fail, what drugs are used?

Back 39

biologics:

Anti-TNF Abs (infliximab, etanercept, adalimumab)

Abatacept (recombinant fusion protein)

Front 40

Methotrexate is the DOC for RA, if sxs remain, what is the next step?

Back 40

add Anti-TNF Abs: Infliximab, etanercept, adalimumab

Front 41

_________, a chimeric IgG1 monoclonal Ab-->

Anti-TNF-alpha

-used for RA & Crohn's disease*

SE: develop ANA (already present in RA) & normal monoclonal Ab SE's

*CI in CHF pts

Back 41

*Infliximiab (remicade)

Front 42

______, dimeric fusion protein w/ human IgG1-->

Anti- TNF-alpha & TNF-beta

-used for RA, polyarticular juvenile RA*, & psoriatic arthritis*

SE: develop anti-dsDNA Abs (seen in SLE), ANA

Back 42

Etanercept (enebrel)

Front 43

_____, human IgG1 monoclonal Ab-->

Anti-TNF-alpha

-used in RA (only)

Back 43

Adalimumab (humira)

Front 44

________ may also be used in pts w/ RA refractive to methotrexate (DMARDs) & is cheaper than Anti TNF-Abs w/ less global SEs

*CI w/ Anti TNF-Abs & w/ Anakinra (IL-IR antagonist, also used for (adult) RA not responding to DMARDs)

Back 44

Abatacept

Front 45

Abatacept is a recombinant fusion protein composed of chimeric CTLA-4 + human IgG Fc

MOA?

Back 45

CTLA-4 on T cells binds to CD80/CD86/B7 on APCs (Abs)-->

prevents costimulatory CD28 on T cells from binding to B7 (TCR recognizes autoimmune Ag presented by MHC on APC, but also requires costimulatory binding to be activated)-->

prevents T cell activation-->

T cell anergy-->

decreases the amount of autoreactive T cells

& CTLA-4 binding to B7 sends inhibitory signals to active T cells-->

down-regulating activity

Front 46

________ is a humanized IgG1 monoclonal Ab that binds to IgE fc region-->

IgE antagonist

*used to tx asthma

Back 46

Omalizumab

(per Krishna)

Front 47

Multiple Sclerosis (MS) is an inflammatory disease of CNS white matter. Auto-Abs to _____ & _____ cause (triad):

mononuclear cell infiltration

demyelination

scarring (gliosis)

*predominantly in females (20-35)

*Type 4 HSN**

Back 47

Auto-Abs (activated T cells) to

myelin basic protein (MBP) &

myelin oligodendrocyte glycoprotein (MOG)

*causes demyelination, sx depend on area affected

Front 48

How is relapsing-remitting MS (85% of cases) tx?

(reduces relapses by 33%)

what is the MOA?

Back 48

IFN-Beta (1a or Ib)

(or w/ Natalizumab, per Krishna)

MOA:

interferes w/ costimulatory molecules (B7/CD28 & CD40/CD40L)-->

reduces T cell activation

deviates response toward TH2-->

dampens TH1 response

interferes w/ T cell adhesion to endothelium-->

prevents migration across BB

Front 49

When relapsing-remitting pts who have been taking IFN-beta begin to show neurological deterioration, it becomes secondary progressive MS.

How is this tx?

(reduces relapses by 67% (better than IFN-Beta)

MOA?

Back 49

Mitoxantrone

MOA:

intercalates DNA-->

inhibits DNA synthesis

Front 50

Immunostimulatory drugs are used to tx?

(immunizations, cytokines, levamisole, thalidomide, BCG)

Back 50

infection

Immunodeficiency

cancer

Front 51

_____________ is used post-surgery for Dukes class C colorectal cancer & to tx Hodgkin's disease

*stimulates immune response by activating macrophages

what SE's does it cause?

Back 51

Levamisole (ergamisol)

(originally anti-parasitic)

SE: agranulocytosis

Front 52

__________ is used in Multiple Myeloma, Erythema nodosum leprosum (leprosy), & skin manifestations of SLE

*Has mixed effects--> inhibits TNF-alpha & neutrophils & inc IL-10 (immunosuppressive), but also Enhances Cell Mediated Immunity

what SE's does it cause?

Back 52

Thalidomide (thalomid)

(originally sleep aid)

SE: teratogenesis, thrombosis (in multiple myeloma pts)

Front 53

Multiple myeloma pts taking thalidomide can be given _________ if they develop thrombosis

Back 53

Warfarin

(Gemcitabine is also an alt. tx for multiple myeloma & lymphoma per Krishna)

Front 54

__________ is used as an adjuvant in bladder cancer

*activates macrophages-->

enhances cell-mediated immunity

Back 54

BCG (Bacille Calmette-Guerin)

*viable strain of bovine Tb (mycobacterium bovis)

Front 55

Without _____________ there is no immune system.

What limits their use?

Back 55

cytokines (IFN, CSF, IL)

SEVERE systemic SEs--> fever, flu-like sx, anorexia, fatigue, malaise (may be enough to kill pt)

Front 56

(G-/GM-)CSF & IL-3 push hematopoetic cells towards ________ lineage

What is G-/ GM-CSF used for?

Back 56

myeloid lineage

GM-CSF used in pre-term neonates, neutropenic pt, & cancer pts receiving chemo

Front 57

_______ pushes hematopoetic cells towards lymphoid lineage

Back 57

IL-7

Front 58

_______ is used to tx hairy cell leukemia, malignant melanoma, kaposi's sarcoma, & Hep B & C

Back 58

IFN-alpha

(IFN-beta used in MS*)

Front 59

_____ is used to tx chronic granulomatous disease

Back 59

IFN-gamma

Front 60

_____ is used to tx METASTATIC renal cell carcinoma

*non-metastatic tx w/ surgery*

Back 60

IL-2

Front 61

___________ immunization involves administration of pre-formed abs from vaccinated individual (artificial) or from mother to fetus (natural)

&

conveys immediate, short lived (humoral immunity) protection against Ag,

BUT, does NOT lead to development of cell mediated immunity

Back 61

Passive Immunization (IVIG & Hyperimmune globulins)

(**Active immunizations (vaccinations) DO induce host immune response & lead to formation of cell-mediated immunity against future infection)

Front 62

When are IVIGs indicated?

(passive immunity, made from pooled plasma, largely IgG, non-specific)

Back 62

XLA, HyperIgM immunodeficiency

risk of exposure to Rabies or Hep B (not-confirmed)

Tetanus infection (or botulism, diptheria)

Front 63

When are Hyperimmune globulins indicated?

(passive immunity, made from high titers of Ag specific Ig's)

Back 63

Hep B infection

Rabies (1 shot + 5 doses of vaccine)

Tetanus infection

Hemolytic Disease of Newborn

VZV, CMV, RSV

Front 64

when is Rho (D) immune globulin indicated?

(hyperimmune globulin)

Back 64

to prevent hemolytic disease of the newborn

give mother @ 28 wks & immediately after delivery (prevent development of anti-Rh IgG)

If Rh (-) mother has hx of pregnancy w/ Rh (+) fetus (Rh + dad)-->

Will develop Anti-Rh IgG-->

Anti-Rh IgG crosses placenta & attacks second Rh (+) child--->

hemolytic disease of newborn

Front 65

________ is indicated in metastatic breast cancer

*binds to tumor expressing human epidermal growth factor receptor (HER-2/neu)-->

blocks ligand binding & down-regulates receptor

Back 65

*Trastuzumab (herceptin)

Front 66

_______ is indicated in refractory cases of non-Hodgkin's lymphoma

*murine-human monoclonal IgG1 (human Fc) Ab-->

binds to CD20 on B cells-->

Ab-dependent cellular cytotoxicity-->

apoptosis of malignant lymphoma cells

(doesn't interfere w/ healthy B cell signalling, bc only CD19 & CD21 are involved)

Back 66

*Rituximab (rituxan)

(can also be used in RA to wipe out B cells, per Krishna)

Front 67

________ is indicated for prophylactic tx of RSV in exposed neonates

*monoclonal Ab-->

binds fusion (f) protein of RSV-->

neutralizes infectivity

Back 67

*Palivizumab (synagis)

Front 68

________ is indicated post cardiac intervention (angioplasty, stent, etc) to prevent complications d/t clot formation

*Fab monoclonal Ab-->

binds to GPIIb/IIIa receptors on activated platelets (glycoprotein 2b/3a antagonist)-->

prevents binding of adhesion molecules to receptor-->

inhibits platelet aggregation

Back 68

*Abciximab (reopro)