Lecture 33 - Immunopharmacology

Question 1

immunosuppressive drugs are used for three main reasons

Answer 1

1) suppression of rejection of transplanted organs and tissues
2) suppression of ‘Graft vs. Host’ Disease (GVHD)
3) autoimmune diseases (ex: lupus, rheumatoid arthritis, psoriasis, ulcerative colitis)

Question 2

what is graft vs. host disease (GVHD)?

Answer 2

immunocompetent cells in the donor graft that mount an immune response against the host

Question 3

an autoimmune disease is driven by the inappropriate response of the _______ towards healthy parts of the body

Answer 3

adaptive immune system

Question 4

there is a lot of overlap between immunosuppressants and:

Answer 4

cancer chemotherapeutic drugs

Question 5

autoimmune disease primarily affecting the joints

Answer 5

rheumatoid arthritis

Question 6

a multi-organ autoimmune disease with a characteristic rash (particularly on the cheeks)

Answer 6

lupus

Question 7

what are the two key branches of the immune system?

Answer 7

adaptive and innate

Question 8

what are the two key phases of the adaptive immune response?

Answer 8

the induction phase and the effector phase

Question 9

• recognition and presentation of foreign antigen by an antigen presenting cell (APC)
• activation and proliferation of naive T helper cells (Th0) into Th1 and Th2 cells
  these are both characteristics of:

Answer 9

the induction phase of the adaptive immune response

Question 10

• cell mediated T cell responses derived from Th1 cells
• antibody mediated responses from B cells derived from Th2 cells
• both processes lead to immune cells “killing” infected or foreign cells
  these are all characteristics of:

Answer 10

the effector phase of the adaptive immune response

Question 11

what are the five key targets of immunosuppressant drugs?

Answer 11

• inhibition of IL-2 production/action
• inhibition of cytokine gene expression (glucocorticoids)
• cytotoxicity
• inhibition of nucleic acid synthesis
• blockage of various T cell surfaces

Question 12

activation of Th0 cells and clonal expansion of T cells requires:

Answer 12

the cytokine IL-2 (produced by proliferating T cells)

Question 13

IL-2 production is controlled by intracellular signalling cascades, including:

Answer 13

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

Question 14

list two examples of calcineurin inhibitors

Answer 14

cyclosporine and tacrolimus

Question 15

activation of the T cell receptor generates a Ca++ signal leading to ____ and ____

Answer 15

activation of calcineurin, dephosphorylation of NFAT

Question 16

what does dephosphorylated NFAT do?

Answer 16

migrates to the nucleus, leading to expression of IL-2 that is required for activation and proliferation of T cells

Question 17

what do calcineurin inhibitors do?

Answer 17

bind to their targets and suppress calcineurin-IL2 gene transcription

Question 18

what is the molecular target of cyclosporin?

Answer 18

cyclophillin

Question 19

what is the molecular target of tacrolimus?

Answer 19

FKBP

Question 20

drugs that interfere with the downstream signals of IL-2 receptor activation

Answer 20

proliferation signal inhibitors

Question 21

give an example of a proliferation signal inhibitor

Answer 21

rapamycin (aka sirolimus)

Question 22

what is the molecular target of rapamycin?

Answer 22

FKBP

Question 23

the rapamycin-FKBP complex inhibits a protein called:

Answer 23

mammalian target of rapamycin (mTOR)

Question 24

what is mTOR (mammalian target of rapamycin)?

Answer 24

a major pathway responsible for promoting cell growth and proliferation

Question 25

FKBP is an acronym for:

Answer 25

FK506 binding protein

Question 26

a family of proteins that are 'peptidyl-proline cis-trans isomerases' (protein folding chaperones) that have a variety of endogenous binding partners

Answer 26

FKBP proteins

Question 27

both ____ and ____ are part of the same larger protein family of ____, which help cytokines to fold into the right shape

Answer 27

FKBPs, cyclophilins, immunophilins

Question 28

leads to cross linking of neighbouring DNA bases, interfering with DNA replication

Answer 28

cyclophosphamide (a cytotoxic alkylating agent)

Question 29

cytotoxic agents are most effective in rapidly dividing cells, so these drugs are useful in both ____ and ____

Answer 29

cancer treatment, suppression of rapidly dividing immune cells

Question 30

inhibits synthesis of nucleotides and interferes with cell dividsion when metabolized to the "fradulent" nucleotide 6-mercaptopurine

Answer 30

azathioprine (a cytotoxic agent)

Question 31

6-mercaptopurine inhibits purine nucleotide biosynthesis and metabolism by inhibiting an enzyme called:

Answer 31

phosphoribosyl pyrophosphate amidotransferase (PRPP amidotransferase)

Question 32

what is the rate limiting factor for purine synthesis?

Answer 32

production of inosine monophosphate (IMP)

Question 33

large Y shaped proteins consisting of four polypeptide chains (two identical light chains and two identical heavy chains) that are secreted from B cells in response to an immune reaction

Answer 33

monoclonal antibodies

Question 34

the structure of the antibody can be portioned into two ____ and the ____

Answer 34

antigen binding fragments (Fab), crystalizable fragment (Fc)

Question 35

part of the antibody which determines antigen specificity

Answer 35

antigen binding fragments (Fab)

Question 36

part of the antibody which determines the antibody 'class'

Answer 36

crystalizable fragment (Fc)

Question 37

different classes of crystalizable fragment (Fc) regions are recognized by receptors of different immune cell types, leading to:

Answer 37

different immune responses

Question 38

since antibodies are grown in other animals (ie: mice), how do we prevent them from being broken down by the human immune system?

Answer 38

use 'chimeric' or 'humanized' versions of mouse monoclonal antibodies, which reduces their antigenicity and increases their lifetime in the body

Question 39

involves replacement of conserved regions of the mouse monoclonal antibody with corresponding sequences from human antibodies

Answer 39

'chimeric' or 'humanized' antibodies

Question 40

therapeutic monoclonal antibodies have names that end in:

Answer 40

"mab"

Question 41

a humanized IgG1 that recognizes CD52 found on many immune cells, including T and B cells

Answer 41

alemtuzumab

Question 42

how does alemtuzumab work?

Answer 42

the IgG1 domain is recognized by phagocytic immune cells, the CD52 region binds to B cells, and leads to immune-mediated destruction of otherwise healthy B cells

Question 43

a chimeric mouse-human IgG1 that binds to CD25, part of the IL-2 receptor on activated T cells

Answer 43

basiliximab

Question 44

what does basiliximab do?

Answer 44

causes immunosuppression by blocking IL-2 from binding to activated T cells (acts as an IL-2 'antagonist')