Immunopharmacology

Question 1

immunosuppressant applications

Answer 1

1. suppression of rejection of transplanted organs and tissues
2. suppression of graft-vs-host disease: donor lymphocytes reacting against host
3. auto-immune diseases (lupus, arthritis)

Question 2

1. suppression of rejection of transplants

Answer 2

antigens may be recognized as non-self and elicit an immune response that attacks the donor organ

Question 3

2. host-vs-graft disease

Answer 3

if there are immunocompetent cells in the donor graft that mount an immune response against the host
main targeted tissues are liver, skin, mucosa, gut

Question 4

3. auto-immune diseases

Answer 4

rheumatoid arthritis - affect joints
lupus - multi-organ
ulcerative colitis - T-cell infiltration + ulceration in the colon
psoriasis - scaly patches of skin

Question 5

immune response

Answer 5

induction phase
effector phase

Question 6

induction phase

Answer 6

antigen presentation
clonal expansion and maturation

Question 7

antigen presentation

Answer 7

recognition and presentation of foreign antigen:
antigen presenting cells will internalize and break down a foregin, invading body by breaking down its proteins to eventually present those antigens through a receptor system to T helper cells

Question 8

autocrine loop

Answer 8

synthesis of interleukin 2 by T helper cells acts directly back onto its synthesizing cells = positive feedback

Question 9

clonal expansion and maturation

Answer 9

activation and proliferation of naive T helper 0 cells into T helper 1 and 2 cells

Question 10

effector phase

Answer 10

cell-mediated T-cell responses derived from T helper 1 cells (killing infected or foreign cells): T cells will directly attack infected cells; T helper 1 cells will secrete cytokines
antibody-mediated responses derived from T helper 2 cells (activation of B cells): B cells generate antibodies that get recognized by T cells → attached tissue will be killed

Question 11

key drug targets in immune response

Answer 11

1. inhibition of IL-2 production/action
2. inhibition of cytokine gene expression (glucocorticoids)
3. cytotoxicity (killing immune cells or preventing their maturation/expansion)
4. inhibition of nucleic acid synthesis
5. blockage of various T-cell surface receptors to prevent immune activation (e.g. antigen presentation machinery)

Question 12

1. inhibition of IL-2 action

Answer 12

i) autocrine loop where T cells are generating IL-2 which acts on a receptor on the T helper cell to cause differentiation into T helper 0 and divide and proliferate
ii) proliferation and continued differentiation of the T helper 1 cells into generation of cytotoxic T cells and other cells mediating cell-based immunity

Question 13

2. Inhibition of cytokine gene expression

Answer 13

some T helper cells will generate cytokines after generation → glucocorticoids will have a suppressive effect on the production of cytokines from those T helper cells

Question 14

3. cytotoxicity

Answer 14

any stage of cell response where the cell is undergoing cell division - especially where expansion from precursor cells into larger numbers of the subsequent generations of cells occurs → inhibition with drugs that prevent cell division or DNA replication in a non-specific way

Question 15

4. inhibition of nucleic acid synthesis

Answer 15

nucleic acid synthesis is necessary during the replication and division of cells

Question 16

5. blockage of various T-cell surface receptors to prevent immune activation

Answer 16

receptor complex where there is an interface between the antigen presenting cell and the T helper cell → drugs that block it inhibit immune system activation at the earliest stages of the response

Question 17

Immunosuppressive drug classes

Answer 17

calcineurin inhibitors
proliferation inhibitors
alkylating agents
nucleotide analogues

Question 18

T cell expansion signalling pathways

Answer 18

calcineurin-NFAT pathway (nuclear factor of activated T cells)
Jak/STAT pathway

Question 19

Calcineurin-NFAT pathway

Answer 19

antigen presenting cell interfaces with the T cell receptor in early precursor T helper cells
T cell receptor (trans-membrane) gets activated and produces calcium signal that triggers activity of phosphatase calcineurin
calcineurin dephosphorylates NFAT in cytoplasm → migrate into nucleus and influence gene transcription of cytokine IL-2

Question 20

Jak/STAT pathway

Answer 20

IL-2 activates IL-2 receptor → mTOR stimulates downstream signalling to promote translation of IL-2 which leads to T-cell differentiation
positive feedback loop leads to gene transcription of IL-2 and other steps to promote cell growth

mTOR is involved in the growth + division of cells

Question 21

calcineurin inhibitors

Answer 21

cyclosporin: binds to cyclophilin to form a complex that inhibits calcineurin
tacrolimus: binds to FKBP to form a complex that inhibits calcineurin
by suppressing calcineurin’s phosphatase activity, the drugs suppress pathway that leads to IL-2 gene transcription = inhibit T cell maturation and proliferation

Question 22

proliferation signal inhibitors

Answer 22

act on Jak/STAT pathway
rapamycin: binds to FKBP - complex inhibits mTOR protein complex = inhibitory effect on cell division and growth

Question 23

Alkylating agents

Answer 23

cyclophosphamide: generates intra-strand cross linking by methylating bases in DNA chain → mutations, interfere with replication
most effective in rapidly dividing cells

Question 24

Nucleotide analogues

Answer 24

Azathioprine: metabolized into 6-mercaptopurine (fraudulent nucleotide) - inhibits synthesis of nucleotides + intereres with cell division
similar structure to guanine → inhibitor of endogenous bases

Question 24

Antibody-based therapies

Answer 24

monoclonal antibodies
humanization/chimerization

Question 25

antibody structure

Answer 25

Fab region: two light chains bound to two heavy chains by disulfide bond - determines antigen specificity
Fc region: determines antibody class (conserved region - tail has specific sequence recognized by receptors on different cell types → different immune responses)

Question 26

Monoclonal antibodies

Answer 26

antibodies recognize specific antigens expressed in ‘bad’ cells
raised in other animals
can be a problem because our body will recognize them as foreign and degrade them
therapeutic - names end with -mab → -umab, -zumab

Question 27

Humanized/chimerized monoclonal antibodies

Answer 27

modified mouse antibodies designed to evade destruction by human immune system

reduces antigenicity and increases lifetime in the body
mix fab region with components of human antibody
-imab, -ximab

Question 28

Alemtuzumab

Answer 28

humanized IgG1 that recognizes CD52
binds to receptor on T cell surface and causes them to die = direct inhibition of T-cell receptor
IgG1 Fc domain is recognized by phagocytic immune cells

Question 29

Basiliximab

Answer 29

chimeric IgG1 that binds to CD25 (IL-2 receptor) on activated lymphocytes
causes immunosuppression by blocking IL-2 from binding → directly inhibits autocrine activation of IL-2 receptor