Immunomodulators Flashcards
What is the major cytokine secreted by activated T cells and what is its receptor? What is its function
IL2
CD25
Proliferation and clonal expansion of T cell population
What is the major cytokine of the TH1 reponse? What are the 2 major cell types affected? What type of pathogens are targeted?
IFN-gamma
Cytotoxic T cells, NK cells
Intracellular Pathogens
What is the major cytokine of the TH2 response? What is the end product? What type of pathogens are targeted?
IL4
IgE antibodies
Multicellular parasites
What is the major cytokine of the TH17 response? What type of pathogen is targeted?
IL17
Extracellular bacteria and fungi
What type of TH response is associated with allergic disease? Autoimmune disease?
TH2
TH17
What is the major role of immuno-stimulants? What is a general description / characteristic of these types of drugs?
Activate / enhance immune response
Usually normal agonists of immune system
What types of adverse effects are associated with immunostimulants?
They generally reflect systemic inflammatory response (e.g. fever / chills, flu-like symptoms)
What are the 2 examples of adjuvants provided in the class?
Alum
BCG
What is the use of alum in medicine? How does it exert its effects?
Alum is used in vaccines
Reacts with antigens, forms deposits that prolong their exposure to immune system
What is BCG? How does it work? What type of disease is it used to treat?
Attenuated bacillus calmette-guerin
Activates pattern recog. receptors on APCs
Used to treat bladder cancer (topically)
In what scenario can BCG be harmful?
Can be harmful if it administed systemically, as it can lead to septic shock
What are the 2 cytokines used clinically provided as examples?
IL2
Interferons
What is the use of IL2? What 2 diseases is it used for? What are 3 potential side effects with its use?
Proliferation of activated T cells, IFN production, cytotoxic killer cell production
Metastatic melanoma, renal cell carcinoma
Can cause capilary leak syndrome, hypotension and reduced organ perfusion. Possibly fatal
What are the 3 interferons used clinically?
Gamma
Alpha
Beta
What is the effect of IFN-gamma? What is it used for?
Stimulates cell mediated cytotoxic immune response
Used for recurrent infections
How are the growth inhibitor drugs comparable to antineoplastic agents? What is a general principle regarding the combination use of growth inhibitor drugs?
Generally the same drugs, just used in lower doses
Try to combine drugs with non-overlapping side effects
There are 2 adverse effects associated with all immuno-suppressants. They are _
Increased risk of infection
Increased risk of cancer
There are 5 drugs provided as examples of general growth inhibitors. They are _
Cyclophosphamide Azathioprine Mycophenolate mofetil Methotrexate Leflunomide
How does cyclophosphamide work? What is it used for?
Cross links DNA, kills all proliferating cells
Autoimmune disease, bone marrow transplant
How does Azathioprine work? What is it used for?
Metabolized into thioguanine, inhibitrs purine synthesis and damages DNA.
Used for renal (and other transplantation), autoimmune diseases
How does xanthine oxidase affect azathioprine? How is this dealt with?
Xanthine oxidase inactivates azathioprine
Inactivation can be blocked with coadmin with allopurinol
How does mycophenolate mofetil work? What is it used for?
Blocks purine synthesis.
Used in solid organ transplant, autoimmune disease
How does methotrexate work? What is it used for?
Blocks dihydrofolate reductase (DHFR), blocks thymidine and purine synthesis
Used for RA, autoimmune diseases
How does leflunomide work? What is it used?
Inhibits blocks pyrimide synthesis
Used for RA, autoimmune diseases
Among the growth inhibitor compounds, which 2 are renown for less pronounced myelosuppression but hepatotoxicity?
Methotrexate
Leflunomide
Among the growth inhibitor compounds, which is associated with infertility?
Cyclophosphamide
Among the growth inhibitor compounds, myelosupression, nausea and vomiting are common to which 3?
Cyclosporin
Azathioprine
Mycophenolate mofetil
Glucocorticosteroids have anti-inflammatory and immunosupressive effects. One mechanism to achieve this is to induce transcription of target genes. What is the example target gene provided and what is the next effect?
Increase transcription of annexins
Inhibit PLA2 and subsequently lipid derived mediators
What is the major use of prednisone (2)
Immunosuppresant for solid organ and hematopoeitic stem cell transplant
Autoimmune disease treatment
What are 5 side effects associated with Prednisone? Under what conditions would these effects be noticed?
Cushing’s Syndrome Osteoporosis Glucose intolerance Hypertension Susceptibility to infection Daily infusion for longer than 2 weeks
How do tacrolimus and cyclosporine work? What are their binding partners?
The block T-cell receptor signalling by blocking calcineurin
Cyclosporin binds cyclophilin
Tacrolimus binds FKBP12
The major use of cyclosporine and or tacrolimus is for the transplantation of what 3 organs? What other type of disease is it used for?
Renal, liver, heart
Inflammatory (asthma)
How do cyclosporin and tacrolimus compare with regards to potency?
Tacrolimus is 10-100 times more potent
What are the major side effects associated with tacrolimus and cyclosporin? (4) Which is major?
Nephrotoxicity (major)
Hypertension
Hyperglycemia
Liver DIsfunction
IL2 is the major immune system growth signal. What is the major drug target for modulating IL2 signaling? What drugs target this?
IL2 signals via MTOR. Sirolumus and everolimus block MTOR activity
How does sirolimus (and everolimus) interact with cyclosporin and tacrolimus?
Sirolimus is synergistic with cyclosporin
Sirolimus is antagonistic with tacrolimus (same target (FKBP12))
The 2 major uses of sirolimus are _
Preserve solid organ transplant
Treat steroid resistant graft v. host disease following hematopoeitic cell transplant
The major side effect of sirolimus is _. Others (4) include
Myelosupression
Hyperlipidemia, hypertension, edema, hepatotoxicity
How is Rh hemolytic disease caused?
If an originally Rh negative mother develops Rh antibodies during a previous pregnancy, these antibodies can attack the fetus and cause hemolytic disease
What can be done to prevent hemolytic disease in a pregnant woman? How does it work?
Adminster RhD immunoglobulin
Binds up free D antigen, prevents initiation of immune response against D antigen
What is belatacept? How does it work?
It is a igG with a high affinity B7 ligand. B7 is needed to bind along with the antigen to generate the T cell response. Block T cell binding to B7, leading to anergy
What are 5 side effects associated with the use of belatacept?
Anemia, neutropenia, peripheral edema, increased risk of infection and malignancy, PTLD
What is anti T cell globulin? What is its main effect? How often can it be used?
Anti-T cell globulin is made by repeated injection of human T cells into other mammals
Causes opsonization and destruction of T cells, major depletion up to a year
One time use
Anti-T cell globulin can cause cytokine release syndrome. How can it be prevented? What are 2 other side effects of anti T cell globulin?
Pretreatment with acetamenophen and antihistamines
Serum sickness, anaphylaxis
What is alemtuzumab? What is the effect?
A humanized anti CD52 antibody, binds CD52, which is expressed on various immune cells
Depletes call cells expressing CD52 (T and B cells, moncytes, macrophages, NK cells) for a year
What is the major side effect of alemtuzumab?
Myelosupression, flu like symptoms
What is basiliximab? How does it work?
It is a humanized anti CD25 antibody
Binds the alpha chain of CD25, found only on activated T cells, therefore depletes only activated T cells
What are the 3 major antigen presenting cells in the body? What receptor subtype do they express?
B cells, dendritic cells, macrophages
MHC II
What is the major coreceptors found on T cells and the APCs?
T cells express CD28
APC express B7
What T helper cell response is associated with allergies? What is the associated antibody?
TH2 cells
IgE
What T helper cell response is associated with autoimmune disease? What is the associated cytokine?
TH17
IL-17
Why are immunostimulants considered non-specific?
Because they upregulate all components of the immune system, especially APCs to increase the likelihood of T-cell activation
What is the major means by which glucocorticoids exert their antiinflammatory and immunosuppresive actions?
Cause the expression / suppress the expression of target proteins
What are 2 specific notable genes that are suppressed by glucocorticoid? What are their funtions?
IL2 - Clonal expansion of T cells
IFN-gamma - Activation of macrophages
What is a major advantage of glucocorticoids compared to the growth inhibitor molecules?
No significant myelosuppresion associated with glucocorticoids
What is the downstream target of calcineurin? What type of activity does it have? What is the effect of this downstream target?
NFAT
Calcineurin (A phosphatase) dephosphorylates NFAT
NFAT translocates to nucleus, activates cytokine transcription
What are 4 ways that antibodies can be used in human disease?
- Neutralize / opsonize targets
- Passive immunity
- Target disease specific antigen
- Deplete cell mediators of immune system
What are the 3 types of antibodies used for medicines? Which can only be used once? Why?
Human
Animal (Single use)
Chimeric
Recognized and destroyed during subsequent uses
What are side effects associated with repeated animal antibody use? (3)
Antibody destruction
Allergic reaction
Serum sickness
What is a specific neoplasm associated with the use of belatacept? What specific population is at risk? What is belatacept used for?
Posttransplant lymphoproliferative disorder (PTLD)
Epstein Barr Virus negative patients
Kidney transplantation
How does the side effects of basiliximab compare to other antibody modulating agents?
Mild, because its target (activated T cells) is so much narrower
