Transplantation and Immunosuppression Flashcards
Autograft
from one part of the body to another
Isograft
between genetically identical twins
Allograft
between different members of the same species
Xenograft
between different species
Sir Peter Medawar (Nobel prize 1960)
“Graft rejection is an adaptive immune response”
Skin transplant rejection
- mediated by lymphocytes
- specific response
- escalating intensity with exposure
- demonstrates memory
What graft specific antigens are targeted?
- MHC (class I&II)
- class I present CD8+ T cells (on all nucleated cells(
- class II present to CD4+ Tcells (restricted to DC, macrophages, Bcells etc)-APCs
MHC are polymorphic
HLA - human leukocyte antigen
-polymorphic therefore an exact match is unlikely
Human MHC is located on which chromosome?
chromosome 6
Serologic HLA testing
-less common now in era of molecular HLA testing
- uses antibodies specific for different HLA alleles
- bind to cells ecpressing specific HLA
- detect bound antibody by ability of complement to lyse the cells
- lysed cells take up dye
- can therefore map donor/recipient HLA alleles and optimise compatibility of transplant
How would you determine if a patient has any pre-formed antibodies to the donor (HLA) :Cytotoxic cross mathing
- cells (T and B separated) from the potential donor
- patient serum added
- complement added
- no antibody binding to cells, cels are not killed by complement action (live cells stain green)
- patient has HLA antibody that binds to HLA antigen on cells in well, causing cells to be killed by complement action (stained red)
- Add stain to distinguish live and dead cells
Allorecognition: INDIRECT
- uptake of allongenic antigen by host APC
- donor antigen degraded into peptides and presented on recipient MHC as for any exogenous antigen
- activated T cells can provide help to effector cells (Macrophages, antigen specific Bcells etc)
Allorecognition: DIRECT
- donor APC (passenger leukocytes) can leave the graft and migrate to the draining lymph node
- appropriate TCRs can directly recognise aloo-MHC as foreign (a mixed lymphocyte reaction;MLR)
- T cells are strongly activated, and drive effector responses
- important in early response
Stages of graft rejection:
- hyperacute
- acute
- chronic
Hyperacute:
- usually requires sensitisation/Ab formation
- less prominent in first allografts
- Ab and complement mediated
- occurs following vascularisation (minutes to hours)
- look over stages
Acute transplant rejection:
- cellular response to graft, involving CD4 and CD* Tcells and effectors (macrophages via IFNg/TNF))
- help B cells(via IL-4)
- rapid
- can start about a week after transplant
- occurs most often within the first year
Chronic transplant rejection
- slowly progressive, long term loss of function (after 1 year)
- associated with low grade chronic DTH, fibrosis, vascular pathology
Corticosteroids
- powerful anti-inflammatory drugs
- bind to steroid receptors in cell cytoplasm
- affect gene transcription (prevent production of cytokines IL-1,IL-3,IL-4, TNF, GM-CSF)
- block prostaglandin production
- reduce cell migration
- promotes inflammatory cell apoptosis
Nucleotide synthesis inhibitors
- azothioprine and mycophenolate mofetil (MPA)
- blocks purines synthesis
- inhibits DNA and RNA synthesis
- prevents lymphocyte division
- prevents IL-2 production and lymphocyte activation
- toxicity to other dividing cells
Calcineurin Inhibitors
- cyclosporin revolutionised kidney transplantation in the 80s
- complexes with calcineurin to prevent NFAT de-phosphorylation
- NFAT can’t induce IL-2 gene transcription
Cytokine action inhibitors
- rapamycin (sirolimus)
- blocks mTOR(mammalian target of raamycin)
- prevents cell cycle (g1->S)
Biologic agents (antibodies and fusion proteins)
- Anti CD3 (OKT3)
- disables CD3 receptor
- Anti IL-2 receptor (CD25)
Side effects of these immunosuppresants
- corticosteroids (growth retardation, osteoporosis, hypertension, obesity diabetes)
- Nucleotide synthesis inhibitors (bone marrow suppression, hepatic dysfunction, hair loss, GI effects)
- Calcineurin inhibitors (diabetes etc)
- Antibodies (cytokine release syndrome etc)
what is donor specific tolerance?
- introduced to the recipient
- research ongoing
- avoids long term treatment with broad acting immunosuppressants
Self tolerance
- control or removal of T cells specific for innocuous or self antigens
- active processes include: regulation/suppression, anergy, apoptosis