Immunosupressants Flashcards
what are 3 applications of immunosuppressants?
- suppress rejection of donor organs/tissues
- suppress ‘Graft-vs-Host’ disease (GVHD)
- auto-immune diseases
what is the ‘Graft-vs-host’ disease?
donor lymphocytes (on graft) begin to attack host (opp rxn to transplant rejection: host->donor)
what causes the transplant rejection rxn?
antigens on donor organ are recognized as ‘non-self’ and host initiates immune response to attack it
what are 4 ex of autoimmune diseases?
rheumatoid arthritis, lupus, ulcerative colitis, psoriasis
t/f: cancer chemotherapeutic drugs and immunosuppressants are very different
false, there is great overlap btwn immunosuppressants and cancer chemotherapeutic drugs (stop rapidly dividing cells)
what are the 2 main phases of the adaptive immune response?
induction and effector
what are the 2 parts of the induction phase of the adaptive immune response?
antigen presentation and clonal expansion/maturation
what is the antigen presentation phase?
an antigen-presenting cell absorbs, processes, and expresses an antigen to a T-helper precursor cell which activates that clonal expansion and differentiation phase
what is the clonal expansion and maturation phase? (3)
T-helper precursor cells release IL-2 which has + feedback causing incr division and differentiation into T-helper 0 cells, Th0 cells secrete IL-4 (same + feedback as IL-2) and cause differentiation into Th1 and Th2 cells, Th1 cells become mature Th1 cells or cytotoxic t-cells and Th2 cells become B-cells (both by clonal expansion)
what is the effector phase? (3)
B-cells produce antibody-mediated response (Abs against Ags), T-cells produce cell-mediated response (Th1 cells secrete cytokines, cytotoxic t-cells kill infected cells)
what is the adaptive immune response aka?
specific immune response
what phase of the adaptive/specific immune response do most immunosuppressant drugs exhibit their effects?
induction phase
what 5 steps/mechanisms do immunosuppressant drugs target/utilize?
- inhibit IL-2 (+ feedback)
- inhibit cytokine gene expression (glucocorticoids)
- cytotoxicity (kill immune cells/prevent maturation/expansion)
- inhibit nucleic acid synthesis (rapid repl’n during clonal expansion)
- block t-cell surface receptors (Abs block Ag-presentation/immune response activation)
what does activation of Th0 cells require?
activation of calcineurin-NFAT (nuclear factor of activated t-cells) signalling pathway
what is that calcineurin-NFAT pathway?
t-cell receptor (interacts w/ APC) activation generates Ca signal (via PLC) that activates calcineurin (phosphatase) which dephosphorylates NFAT
what can dephosphorylated NFAT do? (3)
migrate to t-cell nucleus, act as a transcription factor and express IL-2 gene (for t-cell maturation/proliferation)
what are 2 ex of calcineurin inhibitors?
cyclosporine and tacrolimus
what are the targets of cyclosporine and tacrolimus resp.?
cyclophilin and FKBP
what do drug-bound cyclophilin and FKBP do?
suppress calcineurin, decr NFAT transcription of IL-2 and suppress t-cell maturation/proliferation
what do proliferation signal inhibitors do?
interfere w/ signals of IL-2 receptor activation
what is a major pathway responsible for cell growth and proliferation? (affected by proliferation signal inhibitors)
mTOR
what is an ex of a proliferation signal inhibitor?
rapamycin (aka sirolimus)
what is the target and effect of rapamycin/sirolimus?
FKBP (same as tacrolimus)
t/f: rapamycin/sirolimus has the same effects as tacrolimus when bound to FKBP
false, rapamycin-FKBP doesn’t inhibit calcineurin
what does rapamycin-FKBP do?
inhibits mTOR (mammalian target of rapamycin) protein complex
what are 4 effects of IL-2R activation?
genome replication, cell division, clonal expansion, further IL-2 expression (+ feedback)
how does rapamycin/sirolimus-FKBP inhibit t-cell growth/proliferation?
targets and inhibits mTOR which decr IL-2 pathway
what are cytotoxic agents?
“dirty drugs” (less specific) that interfere with DNA repl’n in rapidly dividing cells
what is cyclophosphamide?
alkylating agent that generates intrastrand cross-linking btwn bases which interferes w/ DNA repl’n/division (rapidly dividing cells: cancer, immune)
what is azathioprine?
purine analog so interferes w/ appropriate purine synthesis (competes for enzymes) and prevents cell repl’n/division (rapidly dividing cells: cancer, immune)
what are 2 cytotoxic immunosuppressants?
cyclophosphamide and azathioprine
what is the general structure of an antibody (Ab)?
2 heavy chains, 2 light chains
what/where is the Fab vs Fc region on an Ab?
Fab: determines Ag specificity (variable); upper
Fc: determines antibodies class (conserved); lower
how can Abs potentially target/treat troublesome cells?
Abs can be raised to recognize specific antigens on tumour/hyperactive immune cells (autoimmune) and stop them from dividing
what is the Fc region of an Ab recognized by?
different immune cells (diff responses)
what is the issue w/ using non-human Abs for treatment?
are recognized as non-self and targetted/degraded by our immune system
What is the solution to the issue w/ using non-human Abs?
Use “chimeric” or “humanized” version of murine/mouse monoclonal Abs so host is less likely to recognize/destroy them
What are humanized/chimerized Abs?
Human Fc region of Abs with foreign Fab region to resemble human Abs (decr rejection)
What do therapeutic monoclonal Abs end w/?
“Mab” (human: -umab/-zumab, chimerized: -imab/-ximab)
what is alemtuzumab?
humanized IgG1 Ab that binds to CD52 receptor on immune cells
how does alemtuzumab trigger immune cell death?
IgG1 Fc domain (human) is recognized by phagocytic immune cells which lyse or phagocytose the cell
t/f: alemtuzumab is a very specific immunosuppressant
false, it is not specific as it will destroy healthy and destructive T and B cells
what is basiliximab?
chimeric mouse-human IgG1 Ab that binds to CD25 part of IL-2 receptor on activated lymphocytes
how does basiliximab exhibit immunosuppressant effects? (2)
IL-2 antagonist (prevents clonal expansion) and triggers lysis/phagocytosis by phagocytic immune cells (recognize Fc region)
