Immunomodulatory Drugs (Quelle) Flashcards
Immuno-modulatory agents target elements of ______ immunity while anti-inflammatory agents target elements of _____ immunity.
adaptive; innate
______ target both adaptive and innate immune system responses, but most often affect inflammatory cytokines.
disease modifying antirheumatic agents (DMARDs)
IL-2 receptor that plays critical role in autocrine signaling and clonal expansion of CD4+ T cells
CD-25
what principal cytokines are expressed by these T cells? Th1: _____ Th2:_____ Th17_____
Th1: IFN gamma Th2: IL-4 Th17: IL-17
T helper cell that is associated with inflammatory response against extracellular bacteria and fungi and is associated with autoimmune disease
Th17
T helper cell response that is associated with increased cell mediated cytotoxicity and is effective against intracellular pathogens
Th1
Which of these is NOT associated with a Th2 helper cell response?
A. Stimulates the production of IgE
B. Associated with allergic disease
C. Associated with autoimmune disease
D. Secretes mainly IL-4
E. Effective against multicellular parasites
C. The Th2 helper cell response is associated with allergic disease and humoral immunity; autoimmune disease is associated with a Th17 cell response.
All of these are limitations of immunostimulants EXCEPT:
A. they have long half lives
B. they do not promote specific immune reactions
C. they may confer deleterious systemic inflammatory damage
D. they cause flu-like symptoms
E. they must be administered parenterally
A. Immunostimulants have a poor pharmacological profile - they have short have lives, are not available in an oral form, and are expensive. Applications of immunostimulants include: enhanced vaccination response (they’re adjuvants), chronic infectious disease, immunodeficiency disorders, cancer
____ are often used to boost the efficacy of vaccines, mediating their immune-promoting effects on antigen presenting cells
adjuvants
most common adjuvant in human vaccines and has few side effects; forms insoluble deposits with antigen that preserve the antigen within the host for longer periods of time, prolonging its exposure to the body’s immune response
Alum
adjuvant that is useful in treating bladder cancer, whose surface antigens interact directly with pattern recognition receptors on APCs, increasing their activity
BCG (live attenuated bacillus calmette-guerin); also directly activate leukocytes to produce a systemic inflammatory response
cytokines given therapeutically that are useful in the treatment of melanoma and renal cell carcinoma, but are associated with capillary leak syndrome, hypotension and reduced organ pefusion
IL-2
Which of the following is NOT a clinical indication for treatment with immunosuppressants?
A. Rheumatoid arthritis
B. Chronic ocular inflammatory disease
C. Peanut allergy tolerance
D. Kidney transplant
E. Selective immunosuppression
C
Name the 3 adverse effects that are common to all general immunosuppressants.
- Increased risk of infection (myelosuppresion)
- Increased risk of cancer
- GI disturbances
antineoplastic immunosuppressant that cross-links DNA, effectively killing proliferating cells and preventing the expansion of antigen-specific lymphocytes
cyclophosphamide
drug whose uses include a variety of auto-immune diseases and bone marrow transplant
cyclophosphamide
purine synthesis inhibitor that gets incorporated into newly synthesized DNA as thioguanine and is inactivated by xanthine oxidase
azathioprine
drug whose uses include renal and other tissue transplanation, lupus, and rheumatoid arthritis
azathioprine
purine synthesis inhibitor used for solid organ transplant as an alternative to cyclosporin
mycophenolate mofetil
anti-metabolite that inhibits DHFR and is the drug of choice in rheumatoid arthritis
methotrexate (in addition to the usual immunosuppressant side effects, this drug’s also include mucosal ulcers and modest hepatotoxicity)
pyrimidine inhibitor that is very similar to methotrexate
leflunomide
class of drugs that mediate their anti-inflammatory and immunosuppressive effects through the binding of receptors that alter gene transcription, and are the first line choice for solid organ and stem cell transplant
glucocorticosteroids
Which of these is NOT an adverse effect associated with glucocorticoid treatment?
A. ulcers
B. glucose intolerance
C. osteoporosis
D. Cushing’s syndrome
E. marrow toxicity
F. hypertension
E
____ is a transcription factor that, when dephosphorylated by _____, translocates to the nucleus to drive transcription of cytokine gene expression (e.g., IL-2, FasL, IFN gamma, etc)
NF-AT; calcineurin (this is the TCR-induced signaling pathway, a target of immunosuppressant therapy)
what is the mechanism of action of calcineurin inhibitors like cyclosporin and tacrolimus?
cyclosporin and tacrolimus each bind a cellular protein (cyclophilin and FKBP12, respectively) which causes that protein to bind directly to calcineurin, prohibiting its phosphorylase activity (ie, it cannot dephosphorylate NF-AT, and this leads to reduced cytokine expression)
immunosuppressant that is effective with or without the use of other immunosuppressants and is commonly used in kidney, liver and cardiac transplant
cyclosporine
what are the most significant adverse effects of cyclosporine?
nephrotoxicity and increased cancer incidence have been documented
what is a distinguishing feature of tacrolimus from cyclosporine?
it is 10-100 times more potent
protein that is a component of the IL-2 receptor signalling pathway, and is a significant regulator of mRNA expression for proteins that are required for cellular proliferation
mTOR
mTOR is the target for what drug?
sirolimus (rapamycin) sirolimus uses the same protein as tacrolimus, FKBP12, and employs the same mechanism of binding and interrupting mTOR’s ability to phosphorylate its target protein
this drug may be useful in the treatment of steroid-resistant graft vs. host disease in stem cell transplants, and works synergisticaly with cyclosporine
sirolimus
why would you not use sirolimus with an anti-metabolite like methotrexate of azathioprine?
they share the significant adverse effect of myelosuppression
Which of these is NOT a therapeutic advantage of antibodies?
A. they provide passive immunity when host immunization is unwanted
B. they target disease-specific antigens and therefore have many practical applications in cancer
C. they can be conveniently administered in an oral preparation
D. they have long half lives
E. they mimic normal host antibodies to target/opsinize antigenic targets
C. Parenteral administration is required for antibody therapy.
what is the main drawback of using animal-derived antibodies to provoke an immune response?
they are different enough in their constant regions from human antibodies that an anti-antibody response may be mounted, which can lead to antibody desctruction, allergic reaction and serum sickness
what is the advantage of using Fc fusion proteins over chimeric “humanized” antibodies?
Fc fusion proteins, though variable in their ability to provoke a complement response, have a longer half life than chimeric antibodies, giving them a pharmacologic profile that is more similar to natural human antibodies
drug used to prevent initiation of immune response in an Rh negative mother to fetal Rh(D) antigen
Rh(D) immune globulin (RhoGam)
two drugs that block t cell receptors, preventing their activation and targeting them for destruction
Anti-T cell globulin (ATG) and belatacept
fusion protein of a high-affinity B7 ligand and an IgG Fc domain that blocks the CD28 co stimulatory T cell receptor, causing the T cell to become anergic
belatacept(approved for use in kidney transplant)
which of the following is NOT an adverse effect associated with belatacept?
A. malignancy
B. systemic inflammation
C. increased risk of infection
D. PTLD (posttransplant lymphoproliferative disorder)
E. anemia and neutropenia
B
the main effect of this drug is prolonged T cell depletion; but with repeat use, it may cause cytokine release syndrome with the potential for serum sickness and anaphylaxis
(Anti-T cell globulin) ATG
this mouse monoclonal antibody produces prolonged T cell depletion but because of severe cytokine release syndrome was pulled from the market in 2010
Anti-CD3
this immune-depleting drug targets a protein expressed on T/B cells, monocytes, macrophages and NK cells
Anti-CD52
humanized antibody that works through the depletion of a variety of cells involved in adaptive and innate immune reactions, and whose adverse effects include myelosuppression and flu-like symptoms
Alemtuzumab
antibody that blocks and opsonizes the alpha chain of the IL-2 receptor (CD25) which is present on activated T cells; it is well tolerated, demonstrating reduced immunosuppression compared to drugs like ATG and Alemtuzumab
basiliximab
