E2 Specific immunosuppression Flashcards
Define ALG
- where derived from
- short term target
- long term target
Anti-Lymphocytic Globulin
- large animals purifying IgG
- Small long-lived Peripheral Lymphocytes circulating between Blood and lymph node
- Thymus-dependent lymphocytes from the “Cuffs” of lymphoid Follicles depleted as they participate in recirculating pool
Define ALG
- Describe Mechanism
2. cellular consequences
Anti-Lymphocytic Globulin
- Bind to surface of Ag-recognising Tc/ Cytotoxicity by serum complement
- Specific destruction of T, consequent impairment of DTH, (Ab response intact)
Define ALG
- Describe side effects
2. limitations of use
Anti-Lymphocytic Globulin
1. serum sickness: Ag-Ab precipitates in kidney –> body removes by complement = Ab damage
Lymphoma at injection site
2. eventually due to side effects ALG becomes ineffective - therefore first line treatment: stops organ being rejected in first instance but not long term strategy
Describe cyclosporin A
- what type of molecule
- describe structure
- what advantage does it provide
- side effects
- Macrolide
- 11 membered ring of peptide a.a
- w/ CsA kidney doesnt need to be tissue matched
- ~toxicity/ nephrotoxicity
Decribe the 3 Macrolide molecules
what must they all be bound to
Cyclosporin A
FK-506
Rapamycin
- all agonists which induce a state of immunosuppression
(their binding protein to produce protein complex)
name Macrolide antagonists
L-685,818
506BD
- prevent the immunosuppressive action of macrolide agonists
cyclosporin A - provides
potent suppression of:
- alloantigen-specific Tc no. (Tc against antigen)
- T-cell proliferation
- cytotoxic Tc no.
- IL-2 & IFNy
Describe FK506
- how much more potent than CsA
- side effects
clinically identical to CsA
100x potency
same as CsA but nephrotoxicity less ~due to smaller dose
Describe rapamycin
- when effective
- potency compared to FK506
- side effects
Effective even after Tc activation
Especially highly histoincompatible organs (heart)
Greater potency & graft survival time than FK506
No major renal toxicity but: in experimental animals can lead to
- GI ulceration/
- vasculitis
- testicular atrophy
Name the binding receptor for CsA, FK506 and rapamycin
what are the type of binding proteins & describe function
CsA binds cyclophilin
FK506 and rapamycin bind FKBP
- pepidyl-prolyl isomerases (PPIs) –> Rotamases
(enzymes which catalyse the rotatation of protein as folded which helps formation of tertiary structure)
Is inhibiting rotamase activity correlated to immunosuppression
- how was this shown
No as antagonist which themselves have no intrinsic activity are able to inhibit rotamases
There rotamase activity not involved in suppression
Explain the effect of CsA and FK506 on calcineurin
Inhibits calcineurin (a phosphatase) from removing the P from NFATc therefore cant translocate to nucleus (therefore can contribute to (Tc?) DNA formation - (no transcription/ production of Il-2 –> no Tc)
(calcineurin is key to Tc activation)
How does rapamycin prevent cell cycle progression
Rapamycin (SRL) binds FKBP which inhibits mTOR
this prevents:
- ribosomal protein activation (S6 kinase)
- Cyclins (control cell cycle progression)
- cyclin dependent kinases (cdk & elF4F)
- ultimately inhibits cell cycle at G1 preventing S phase –> prevents cell cycle progression
summary of observations CsA/ FK506
A) Affect Ca2+ pathways
B) Inhibit Ca2+ ionophores i.e. direct Ca2+ (in making intracellular Ca available) - work at step after Ca generation.
C) Do not affect generation of Ca2+ (affects its subsequent release)
CsA/ FK506 target pathways after Ca2+
