Pharmacology Immunosupressants I Flashcards
T- Cell Activation
MHC peptide complex tcr-cd3 (signal 1) + CD 80/86 (B7) costimulatary cd28 (signal 2) = required for activation
Allograft rejection
Recipients immune system attacks foreign antigens in allograft
GVHD. ( graft versus host disease)
Competent immune cells in allograft ( bone marrow , stem cell) recognize the recipients antigens as foreign
Hyperacute rejection
Performed host antibodies against alloantigens bind grafted vascular endothelium and complement is activated —> necrosis. Happens within minutes to hours
Acute rejection
Cellular humoral or both . Happens within days to weeks
Chronic rejections
Happen gradually over several years.leads to fibrosis and loss of graft function
Positive point of many immunosuppressives
They block multiple targets. Which allows for low dose of drugs to be used so less toxicity risk
TherApy for prevention of acute organ rejection
- Calcineurin inhibitor ( or mTOR inhibitor or CTLA4 inhibitor)
- Antimetabolite
- glutocorticoid
Established acute allograft rejection
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
Exceptions to general therapy approach
Lung transplantation- gluticorticoid omitted for several weeks to promote bronchial anastomosis healing
Liver requires less immunosuppression. Only calcineurin inhibitor required to suppress long term
Immunization during immunosuppressant therapy
NO LIVE VIRAL IMMUNIZATIONS DURING TREATMENT
RATG (thymoglubin)
-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
RATG Adverse effects
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
Alemtuzumab
- 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
Alemtuzumab toxicity
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
Baxiliximab
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
Basiliximab toxicity
Anaphylaxis , infections/ lymphoproliferative disorder
NO CYTOKINES RELEASE SYNDROME
NO SIGNIFICANT METABOLIC DRUG INTERACTIONS METABOLIC INTERACTION S
Glutocosteroids
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
Glucocorticoids use
- GVHD prevention and treatment
- Prevention and treatment of transplant rejection
Induction and maintenance of allograft; acute transplant rejection - Management of cytokine release syndrome, infusion reactions
Gluticosteroids toxicity
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
