FMS Week 10: Immunosuppressive Drugs Used in Organ Transplantation Flashcards
1
Q
Experiments using genetically engineered pigs to grow human organs
A
2
Q
Attempts to regenerate organs in vivo
A
3
Q
Crispr deleting genes of porcine pancreas
A
4
Q
Types of Kidney Allograft Rejection
4 Listed
A
- Hyperacute
- Accelerated Acute
- Acute
- Chronic
5
Q
Hyperacute Kidney Allograft Rejection drug treatment
2 listed
A
- Untreatable
- Rare because of better matching, graft preservation in transit, better induction protocols
6
Q
Accelerated Acute Kidney Allograft Rejection Drug Treatment
A
Rarely Treatable
7
Q
Acute Kidney Allograft Rejection Drug Treatment
9 Listed
A
Treated with
- Cyclosporine
- Tacrolimus
- Sirolimus
- Azathioprine
- mycophenolate
- cyclophosphamide
- methotrexate
- glucocorticoids
- mAbs
8
Q
Chronic Kidney Allograft Rejection Drug Treatment
A
Same as acute slows progression
9
Q
Acute Antibody-Mediated Rejection
4 Listed
A
- Antibodies against donor antigens bind to antigens expressed on endothelial cells in the graft vessel
- The subsequent complement activation and cell adhesion result in endothelial-cell necrosis, followed by platelet deposition and coagulation
- Mononuclear cells adhere to the endothelium of the glomeruli
- This process is accompanied by C4d deposition in the glomeruli and peritubular capillaries and in the peritubular capillaries and in the peritubular capillaries between ghost outlines of the renal tubules
10
Q
Chronic Antibody-Mediated Rejection Histological description
A
Antibody-Mediated rejection results in transplant glomerulopathy, with thickened glomerular capillaries and double contours accompanies by C4d in peritubular capillaries containing mononuclear cells and flocculent subendothelial material below an activated endothelial cell of the glomerular capillary
11
Q
Immunomodulation Mechanisms
3 Listed
A
- immunosuppression
- specific induction of tolerance
- immunostimulation
12
Q
Most current drugs are?
A
Immunosuppressive
13
Q
Immunosuppressants are used for?
3 Listed
A
- Organ transplantation
- Immune cell cancers
- Autoimmune diseases
14
Q
Immunosuppressants treatment timeline
A
Historically requiring lifelong treatment after transplantation
15
Q
Suppression of the immune system results in Increased rates of…
3 Listed
A
- infection
- cancer
- can even trigger Autoimmunity
16
Q
Transient immunosuppressive therapy & durable chimerism
A
new techniques using donor hematopoietic stem cells and regulatory T cells with the graft suggest durable chimerism may allow transient immunotherapy
17
Q
Guiding principles of Organ Transplantation
6 Listed
A
- ABO compatible HLA matching
- Combinational chemotherapy
- Prophylactic treatment for CMV, EBV, HSV, Influenza
- Engraftment (induction) doses > maintenance doses unless poorly functioning graft after surgery, in which case all drugs may be withdrawn and MAB treatment initiated
- Careful investigation of dysfunctional episodes - is it due to graft rejection or drug toxicity, or infection
- Continuous evaluation of dose:effect ratio of the administered drugs because of toxicity, notably to the kidney
18
Q
Adrenocortical Steroids Examples
3 Listed
A
- Prednisone
- Prednisolone
- others
19
Q
Adrenocortical Steroids are used alone or
A
in combination with other immunosuppressants
20
Q
Adrenocortical Steroids Mechanism
6 Listed
A
21
Q
Glucocorticoid toxicities associated with chronic use
6 Listed
A
22
Q
Glucocorticoids mechanism of Action
6 Listed
A
23
Q
Polyclonal immunomodulatory Antibodies used as adjuncts in organ transplantation
2 Listed
A
- Antithymocyte (ATG)
- Antilymphocyte globulins (ALG)
24
Q
Monoclonal immunomodulatory Antibodies used as adjuncts in organ transplantation
4 Listed
A
25
ATG AKA
Antithymocyte globulin (ATG)
26
ALG AKA
Antilymphocyte globulin (ALG)
27
ATG and ALG origin
e.g. from horse or sheep immunized with human T lymphocytes
28
Immunomodulatory Polyclonal Antibodies function
3 Listed
* Polyclonal Antibodies to HLA I & II and to multiple CDs: 2, 3, 4, 8, 11a, 18, 25, 44, 45...
* These Abs block immune cell function by binding to the surface and they deplete circulating lymphocytes or thymocytes by direct cytotoxicity (complement & antibody-mediated cellular cytotoxicity; CDCC, ADCC)
* IVIG administration also decreases HLA antibodies and is effective in allograft rejection episodes
29
Immunomodulatory Polyclonal Antibodies Toxicities
3 listed
30
Immunomodulatory Antibodies: Monoclonal - Muromonab-CD3 (OKT-3) Function
5 Listed
* Ab against CD3, the TCR complex, blocking antigen recognition and T-cell function
* Causes internalization of TCR and increases apoptosis
* T cell death due to complement activation
* T cell margination and redistribution to nonlymphoid organs
* T cells disappear from circulation in minutes returning 1 week after cessation of OKT-3
31
Muromonab-CD3 (OKT-3) is a
Immunomodulatory Monoclonal Antibody
32
Muromonab-CD3 (OKT-3) Toxicities
4 Listed
33
Immunomodulatory Antibodies: Monoclonal Anti-CD25 (IL-2R) examples
2 listed
* Daclizumab
* Basiliximab
34
Immunomodulatory Antibodies: Monoclonal: Daclizumab, Basiliximab are?
2 listed
* Anti-CD25 (IL-2R) antibodies
* humanized and chimeric (human-murine) monoclonal antibodies
35
Immunomodulatory Antibodies: Monoclonal Anti-CD25 (IL-2R) Function
4 Listed
36
Immunomodulatory Antibodies: Monoclonal: Anti-CD20 drug name
Rituximab
37
Rituximab
Immunomodulatory Antibodies: Monoclonal: Anti-CD20
38
Rituximab function
* Anti-CD20 on B cells
39
Rituximab is used in?
2 Listed
* Antibody-mediated transplant rejection and post-transplant lymphoproliferative disorder (EBV reactivation)
* also used in B-cell cancer and antibody-dependent autoimmune disease
40
Immunomodulatory Antibodies: Monoclonal: Anti-CD52 drug name
Alemtuzumab
41
Alemtuzumab is a?
Immunomodulatory Antibodies: Monoclonal: Anti-CD52
42
Alemtuzumab function
3 listed
* hMAB against CD52 on lymphocytes (T,B and NK cells, monocytes and macrophages)
* causes extensive lympholysis due to apoptosis
* Causes prolonged mostly T and some B cell depletion allowing drug minimalization during acute rejection
43
Alemtuzumab used in?
4 Listed
Has shown promising results in
* organ transplantation
* effective in induction protocols
* approved for CLL
* CRS
44
Abatacept and Belatacept are inhibitors of?
T Cell Activation
45
Costimulatory blockade explanation and effect
3 Listed
2 signals are required for T cell activation
* TCR and a costimulatory receptor-ligand pair
* Blocking CD80/86 (B7) attachment to CD28 on T cells prevents activation producing energy
46
Abatacept function
Fusion protein containing the extracellular domain of CTLA-4 and an Fc fragment that inhibits B7-CD28 bonding
47
Belatacept Function
Second generation CTLA-4-Fc fragment blocking co-stimulation and T cell activation
48
Immunosuppressants main categories
3 Listed
* Calcineurin Inhibitors
* Antiproliferative Agents
* Antimetabolites
49
Calcineurin Inhibitors examples
2 Listed
* Cyclosporine (Cyclosporin A, CsA)
* Tacrolimus (FK506)
50
Antiproliferative Agents Examples
2 Listed
* Sirolimus (Rapamycin)
* Everolimus
51
Antimetabolites Examples
2 Listed
* Mycophenolate mofetil
* Azathioprine
52
Cyclosporine Mechanism of Action
5 Listed
53
Cyclosporine Pharmacokinetics
3 Listed
54
Cyclosporine Toxicities
6 Listed
* Nephrotoxicity (limiting, believed due to arteriolar vasculopathy and ischemic glomerulosclerosis)
* Neurotoxicity (tremor, limb parestesias, seizures, hallucinations)
* Hirsutism
* Hypertension
* Hyperlipidemia
* gum hyperplasia (due to inhibition of PGI2 (Prostacyclin))
55
Cyclosporine Clinical Uses
5 Listed
* "breakthrough drug" that permitted organ transplantation
* Used for kidney, liver, heart, lung, bone and other tissue transplants
* Rheumatoid arthritis
* psoriasis
* other autoimmune disorders
56
Recurrent Gum Hyperplasia caused by?
Cyclosporine-associated gingival hyperplasia
57
Lip Hypertrophy caused by treatment with?
Cyclosporine
58
Lip Hypertrophy reversed with
Tacrolimus
59
Tacrolimus (FK506) Mechanism of Action
3 Listed
60
Tacrolimus (FK506) is metabolized by?
Extensively metabolized by hepatic CYP3A4 (like CsA)
61
Tacrolimus limiting factor
Neprhotoxicity; like cyclosporine is
62
Cyclosporine limiting factor
Nephrotoxicity; like Tacrolimus is
63
Tacrolimus Toxicities
6 Listed
* Nephrotoxicity
* Neurotoxicity
* Hypertension
* Hyperkalemia
* Hyperglycemia
* Diabetes
64
Glucocorticoids + Tacrolimus is...
Especially diabetogenic
65
Tacromilus can cause \_\_\_\_\_\_\_\_\_.
Diabetes, and is considered diabetogenic
66
Sirolimus AKA
Rapamycin
67
Sirolimus is a
2 Listed
* mTOR inhibitor
* Antiproliferative Agent
*
68
mTOR is a what and its inhibition causes?
69
Sirolimus prevents
Phsophorylation of CDK2-E and cell-cycle arrest in G1
70
Sirolimus Mechanism of Action
4 Listed
71
Sirolimus Toxicities
7 Listed
72
Mycophenolate Mofetil class of drug
Antimetabolites
73
Mycophenolate Mofetil is a prodrug for?
Mycophenolic Acid (MPA)
74
MPA AKA
Mycophenolic Acid
75
Mycophenolate Mofetil Mechanism of Action
3 Listed
76
Mycophenolate Mofetil prevents synthesis of?
GTP
77
MPA is ___________ before urinary excretion
Glucuronidated
78
Mycophenolate Mofetil is used in conjunction with?
2 Listed
* Glucocorticoids
and
* Calcineurin inhibitors
79
Mycophenolate Mofetil replaced the older?
Azathioprine
80
Mycophenylate Mofetil Toxicities
3 Listed
* Leukopenia
* Diarrhea
* Vomiting
81
Azathioprine is a prodrug for
6-Mercaptopurine
82
Azathioprine Mechanism of Action
4 Listed
83
Azathioprine inhibits synthesis of
* ATP
&
* GTP
84
Azathioprine Toxicities
3 Listed
85
Immunosuppression increases the risk for?
3 Listed
* Cancer
* Viral infections
* Bacterial infections
86
20-40% of renal/liver transplant recipients will ...
Develop cancer within a decade after transplantation
87
Most common type of post-transplant malignancy
Cutaneous Squamous Cell Carcinoma
88
immunosuppressants most likely to cause cancer
Calcineurine inhibitors (cyclosporine, tacrolimus) \> mTOR inhibitors (sirolimus, everlimus)
89
PTLD AKA
Post-transplant proliferative disorder
90
PTLD occurs in ______ and has a higher incidence in those receiving ____________ and ____________ therapy.
* ~1%
* anti-thymocyte (ATG, ALG, OKT3)
* Tacrolimus
91
PTLD is
B cell proliferation and hyperplasia after EBV infection that can lead to B cell lymphoma
92
EBV AKA
Epstein-Barr Virus
93
Durable Chimerism Studies
94
Immunosuppressive Agents Sites of Action
