Immunosuppression Flashcards
what is innate immunity?
non-specific immunity –> does not require priming
what are 6 components of innate immunity?
- complement
- granulocytes
- monocytes/macrophages
- NK cells
- mast cells
- basophils
what is acquired immunity?
learned immunity –> depends on antigen exposure or priming
what are the 2 types of effector cells for acquired immunity?
- B cells
- T cells
Th1 is responsible for which type of adaptive response?
cell-mediated
What does Th1 produce?
Produce IL-2
how are CTLs activated and what is their activity?
APCs activate CTLs by themselves OR with the help of Th1 (cross-presentation)
IL-2 is produced to induce proliferation
activated CTL can recognize and kill tumour cells
describe T cell activation
multiple ways that T cells interact with APCs to stimulate response
SIGNAL 1: APC presents antigen to TCR
SIGNAL 2: co-stimulatory molecules are expressed
what type of T cell causes a humoral response?
Th2
what is the goal of the immune response?
to discriminate self from non-self
what is immunosuppression?
minimize impact of exaggerated/inappropriate immune response
what are 4 uses of immunosuppressive agents?
- autoimmune disease
- isoimmune disease (Rh hemolytic disease)
- organ transplant
- prevention of cell proliferation (stents)
approx how many ppl in USA suffer from autoimmune disease?
23.5 million ppl in USA
describe Rh hemolytic disease of the newborn
FIRST BABY Rh+ and Rh- mother
- when blood mixes during birth, mother’s immune system will detect Rh as foreign and make antibodies against Rh
SECOND BABY Rh+ and Rh- mother
- mother’s blood has Ab against Rh
- RBC will lyse –> bad for baby
why are there complications with organ transplants?
many possible MHC –> diff combos of HLA
recipient reacts to non-self MHC
what are 3 targets for immunosuppressive drugs? which has the lowest selectivity? which has the highest selectivity?
- cell proliferation (low selectivity)
- T cell function
- Ab approaches: Ag recognition (high selectivity)
describe 2 actions of glucocorticoids
inhibit transcription of pro-inflammatory genes
OR
increase transcription of anti-inflammatory genes
what are 3 pro-inflammatory genes that are inhibited with glucocorticoids?
- IL-1
- IL-2
- IL-6
what are the results of glucocorticoid action? (3)
- reduced inflammation
- reduced immune cell signaling and proliferation
- immunosuppression
Describe innate immune signaling during COVID infection
CYTOKINE STORM
- cytokines and inflammation everywhere
PANOPTISIS
- killing cells in many ways
Describe the use of dexamethasone for hospitalized COVID patients
Different recommendations based on severity of COVID
Dexamethasone may be recommended for COVID patients who require supplemental O2
What is the purpose of cytotoxic drugs?
To kill cells
What are 4 examples of cytotoxic drugs?
- Cyclophosphamide
- Azathioprine
- Mycophenolate Mofetil (MMF)
- Methotrexate
What type of agent is cyclophosphamide?
DNA alkylating agent
(Nitrogen mustard-like drug)
What is cyclophosphamide used for?
Anti-cancer drug and immunosuppressant
What does cyclophosphamide cause?
Covalently binds DNA
- irreversible until NER
- produces INTERSTRAND DNA crosslinks
What is azathioprine metabolized into?
Azathioprine metabolized to 6-mercaptopurine
What does Azathioprine do?
Inhibits purine synthesis —> ultimately blocks DNA/RNA synthesis
What does mycophenolate mofetil (MMF) do?
Inhibits inosine monophosphate dehydrogenase —> blocks DE NOVO purine synthesis
This inhibits T and B cell proliferation
Why does mycophenolate motefil inhibit T and B cell proliferation?
T and B cell proliferation requires de novo purine synthesis and MMF blocks de novo synthesis
which cytotoxic drug is most specific? why?
MYCOPHENOLATE MOFETIL
It is more specific for immune cells
Describe the action of methotrexate
Similar to DHF so it tightly binds DHF reductase and blocks THF production
Therefore, blocks methyl transfer reactions so thymidine is not available
What are the 3 drugs that target T cells?
- Cyclosporine
- Tacrolimus
- Sirolimus
Which 2 drugs are Calcineurin inhibitors?
- Cyclosporine
- Tacrolimus
What type of molecules are cyclosporine and tacrolimus?
Large, complex molecules
what do calcineurin inhibitors do in general?
block calcineurin to inhibit T cell response
what does cyclosporin do?
binds cyclophilin to remove phosphate group from TF to inhibit IL-2 transcription
what does tacrolimus do?
binds FKBP to remove phosphate group from TF to allow IL-2 transcription
what does sirolimus do?
blocks mTOR which is involved in cell cycle for G1 to S phase transition
this inhibits Cdk2 to prevent activated IL-2R from causing its effects –> no T cell proliferation
what is an example of polyclonal Ab?
Anti-thymocyte globulin (ATG)
what does anti-thymocyte globulin do?
rapidly kills peripheral T cells –> prevents initial graft rejection
why are polyclonal Ab less beneficial than monoclonal Ab?
monoclonal Ab are more targeted
what are the 4 types of monoclonal antibodies and their suffixes?
- human (-umab)
- murine (-momab)
- chimeric (-ximab)
- humanized (-zumab)
what is an advantage and disadvantage of using human monoclonal antibodies?
advantage: person won’t reject it
disadvantage: less practical to produce
what is the disadvantage of using murine monoclonal antibodies?
person will reject the mouse antibody
what are chimeric monoclonal antibodies?
some mouse, some human
what is the rejection risk of chimeric monoclonal antibodies?
small rejection risk
what are humanized monoclonal antibodies
all human, just a bit mouse
what is the rejection risk of humanized monoclonal antibodies?
may or may not reject
what type of monoclonal Ab is Muromonab (OKT3)
Murine
what does Muromonab (OKT3) do?
- anti-CD3 –> blocks CD3 on TCR
- induces internalization to block antigen rejection
- reduces CD3+ cells
what was Muromonab (OKT3) used for?
to reverse acute allograft rejection
why is Muromonab (OKT3) no longer on the market?
murine monoclonal antibody –> caused side effect
what is the role of Basiliximab?
binds CD25 (IL-2Ra) to block IL-2 mediated T cell activation
what type of drug is Basiliximab typically used with?
used with calcineurin inhibitors
why is Basiliximab used with calcineurin inhibitors?
prevents acute organ rejection
what type of molecule is Belatacept?
a fusion protein
what does Belatacept do?
binds CD80/86 on APCs to block co-stimulation and prevent T cell activation
what type of monoclonal antibody is Infliximab?
chimeric IgG1 mAb
what is the role of Infliximab?
anti-TNF alpha
why is Infliximab unique?
interacts with immune response, not T cells that mediates the response
what 2 diseases are Infliximab used for?
- Rheumatoid arthritis
- Crohn’s disease
what is the first line of drugs used for autoimmune disease?
STEROIDS –> prednisone, dexamethasone
what is the second line of drugs used for autoimmune disease?
CYTOTOXIC DRUGS –> cyclophosphamide, azathioprine, MMF, methotrexate
what is the third line of drugs used for autoimmune disease?
ANTIBODIES –> Anti-IL-1, Anti-IL-6, Anti-TNF
how to decide which drugs are used for autoimmune diseases?
start with more simple/standard drugs first, if those don’t work then use more complex drugs
what drug is used to prevent Rh hemolytic disease of the newborn?
RhD IgG with a high titer to RhD Ag
what does RhD IgG do?
binds Rh antigen from FIRST BABY so the mother cannot develop anti-Rh antibodies and SECOND BABY does not get Rh hemolytic disease
when is RhD IgG administered?
at 28 weeks gestation and/or within 72h of birth of 1st baby
what is the general approach to organ transplantation therapy?
- select best available ABO blood type-compatible HLA match for organ donation
- give multiple immunosuppressive agents, each with different targets
what is an example regimen for a kidney transplant recipient? (3 drugs)
- tacrolimus
- MMF
- Prednisone
how long do organ transplant recipients have to take immunosuppressive drugs? why?
forever –> always will have foreign proteins present
why is it problematic that immunosuppressive drugs must be taken forever?
some of the drugs can be toxic
why was cyclosporin replaced by tacrolimus?
tacrolimus is less toxic
what drug is used in drug-eluting coronary stents?
sirolimus
what are 2 unwanted effects of immunosuppressive agents?
- increased risk of infections
- increased risk of lymphomas and secondary malignancies
CYCLOPHOSPHAMIDE
like nitrogen mustard
for cancer and immunosuppression
DNA alkylating agent –> covalently binds DNA
Produces interstrand DNA crosslinks
Irreversible until NER
AZATHIOPRINE
becomes 6-mercaptopurine
inhibits purine synthesis
inhibits DNA/RNA synthesis
MYCOPHENOLATE MIFETIL (MMF)
inhibits inosine monophosphate dehydrogenase
blocks DE NOVO purine synthesis
inhibits T and B cell proliferation and function
*more specific for immune cells than cyclophosphamide and azathioprine
METHOTREXATE
similar to DHF
binds DHF reductase
cannot make THF/thymidine
inhibits methyl transfer reactions
glutamated in cells –> cannot leave
MUROMONAB
murine
binds CD3 on TCR
induces internalization
blocks antigen recognition
depletes CD3+ cells
was used to to reverse acute allograft rejection but no longer on market bc of side effects
BASILIXIMAB
humanized
binds IL2Ra (CD25) to block IL-2 induced proliferation
use with calcineurin inhibitors to prevent acute organ rejection
BELATACEPT
fusion protein
binds CD80/86 on APC to block costimulation
cannot activate T cells
INFLIXIMAB
chimeric
anti TNF alpha
(affects immune response instead of directly interfering with TCR/T cell)
for Crohn’s and Rheumatoid Arthritis
