8 - Immunosuppressants Flashcards
(63 cards)
1
Q
Define autograft
A
Organ/tissue moving sites in the same body (self to self)
2
Q
Define allograft
A
Organ/tissue moving from one human to another
3
Q
We want to make organ/tissue transplants as _____-like as possible to prevent rejection
A
Autograft-like
4
Q
Define xenograft
A
Organ/tissue moving from one species to another
5
Q
What are the 3 types of organ/tissue rejection?
A
- Hyperacute = minutes
- Acute = 7-21 days
- Chronic = 3 months
6
Q
What do anti-rejection drugs target?
A
- T-cell and B-cell activation/clonal expansion
- Cytokine production, or
- Antibody action
7
Q
What is a big contributor to the success of organ transplantation?
A
Effective immunosuppressive agents
8
Q
How are antibodies formed?
A
- Antigen binds to antigen receptor, activating a B cell; cytokines are released from helper T cells
- B cell undergoes proliferation to form 2 clones of B cells
- Clones of B cells undergo proliferation and differentiation to form plasma cells (antibody secreting cells) and memory cells (dormant cells)
9
Q
What is the induction phase of the immune response?
A
Antigen recognition on B cell and proliferation of B cell
10
Q
Which drugs target the induction phase of the immune response?
A
- Cyclosporine and tacrolimus inhibit interleukin-2 production
- Glucocorticoids inhibit cytokine gene expression
11
Q
What is the function of interleukin-2 for the immune response?
A
Needed for helper T cells to be activated
12
Q
Indication of cyclosporine
A
- Tx of organ transplantation (kidney, heart, bone marrow)
- Low doses used in autoimmune diseases (ex: RA)
13
Q
What is the MOA of cyclosporine?
A
- Antigen-MHC 2 complex bind to Th-2 cell receptor, increasing intracellular Ca2+
- Ca2+/calmodulin complex stimulates calcineurin => increased activation of transcription factor => increased IL-2 gene transcription
- Cyclosporine binds to cytosolic protein cyclophilin; this complex inhibits calcineurin/NF-AT activation and blocks IL-2 gene transcription
14
Q
What are the functions of cyclosporine?
A
- Decrease activation of T cells (inhibits IL-2 release and decreases expression of IL-2 receptors)
- Reduces function of effector T cells that mediate cell-mediated responses
- Reduces T cell-dependent B cell response
15
Q
What are side effects of cyclosporine and tacrolimus?
A
- Nephrotoxicity (so must monitor kidneys)
- Hypertension
- Increased risk of infection
- Liver dysfunction
16
Q
What drugs do cyclosporine interact w/?
A
- Drugs that inhibit CsA metabolism (Ca channel blockers, antifungals, antibacterials, grapefruit juice)
- Drugs that induce CsA metabolism (anticonvulsants, antituberculosis agents)
17
Q
What is the MOA of tacrolimus?
A
- Similar to cyclosporine
- Binds to immunophilin FK binding protein (FKBP) which inhibits calcineurin phosphatase => decreased activation of transcription factors => decreased IL-2 gene transcription
18
Q
What is the effector phase of the immune response?
A
Production of clones of B-cells, differentiation of clones into T cells or antibodies, and joining w/ antigens at site of tissue injury
19
Q
Which drugs act on the effector phase of the immune response?
A
- Sirolimus (inhibits interleukin 2 mediated gene activation)
- Myclophenolate mofetil and azathioprine (inhibit purine synthesis)
- Cyclophosphamide (alkylates cytotoxic agents)
- Glucocorticoids (suppress immune response)
- Polyclonal and monoclonal antibodies (immunosuppressive)
20
Q
What is the MOA of sirolimus?
A
- Binds to intracellular immunophilins
- Interferes w/ IL-2 signal transduction pathway in activated T cells
- Result = decreased clonal proliferation of T and B cells
21
Q
What is the MOA of mycophenolate mofetil?
A
Potent inhibitor of inosine 5’-monophosphate dehydrogenase (crucial enzyme in purine synthesis)
22
Q
What can impair the absorption of mycophenolate mofetil?
A
Magnesium and aluminum
23
Q
What is the indication of mycophenolate mofetil?
A
Transplant recipients w/ cyclosporine and steroids
24
Q
What is the MOA of azathioprine?
A
- Interferes w/ purine synthesis (inhibit HGPRT enzyme, which catalyzes conversion of purine base to purine ribosyl monophosphate)
- Inhibits clonal T and B cell proliferation of immune response
- Inhibits both cell mediated and antibody mediated immune reactions
25
What are the indications of azathioprine?
- IV loading dose on day of transplantation
- Oral dosing for maintenance
- Used in combination w/ other immunosuppressant drugs
26
What is the major side effect of azathioprine?
Bone marrow depression
27
What is the MOA of cyclophosphamide?
Alkyl groups cross-react w/ 2 DNA nucleophilic sites to inhibit DNA replication and cause subsequent cell death (apoptosis)
28
What are the indications of cyclophosphamide?
Tx of lupus and RA
29
What are side effects of cyclophosphamide?
Bone marrow depression and GI disturbance
30
Which glucocorticoids are used as immunosuppressants?
- Prednisone
- Methylprednisone
- Dexamethasone
31
What do high doses of glucocorticoids cause?
Induce lymphocyte migration to extravascular space and subsequently reduce lymphocyte proliferation
32
Glucocorticoids affect more ___ cells than ___ cells
More T cells than B cells
33
What is the MOA of glucocorticoids?
- Suppress induction and effector phases of immune response
- Inhibit macrophage activation and release of IL-1 beta
- Decrease clonal expansion of T and B cells and IL-2 secreting T cells
- Decrease production and action of cytokines
- Decrease generation of IgG
34
What are the clinical uses of glucocorticoids?
- Anti-inflammatory and immunosuppressive therapy
- Neoplastic diseases (Hodgkin's disease, acute lymphocytic leukemia)
- Replacement therapy
35
What are side effects of glucocorticoids?
- Insomnia and mood changes
- Increased appetite and weight gain
- Suppressed response to injury or infection
- Metabolic effects
36
What are immunosuppressive antibodies?
Antibodies against human lymphocytes or their surface receptors that have significant immunosuppressant actions
37
What are polyclonal antibodies?
- Anti-lymphocyte immunoglobulin (inhibit T cell lysis)
| - Bind to proteins on surface of lymphocytes triggering complement response => lysis of lymphocytes
38
What are adverse effects of polyclonal antibodies?
Newly synthesized antibodies against these polyclonal antibodies could produce anaphylactic reactions
39
What are monoclonal antibodies?
Antibodies against IL-2 receptors (prevent T and B cell activation and proliferation)
40
What are the targets of monoclonal antibodies?
- CD3 proteins w/ antigen receptors
- CD4 co-receptors
- IL-2 receptors
41
What drugs are given to prevent an acute rejection?
High dose glucocorticoids, purine synthesis inhibitors and immunosuppressive antibodies 1-2 weeks prior to transplant
42
Which drugs are given to prevent a chronic rejection?
Low dose triple drug therapy (calcineurin inhibitor, purine synthesis inhibitor, and glucocorticoid)
43
What drugs are used for a breakthrough episode in chronic rejection?
- Cyclophosphamide
- Immunosuppressive antibodies (polyclonal and monoclonal)
- Anti-TNF therapy
44
What is the purpose of primary and peripheral tolerance of the immune system?
Protect itself against autoreactive B and T cells
45
Where does central tolerance occur and what is it?
- Occurs in lymphoid organs
- Clonal deletion of immature lymphocytes in bone marrow (B cells) and thymus (T cells) that recognize self-antigens w/ high affinity
46
Where does peripheral tolerance occur and what is it?
- Occurs beyond lymphoid organs
| - Kills or inactivates mature autoreactive lymphocytes
47
What happens when self-tolerance mechanisms fail?
Adaptive immune system responds as it would to non-self antigens and mounts an immune response
48
What can be caused by the body's inability to eliminate self-antigen?
Sustained response that leads to chronic inflammation
49
Which drugs are anti-IL therapeutics?
- Anakinra
- Canakinumab
- Tocilizumab
50
Which drugs are anti-TNF therapeutics?
- Entanercept (only soluble receptor TNF antagonist)
- Infliximab
- Adalimumab
- Certolizumab
- Golimumab
51
Why are anti-TND and anti-IL effective DMARDs (disease-modifying antirheumatic drugs)?
- Released w/in joint during chronic inflammatory phase
| - Early participants in inflammatory cascade
52
What occur in the 3 phases of rheumatoid arthritis?
- Initiation phase = inflammation w/in joint
- Amplification phase = T cell activation
- Chronic inflammatory phase = tissue injury due to destruction of bone and remodeling of joint
53
Which drugs are used in rheumatoid arthritis therapy?
- NSAIDs
- Glucocorticoids
- Disease-modifying antirheumatic drugs (DMARDs)
54
Which drugs are DMARDs?
- Methotrexate
- Sulfasalazine
- Leflunomide
- Anti-TNF therapies
- Anti-IL therapies
55
What do autoreactive T helper 1 cells cause?
Release interferon and interleukin to activate macrophages that secrete additional cytokines to cause local inflammation
56
What do autoreactive cytotoxic T cells cause?
Extensive tissue damage
57
What affect do inappropriate T cell responses have on autoreactive B cells?
Help autoreactive B cells initiate polyclonal activation and generation of harmful auto-antibodies
58
What do auto-antibodies do?
- Activate complement system to cause inflammation
- Bind receptors to block hormone and NT signals, or
- React w/ antigens in blood
59
What is the purpose of clonal deletion in central tolerance?
To safeguard against autoreactive lymphocytes
60
What does viral infection of a tissue cause?
Activation of non-virus-specific T cells
61
What is molecular mimicry?
Microbial antigens shape epitopes similar to human self-proteins and induce an inflammatory response against the self-antigen
62
What are DAMPs? What can they trigger?
- Damage-associated molecular patterns
- Molecules released from stressed or injured cells that act as danger signals to alert the immune system
- May trigger autoimmunity
63
What can nucleic acids released from dying cells cause?
Can stimulate toll-like receptors (TLRs) on B cells and promote auto-antibody generation
