Pharmacology Immunosupressants I

Question 1

T- Cell Activation

Answer 1

MHC peptide complex tcr-cd3 (signal 1) + CD 80/86 (B7) costimulatary cd28 (signal 2) = required for activation

Question 2

Allograft rejection

Answer 2

Recipients immune system attacks foreign antigens in allograft

Question 3

GVHD. ( graft versus host disease)

Answer 3

Competent immune cells in allograft ( bone marrow , stem cell) recognize the recipients antigens as foreign

Question 4

Hyperacute rejection

Answer 4

Performed host antibodies against alloantigens bind grafted vascular endothelium and complement is activated —> necrosis. Happens within minutes to hours

Question 5

Acute rejection

Answer 5

Cellular humoral or both . Happens within days to weeks

Question 6

Chronic rejections

Answer 6

Happen gradually over several years.leads to fibrosis and loss of graft function

Question 7

Positive point of many immunosuppressives

Answer 7

They block multiple targets. Which allows for low dose of drugs to be used so less toxicity risk

Question 8

TherApy for prevention of acute organ rejection

Answer 8

1. Calcineurin inhibitor ( or mTOR inhibitor or CTLA4 inhibitor)
2. Antimetabolite
3. glutocorticoid

Question 9

Established acute allograft rejection

Answer 9

T cell mediated:
1. Gluticorticoid, high dose pulse then oral taper
2. RATG ( or alemtuzumab if patient doesn’t tolerate rATG)
Antibody mediated:
1. Gluticorticoid, high dose pulse then oral taper
2. IVIG
Individual cases: plasmapheresis/ritumixab

Question 10

Exceptions to general therapy approach

Answer 10

Lung transplantation- gluticorticoid omitted for several weeks to promote bronchial anastomosis healing

Liver requires less immunosuppression. Only calcineurin inhibitor required to suppress long term

Question 11

Immunization during immunosuppressant therapy

Answer 11

NO LIVE VIRAL IMMUNIZATIONS DURING TREATMENT

Question 12

RATG (thymoglubin)

Answer 12

-purified gamma globulin from serum rabbits immunized w/ human thymocytes
- depleting agent tht causes T cell lysis= depletion of circulating lymphocytes
- bind variety of proteins on human T lymphocyte surface (I.e cd20)
-acts on long lived lymphocytes tht circulate btw blood and lymph
Direct cytotoxicity- complement & cell mediated
Block lymphocyte function- bind surface molecules involved In regulation of cell function

• destruction/inactivation of T cells Impairs hypersensitivity and immunity = marked cellular immunity suppression

Question 13

RATG Adverse effects

Answer 13

Common- fever, chills , leukopenia, thrombocytopenia
Infusion reactions- flu-like symptoms , cytokines release syndrome, local site reactions
Serum- rash pruritis, fever, hypotension, lymphadenopathy
Infection- bacterial, viral, fungal, protozal
Pregnancy-use effective contraception during and at least 3 months following treatment

Question 14

Alemtuzumab

Answer 14

• Anti-CD52 monoclonal antibody depleting agent
• bind cd52 on t/b cells-> indices direct antibody dependent cellular cytotoxicity and complement mediated lysis-> depletion of t & B cells -> reduces host immune response against transplanted organs

Question 15

Alemtuzumab toxicity

Answer 15

Common-nausea, vomiting, diarrhea, insomnia
Infusion- flu like symptoms, cytokines release syndrome, local site reaction.
Autoimmune- hemolytic anemia, thrombocytopenia, antiglomerular basement membrane disease
Infection - malignant neoplasms among bacteria,viral,fungal
Pregnancy- contraception during and 6 months after treatment men and women

Question 16

Baxiliximab

Answer 16

MOA
1. Binds high affinity IL-2Ra on surface of activated T cells
2. Competitively blocks IL-2 binding to activated T cells
3. Prevents T cell activation
4. IL-2R downregulation prevents proliferation
Uses:
Induction therapy with GC and cyclosporine
-renal
-heart,liver,lung
-2 doses
Treatment of acute refractory GVHD

Question 17

Basiliximab toxicity

Answer 17

Anaphylaxis , infections/ lymphoproliferative disorder

NO CYTOKINES RELEASE SYNDROME
NO SIGNIFICANT METABOLIC DRUG INTERACTIONS METABOLIC INTERACTION S

Question 18

Glutocosteroids

Answer 18

Binding of CS-GR complex to nuclear elements —> trans repression or transactivation of genes.
Induce lipocortin—> inhibits PLA2-> inhibit synthesis of prostaglandins and lipoxygenase products
- inhibit T cell proliferation
- humoral immunity dampened but little effect on it
Inc in : lymphocyte apoptosis, lymphocyte redistribution
Dec in: chemotaxis, il1,il6,il2, T cell proliferation, lysosomal enzyme release of neutrophils and monocytes

Question 19

Glucocorticoids use

Answer 19

1. GVHD prevention and treatment
2. Prevention and treatment of transplant rejection
   Induction and maintenance of allograft; acute transplant rejection
3. Management of cytokine release syndrome, infusion reactions

Question 20

Gluticosteroids toxicity

Answer 20

Acute effects:
-INCREASE IN plasma cholesterol, salt retention, BP, opportunistic infection
- delayed wound healing
- depressive/ euphoria mood
Delayed effects:
- peptic ulcers /GI bleeding
- reduced growth in children
- cataracts
- osteoporosis, avascular necrosis of bone
CUSHINGS EFFECT:
- moon face, ruddy complexion
-unchallenged fat deposition, Buffalo hump
- weight gain, abdominal obesity
- muscle wasting, weakness of limbs
- thin skin, hirsuitism, acne, bruisability