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IHO 1 > Week2 > Flashcards

Week2 Flashcards

1
Q

PEGylation

A

the addition of polyethylene glycol (PEG) moieties significantly increases half-life and “masks” the drug from the host’s immune system→ decreased immunogenicity and antigenicity
o 12 drugs have been approved
o Approved PEG’d drugs: L-asparaginase, PEG-liposome containing doxorubicin, Interferon α, Methoxy polyethylene, glycol epoetin, Pegfilgrastim

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2
Q

ERYTHROPOIETIN

A

MOA:Most important regulator of the proliferation of committed RBC progenitors (interacts with EPO R on red cell progenitors, EPO R is a member of the JAK/STAT superfamily
produced in the kidney, inverse relationship between Hb level and serum EPO level)
- Exception = chronic renal failure when EPO levels are low – kidneys cannot produce the GF

Pharmacokinetics:Produced in response to severe anemia
Relatively short half-life (IV 3-4 x per week)

Therapeutic Uses:- Anemia (secondary to chronic kidney DZ →
nearly all patients will require Fe supplement; some patients may require folate supplement) (due to primary bone marrow disorders and secondary anemias)
- Reduce need for transfusion in high-risk surgical patients
after phlebotomies for autologous transfusion
Fe overload (hemochromatosis)
- M-PEG-epoetin should not be used in patients with anemia due to cancer chemotherapy (clinical trial found increase in deaths)
- Banned by IOC (increased [RBC] may increase O2 delivery to muscles)

Side Effects:Life threatening: thrombosis
Serious
Common: HTN
Rare: faster tumor growth (head and neck ca), allergic rxn (long term SC admin)

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3
Q

FILGRASTIM

G-CSF

A

MOA: - Regulates production of neutrophils within bone marrow & affects neutrophil progenitor prolif, different, and functional activation

  • Also mobilizes hematopoietic SC, increasing their conc. in peripheral blood
  • Led to use of peripheral blood SCs rather than bone marrow SCs for transplantation

Pharmacokinetics:

Therapeutic Uses:- Cancer chemo-induced neutropenia (esp. FILGRASTIM) – esp. during autologous SC transplantation following high-dose chemo, objective is to prevent systemic infection (neutrophils are 1st line of defense against infection)
- Congenital neutropenia, cyclic neutropenia, myelodysplasia, and aplastic anemia

Side Effects:Serious: allergic reations, splenic rupture (rare)

Innoculous: mild/moderate bone pain (F/P better tolerated than S) (common)

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4
Q

INTERLEUKIN 11

A

MOA: + thrombopoietin → increase platelet production

Pharmacokinetics:

Therapeutic Uses: Thrombocytopenia – particularly following chemo, also idiopathic thrombocytopenia

Side Effects: Serious: A fib (common), hypokalemia (rare)
Innocuous: fatigue, HA, dizziness, mild/mod edema, dyspnea (due to fluid in lungs), anemia (due to hemodilution)
NO FEVER

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5
Q

SAGRAMOSTIM

A

MOA: Stimulates myelopoiesis generally, and neutrophils and monocytes specifically

Pharmacokinetics: - Conjugation product of filgrastim with polyethylene glycol, much longer half-life, injected once per chemotherapy cycle (instead of daily for several days)

Therapeutic Uses: - Cancer chemo-induced neutropenia (esp. FILGRASTIM) – esp. during autologous SC transplantation following high-dose chemo, objective is to prevent systemic infection (neutrophils are 1st line of defense against infection)
- Congenital neutropenia, cyclic neutropenia, myelodysplasia, and aplastic anemia

Side Effects: - Cancer chemo-induced neutropenia (esp. FILGRASTIM) – esp. during autologous SC transplantation following high-dose chemo, objective is to prevent systemic infection (neutrophils are 1st line of defense against infection)
- Congenital neutropenia, cyclic neutropenia, myelodysplasia, and aplastic anemia

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6
Q

THROMBOPOIETIN

A

MOA:
Pharmacokinetics:
Therapeutic Uses:
Side Effects:

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7
Q

• Administration: IV

A

long half-life (detectable in serum 3-6 mo after completion of tx)
• Side effects:
o Infusion reactions: immediate response during infusion
• Not unique to antibodies; seen particularly with cancer chemotherapy drugs
• Sx:
• CV: chest pain, hypo-/HTN, tachy/bradycardia, arrhythmia, edema, ischemia/infarction, cardiac arrest
• Resp: cough, dyspnea, nasal congestion, rhinitis, sneezing, wheezing, bronchospasm, edema, cyanosis, acute respiratory distress syndrome
• CNS: HA, dizziness, confusion, loss of consciousness, anxiety, sense of impending doom
• Skin: rash, pruritis, urticaria, flushing, local or diffuse erythema, conjunctival erythema
• Endocrine: rigors, diaphoresis, fever, generalized feeling of warmth
• GI: n/v, metallic taste, diarrhea, abdominal cramping, bloating
• Urinary: incontinence, renal impairment
• Genital: uterine cramping
• Musculoskeletal: arthralgias, myalgias, fatigue
• 2 types (sx are similar for both types, and are typically managed by slowing the infusion and by administration of antihistamines and other procedures common to management of type I hypersensitivity reactions):
• Typical IgE mediated type I hypersensitivity reaction occurs within minutes (10-12 hours maximum)
o Increased severity and quicker response with repeated exposure
• Cytokine release due to Fc region recruitment of immune effector cells (esp. granulocytes that release cytokines, obviously!) – occurs during the first few hours after infusion
o Worse on 1st infusion, often decreases in severity with subsequent exposures

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8
Q

o Cytokine release syndrome

A
  • Observed particularly with anti-T cell antibodies that can directly activate the T cell receptor before triggering destruction of lymphocytes)
  • Can result in a “cytokine storm”, a kind of positive feedback loop where cytokine release recruits more effector cells that release more cytokines, etc.
  • Shaking chills, fever, arthralgia, diarrhea, vomiting, hypotension and respiratory distress
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9
Q

Lim =

A

immune

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10
Q

Les =

Cir =

A 
Les = infectious lesions
Cir = cardiovascular
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11
Q

• Which of the following drugs has the shortest half-life?

A

o Tumor necrosis factor – half-life in minutes, inject it as close to the tumor as you can

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12
Q

o You are planning to treat a patient who has IBD with infliximab. What test should you perform first?

A

• Mantoux test – need to worry about reactivation of virus with immune suppression

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13
Q

o Myeloid Growth Factors

A

filgrastim (G-CSF), pegfilgrastim, sargramostim (GM-CSF)
• Filgramostim: G-M progenitor → neutrophil
• AE: splenic rupture
• Sargramostim: two sites of action – differentiation of common myeloid progenitor and G-M progenitor
• AE: capillary leak syndrome
• AE for both: bone pain (worse with sargramostim because it acts earlier in differentiation process)

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14
Q

o Megakaryocyte Growth Factors

A

interleukin 11, romiplostim
• IL-11: common myeloid progenitor → megakaryocyte
• AE: A fib
o Allergic reaction and general malaise are AE for all cytokines

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15
Q

MHC 1

A

interleukin 11, romiplostim
• IL-11: common myeloid progenitor → megakaryocyte
• AE: A fib
o Allergic reaction and general malaise are AE for all cytokines

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16
Q

to make a lymphoid progenitor cell

A

• Hematopoietic stem cell (bone marrow) + IL-3, IL-7

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17
Q

CTL activation

A

MHC to CD 4/8
ICAM to LFA
B7 to CD28

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18
Q

= general activators of T cells

A

o IL-2 & IL-15

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19
Q

drive T helper cells → Th1

A

IL-12 & IFN-γ

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20
Q

drives T helper cells → Th2

A

IL-4

21
Q

down-regulates Th1 & TGF-β, down-regulates both Th1 & Th2 subtypes

A

o IL-10

22
Q

• FAS

A

T cells expressing FAS ligand bind to FAS protein on a target → induce caspase activation & apoptosis

23
Q

• B cell surface markers

A

every cell has BCR (antibody), signaling molecules (CD79a, CD79b)
o CD40 = molecule that interacts with Tfh to receive signal to mature into plasma cell

24
Q

o X-linked agammaglobulinemia =
o CD40 ligand deficiency =
o Activation-Induced Cytidine Deaminase Deficiency =
o Common Variable Immunodeficiency =

A 
o	X-linked agammaglobulinemia = an absence of B lymphocytes
o	CD40 ligand deficiency = failure of immunoglobulin class switching
o	Activation-Induced Cytidine Deaminase Deficiency = failure of immunoglobulin class switching
o	Common Variable Immunodeficiency = failure to produce antibodies against particular antigens
25
Q

o X-linked severe combined immunodeficiency =
o DiGeorge syndrome =
o Hemophagocytic lymphohistiocytosis =
o IPEX =

A

o X-linked severe combined immunodeficiency = failure to produce mature T lymphocytes
o DiGeorge syndrome = failure of the thymus to develop correctly
o Hemophagocytic lymphohistiocytosis = failure of CD8+ T cells and NK cells to produce and/or release lytic granules
o IPEX = failure of peripheral tolerance due to defective regulatory T cells

26
Q

Omenn Syndrome =

A

Omenn Syndrome = VDJ recombination failure, cannot produce BCRs or TCRs

27
Q

conjoined ABs?

A

A is a dimer, M is a pentamer

28
Q

• Valence

A

refers to the number of antigenic determinants (epitopes) an antibody molecule can theoretically bind
o IgG: 2 – each Fab arm can bind an epitope independently
o Secreted IgA: 4 – 2 antibody molecules linked together & each can bind 2 things
o Secreted IgM: In theory 10, but puckering event causes it to max out at 5 (Fab portions get squished together)
o Surface IgM – 2 – monomer with 2 Fab portions
o Fab – 1
o F(ab’)2 – 2
o VL or VH: 0 – they do not function independently, need the combo of the two to function

29
Q

complement activation

A

C1q binds to to Fcs

30
Q

RAG

A

enzyme responsible for AB class switching

31
Q

TdT

A

enzyme that randomly adds nucleases to create AB diversity

32
Q

• Activation-Induced (Cytidine) Deaminase (AID)

A

) converts random cytosines in CDR gene regions to uracil
o So a C:G pair becomes a uracil: guanine mismatch
o The uracil bases are excised by the repair enzyme uracil-DNA glycosylase
o Error-prone DNA polymerases then fill in the gap, creating mostly single-base substitution mutations
o At the end of cell division, one daughter may be making a different antibody – can be better or worse

33
Q

o EBV gains entry to B cells and establishes infection by:

A
  • Viral envelope proteins gp350/220 bind C3d complement R (aka CD21) → initiates endocytosis
  • Genome circularizes, and immediate early genes, early genes, and late genes are expressed in sequence
  • The circular EBV genome has multiple promoters → different patterns of gene expression occur during lytic and latent infection
  • Viral particle then bud through cellular membranes to make infectious particles
34
Q

LMP-1

A

o EBV oncogene LMP-1 functions as a constitutively active CD40
• CD40 is normally responsible for CD4+ T-cell dependent activation of B cells
• Get the effect of CD40 without the CD40 ligand having to be there

35
Q

LMP-2

A

o EBV oncogene LMP-2 functions as a constitutively active B cell receptor
• The BCR is normally responsible for antigen dependent B cell activation
• LMP-2 acts as constitutively active BCR, promotes MAPK activation & transcription of fos/jun regulated genes

36
Q

EBNA3C

A

o EBV oncogene EBNA3C functions to bind and activate cyclin D1 complexes (oncogene), resulting in:
• Hyperphosphorylation of retinoblastoma protein (Rb, tumor suppressor)→
• De-repression (activation) of E2F family transcription factors→
• Expression of genes that control DNA replication→
• Cell cycle progression

37
Q

Downey cells

A

• Appearance of atypical lymphocytes or Downey cells in a blood smear is diagnostic for EBV

38
Q

• X-Linked Lymphoproliferative Disease (aka Duncan Disease)

A

o Clinical presentation:
• Fulminant infectious mononucleosis (FIM) = much more severe, rapid in presentation, increased mortality
• Median age 3 yo; average survival after FIM is 1-2 months
• Patients who survive FIM develop lymphoproliferative disorders and dysgammaglobulinemias
• X-linked recessive inheritance
o Molecular basis: mutation that results in a non-functional SAP protein
• SAP contains an SH2 domain that binds phosphorylated tyrosines on SLAM (aka CD150)
• SAP acts as an adapter protein that recruits kinases to the immunological synapse
• SAP depletion → deficiency of IL-4 production by T cells
• IL-4 normally signals CD4H2 differentiation and regulates B cell class switching
o SAP controls apoptotic cell death of activated T cells
• In XLP, SAP is absent, and the immune response has ‘no brakes’
• Impaired AICD (activation induced cell death)

39
Q

• Pernicious Anemia Pearls

A

o Associated with vitiligo and autoimmune disorders
o By definition is slow in onset
o More than just anemia – neuro symptoms too (peripheral neuropathy)
o When in doubt, send for MMA (methylmelonic acid) – builds up if not enough B12

40
Q

• AIHA Pearls

A

o Thorough history that focuses on other autoimmune conditions (RA, SLE, hyper/hypothyroid, scleroderma), drugs (especially new ones, beta-lactams), and recent transfusions of any blood product
o AIHA is associated with lymphoid malignancies (esp CLL) and may precede the lymphoma diagnosis
o Prolonged high dose steroids will lead to Cushing syndrome and comes with increased risk of PJP
o Always give folate supplements with hemolytic anemias
o These patients present problems with transfusions

41
Q

• Nucleated RBC Pearls

A

o Should not be overlooked
o Present in any “overcrowding” disorder of the bone marrow
o Usually present when reticulocyte count is high

42
Q

CD59

A

on host cells, won’t let C9 bind → inhibits MAC

43
Q

• CR1

A

on host cells, decay acceleration of C3bBb, C4b2a AND cofactor for cleavage of C3b, C4b
o Major ligands C3b, C4b
o Monocytes, macrophages, PMN, Eosinophil, RBC, B and T cells
o Transport of immune complexes by RBC
o Promotes immune adherence (binding of opsonized microbes to primate RBCs)
o Promotes phagocytosis in cooperation with Fc receptors
o Blocks formation of C3 convertase

44
Q

• CD46

A

on host cells, cofactor for cleavage of C3b, C4b

45
Q

• DAF (CD55)

A

decay acceleration factor of C3bBb, C4b2a

46
Q

• C1 Inhibitor Deficiency

A

o HAE (hereditary angioedema)
o Recurrent episodes of localized edema in skin, GI tract, or larynx
o C1 inhibitor
• Inhibits C1 esterase (cleaves C4 and cleaves C2)
• Also inhibits MASP, kallikrein, plasmin, Factor XIa and Factor XIIa → affects kinin and coag factors as well
o Uncontrolled complement activation leads to consumption of C4 and C2.
• Possibility of immune complex disease as well
o Prevalence, 2-10:100,000
o Treatment
• Anabolic steroids to increase synthesis of C1 Inhibitor
• Purified C1 Inhibitor
• Kallikrein inhibitors and B2 receptor inhibitors
• Evidence for excess kinin formation responsible for the episodes of edema

47
Q

• Deficiency in DAF (CD55) and CD59

A

o Increased susceptibility of erythrocytes to MAC-mediated lysis
o Complement-mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH)
o Defect in a post-translational modification of the peptide anchors that bind the proteins to the cell membrane → affects both CD55 and CD59
• CD55 – decay accelerating factor
• CD59 – prevents C9 from working
o Recent studies suggest that treatment with an antibody to C5 (eculizumab) reduces hemolysis
• AE: increase in Neisseria infections

48
Q

• CR2 (CD21)

A

o Major ligands C3d, C3dg, iC3b
o B cells, activated T cells, epithelial cells
o CR2 forms an additional signal with antibody to augment stimulation of the B cell to increase the humoral immune response (CR2/CD19/CD81 – secondary signaling).
o CR2 has high affinity for an envelope protein of Epstein Barr virus, allowing the virus to enter the B cell.

IHO 1 (7 decks)

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