Immunopharmacology

Question 1

What are the three applications of Immunosuppressive drugs

Answer 1

1. Rejection: Prevent host from rejecting foreign tissue
2. GVHD: Prevent Graft-Versus-Host Disease, Prevent lymphocytes in foreign tissue from attacking host body
3. Auto-immune: Prevent host rejecting itself

Question 2

Name some auto immune diseases

Answer 2

Lupus, Rheumatoid arthritis, Psoriasis, Ulcerative colitis, Idiopathic Thrombocytopenic purpura

Question 3

What does GVHD affect

Answer 3

Liver, Skin, Mucosa, Gut

Question 4

Rheumatoid arthritis

Answer 4

Auto immune disease affecting primarily the joints

Question 5

Lupus

Answer 5

Multi organ auto-immune disease
Noticeable by rash on cheek
Many tissues are affected

Question 6

Ulcerative colitis

Answer 6

T-cell infiltration and cause ulceration in the colon

Question 7

Psoriasis

Answer 7

Auto-immune disease leading to scaly patches of skin (butterfly rash)

Question 8

What are the phases of adaptive immunity
What are the sub phases

Answer 8

Induction Phase
Antigen-Presentation
Clonal Expansion and Maturation

Effector Phase

Question 9

What happens in the antigen presentation step

Answer 9

Antigen presentation cells internalize foreign cells, will present antigens and activate T helper cells

Question 10

What happens in the clonal expansion and maturation step

Answer 10

T-helper cells differentiate and mature

Question 11

What is the role of Th1

Answer 11

T-helper cells that attack toxic cells

Question 12

What is the role of Th2

Answer 12

T-helper cells that are the precursor to B cells

Question 13

What is the Induction Phase

Answer 13

Recognition and presentation of foreign antigens
Activation and proliferation of naive Th0-cells into Th1 and Th2

Question 14

What is the Effector Phase

Answer 14

Cell-mediated T-cell responses
Th1 activate macrophages that kill infected/foreign cells
Th2 cause antibody-mediated responses leading to the activation of B cells

Question 15

Describe T-cell receptor pathway (Calcineurin)

Answer 15

T-cell receptor is activated
Creates Ca2+ signal
Activates calcineurin (a phosphatase)
NFAT is dephosphorylated by calcineurin
Dephosphorylated NFAT migrates to the nucleus
Expression of IL-2
IL-2 is used to activate and proliferate T-Cells

Question 16

What happens if Calcineurin is inhibited

Answer 16

IL-2 gene transcription is suppressed meaning the activation and proliferation of T-cells is inhibited

Question 17

Cyclosporine

Answer 17

Binds to cyclophilin forming a complex inhibiting calcineurin

Prevents NFAT from being dephosphorylated and prevents NFAT mediated gene transcription of IL-2
Inhibits T-cell maturation and proliferation

Question 18

Tacrolimus

Answer 18

Binds to FKBP and forms a complex to inhibit calcineurin

Prevents NFAT from being dephosphorylated and prevents NFAT mediated gene transcription of IL-2
Inhibits T-cell maturation and proliferation

Question 19

What is the mTOR pathway

Answer 19

mammalian Target of Rapamycin
Responsible for promoting cell growth/division

Question 20

Rapamycin

Answer 20

Binds to FKBP and forms a complex to inhibit mTOR

Suppresses cell responses to IL-2 receptor activation and blocks its downstream signals
Causes less cell growth and division

Question 21

IL-2 receptor

Answer 21

Activation of receptor causes T cell maturation and proliferation

Question 22

What are Cytotoxic Agents

Answer 22

Directly attack DNA to suppress tumour growth

Question 23

What are Proliferation Signal Inhibitors

Answer 23

Inhibits mTOR to interfere with IL-2 pathway
Less T-cell maturation and proliferation

Question 24

What are Calcineurin Inhibitors

Answer 24

Inhibits calcineurin (Phosphatase) to prevent the dephosphorylation of NFAT

Without NFAT there is less expression of IL-2 that is needed for T-cell maturation and proliferation

Question 25

Cyclophosphamide

Answer 25

Interferes with DNA replication by cross linking neighboring bases Useful in rapidly dividing cells Used to treat cancer Used to treat rapidly dividing immune cells

Question 26

Azathioprine

Answer 26

Metabolized to 6-mercaptopurine A fraudulent nucleotide Inhibits synthesis of nucleotides, interferes with cell division, and can prevent DNA replication Effective against rapidly dividing cells during clonal expansion 6-MP can be incorporated into DNA and prevent replication

Question 27

What is an antibody's structure

Answer 27

2 Heavy Chains 2 Light Chains 2 regions Fab region Fc region

Question 28

What is the Fab region of an antibody

Answer 28

Determines antigen specificity, what it can bind and what viruses it can recognize (Antigen-binding)

Question 29

What is the Fc region of an antibody

Answer 29

Determines antibody class (lgA, lgG, lgM) Different classes are recognized by different immune cell types through specific receptors for each class Determines a different immune response

Question 30

Describe the structure of the antibody's Fab region

Answer 30

Variable, creating specificity for different antigens Made up of the light chain with a bit of the heavy chain

Question 31

Describe the structure of the antibody's Fc region

Answer 31

Conserved Made up of only the heavy chain

Question 32

How are antibody-based therapies created

Answer 32

Antibodies are raised in other animals, however, if used as they are they will be rapidly degraded by the immune system before they can have an affect

Question 33

What is humaization/chimerization

Answer 33

Replacement of the conserved region (Fc) of the mouse monoclonal antibody with the corresponding sequence (Fc) from human antibodies. The monoclonal antibody will not be recognized by the immune system Reduces their antigenicity (Ability to induce an effect) Increases their lifetime in the body

Question 34

What are the naming conventions of therapeutic monoclonal antibodies

Answer 34

-umab / -zumab for humanized antibodies -imab / -ximab for chimeric products Murine (mouse) monoclonal antibodies

Question 35

What is the difference between humanization and chimerization

Answer 35

Humanized: Non-human antibody containing protein sequence to make it more human like Chimerized: Antibody containing a conserved region from a human antibody and a variable region from a non-human species

Question 36

Alemtuzumab

Answer 36

Humanized lgG1 that recognizes and binds to CD52 found on many different immune cell types NK cells, complement, and phagocytic immune cells (macrophages, neutrophils, dendritic cells) recognize the lgG1 Fc domain. Leads to cell death by lysis or phagocytosis Effect: Labels cells early in immune response and targets them for destruction Side Effect: Targets both healthy and destructive T and B cells for destruction

Question 37

Basiliximab

Answer 37

Chimeric mouse-human lgG1 that binds to CD25 which is part of the IL-2 receptor (the alpha chain), on activated lymphocytes Interferes with activation of IL-2 receptor IL-2 antagonist that blocks IL-2 from binding to activated lymphocytes Ultimately causes immunosuppression