immunosuppression Flashcards
undesirable immune responses
allergy
organ transplant rejection
autoimmune diseases
HSCT
Haematopoietic Stem Cell Transplantation
treats haematogical maligancies
can be allogenic (donor) or autologous (self)
must destroy host immune system before transplantation
graft versus host disease
complication of HSCT
transplants own mature T cells react against host tissue
severe inflammatory disease
autoimmune diseases
immune response to antigens from own tissue
immunosuppressive drugs mechanisms
1) inhibit cytokine production
2) inhibit cytokine gene expression
3) cytotoxics
4) antibodies
toxicites to host are reversible after reduced dosage, except for increased risk of maligancy which remains
inhibition of cytokine production
tacrolimus and cyclosporine
- inhbits calcineurin
- blocks expressionof IL-2, IL-3, TNF-a
- blocks T cell proliferation
- blocks B cells
- nephrotoxicity, hypertension, malignancy, neurotoxicity
sirolimus
- not calcineurin dependent
- blocks T cell and B cell activation by blocking cytokines
- prevents cell cycle progression
- haematogical toxicities - anaemia
- metabolic and gastro-intestinal effects
inhibiting cytokine gene expression
corticosteroids
-derivaties of steroid hormone
-e,g predisalone
-upregulate PRR genes and cytokine receptors
-downregulate pro inflammatory cytokines
cause fluid retension, bone mineral loss, thinning of skin
cytotoxics
kill rapidly dividing cells - lymphocytes, cancer
-interfere with DNA synthesis
used before HSCT to destory immune system
antimetabolites
cytotoxic
methotrixate, azothioprine
-azothioprine converted to purine antagonist, interferes with nucleic acid synthesis
not as toxic as cyclophosphamide
bone marrow suppression (cytotoxic to lymphocytes, used before HSCT)
alkylating agents
used in HSCT
cyclophosphamide alkylates DNA
highly toxic - even in accumulative dosage
cytopenia, infertility, cardiac toxicity, birth defects
antibodies
against specific antigen
monoclonal:
depleting: trigger destruction of lymphocytes by macrophages and NK cells - ADCC
non-depleting: stop cell being able to carry out function
targets: plasma proteins e.g antiTNFa used in Crohn’s and rheumatoid arthritis
cell surface antigens e.g anti-CD40
toxicity: hypersensitivity, antibodies produced against monoclonal antibodies - autoantibodies
immune suppression in bacterial infections
staphylococci produces TSST-1, acts as super antigen, cytokine storm, lymphocytes undergo apoptosis,organ failure, toxic shock syndrome
mycobacterium lepra - in lepromatous, cell mediated immunity is repressed, no TH1 cytokine, leads to wrong Th response, poor prognosis
immune suppression in viral infections
EBV encodes Il-10 homologue, inhibits TH1 cells, no killing of virally infected cells
HIV infects CD4 cells
