transplantation Flashcards
how much of the world has renal disease
11%
When start dialysis for end stage renal failure - 5yr survival
35%
what can be given as allographs
- Solid organs (kidney, liver, heart, lung, pancreas)
- Small bowel
- Free cells (bone marrow stem cells, pancreas islets)
- Temporary: blood, skin (burns)
- Privileged sites: cornea
- Framework: bone, cartilage, tendons, nerves
- Composite: hands, face
number of patients in UK living with transplant
52000
how long do kidney transplants last
Donated kidneys don’t last forever
Living donor has a higher survival rate - conditions are ideal, and donors are in good health
Deceased donor have a reduced half life
Living 13-14yrs, deceased 10yrs
how can we improve a transplant outcome
want patient and graft survival
improved surgical technique
Improved pre- and post-transplant patient management
* Drug levels
* Infections, cardiovascular disease, diabetes,…
Better understanding of transplant immunology
– > Prevention, diagnosis and treatment of graft rejection
what are the phases of immunological graft rejection
- Phase 1: recognition of foreign antigens
- Phase 2: activation of antigen-specific
lymphocytes - Phase 3: effector phase of graft rejection
what is the most important antigenic determinant of rejection
human leukocyte antigens/major histocompatability complex
ABO is important, and was important in past. Now less of a problem because techniques for removing these Ab before and after transplantation mean you can transplant across blood groups
Minor histocompatability can lead to rejection but less than major
what are the 2 types of immune mediated rejection
T cell mediated rejection
Ab mediated rejection
often have both
what are HLA
MHC is on chr 6
HLA class 1 (A B C) are expressed on all cells
HLA class 2 (DR DQ DP) - expressed on APCs, but can be upregulated on other cells during stress
the ag are on the surface of cells
have peptide binding groove to present ag - presentation of ag on HLA molecules to T cells is central to T cell activation/.
HLA antigens are highly polymorphic
100s of genotypes
Important for defence against infection
why is HLA polymoprphic
to max defense against infection or neoplasm
everyone has a variety of HLA
everyone’s HLA are derived from a large pool of population varieties
issue is the HLA variability provides source of immunisation against the transplanted organ
summarise phase 1 in T cell mediated rejection
interaction between APC which has HLA and the T cell
If T cell see peptide in this way with appropriate co-signals -> activated
write out the mismatches for this
Has 2 of 6 potential mismatches for these sites
Doesn’t mean that the other sites are not importany - eg DQ Is also very antigenic, only using these 3 loci is quite outdated because now know other places are antigenic - but we still use
why is it important to minimise HLA mismatches
improves transplant outcome in terms of graft survival
what is the degree of mismatching when use family for transplant
Encourage relative donation:
To minimise mismatches
Will be 50% matched with parents
In siblings - 25% can have 0MM
how do we determine people’s HLA type and what do we record
PCR
need to record their HLA and any previous transplants MM - because like infection if seen HLA before will -> reaction. So want to avodi repeat mismatches
record new mismatches and Repeat MM from previous transplant highlighted as concern
summarise phase 1 of T cell mediated rejection in situ
Bioth donor and host APC can present to T cell in secondary lympoid organs
T cell activated there and re-circulate
summarise phase 2 of T cell mediated rejection
T cell interact with APC through HLA
T cell proliferates
produces cytokines IL2 and IL15 that have autocrine effect -> more activated
co-stimulatory signal coming from APC -> strengthen activation
summarise phase 3 of T cell mediated rejection
graft damage by immune cells
T cells recirc through the donated organ - arrest and migrate through to intistial space
-> inflammation - recruit macrophages, cytotocxic T cells
-> injury by release of toxins, bas-l, perforin
Monocytes and macrophages release - proteolytic enzymes, cytokines, oxygen and nitrogen radicals
-> inflammation and destruction of tubules -> tubulitis
biopsy result for acute T cell mediated rejection
Loads of lymphocytes and macrophages in the tubules and between the tubules
Inflamatory cells produce cytokines -> injury
Transplant dysfunction and doesn’t filter -> creatine rises
Can attack arteries - intimal arteritis - ie inflammatory cells in intima of artery
Rx for T cell mediated rejection
OKT3 and ATG - deplete T cells by fixing on anti CD3 TCR -» cell death
alemtuzumab - kill by attach to anti CD52 receptor
calcineurin inhibitor - cyclosporin and tacrolimus - inhibit downstream processes that occur after TCR actuivation
mTOR inhibitors - effect pathway after cytokine activation
mycophenolate mofetil or azathiorpine - anti-proliferative drugs
corticosteroids
summarise phase 1 and 2 of B cell mediated rejection
B cell come into contact with ag
Get help form t follicular helper cell in germinal centre to affinity maturate
At germinal centre maturation can get plasma cells or memory B cells
biopsy of Ab mediated rejection
Capillaries of glomeruli are stuffed with inflammatory cells and swollen endothelial cells that are damaged - glomerulitis - defining feature of Ab mediated rejection
Only inflammatory cells are intravascular
None in tubular cells or between tubular
histology of complement in B cell mediated rejection
Footprint signiture of complement activation - immunohist stain fro C4d on endothelium
summarise ABO ab
A and B glycoproteins on RBC but also endothelial lining of blood vessels in transplanted organ - so can leadd to ab mediated rejection
naturally occuring anti-A and anti-B Ab
assays to check for HLA Ab
cytotoxic assays - does recipient serum kill donor’s lymphocytes in presence of complement - detection of deatrh using vital dyes - if cell death = +ve crossmatch - barrier to transplant
flow cytometry - does the recipient serum bind to donor’s lymphocytes - bound antibody detected by fluorescently-labelled anti-human Ig
solid phase assays - does recipient serum bind to recombinant single HLA molecules attached to solid support HLA beads - bound antibody detected
by fluorescently-labelled anti-human Ig (Synthetic beads rater than live cells each coated with different HLA epitope Ab will attach to bead - run through flow cytometry - help quantitate Ab against epitopes)
treatment for Ab mediated rejection
Often need body to be primed eg with infection or ischemia or dip in immunosuppressive drug to allow rejection to occur.
R4emove Ab with plasma exchange
Stop B cell activation
Abti-CD20 - rituximab - b cell depletion
BAFF inhibitors, or co-stimulation blockade molecules
velcade - proteosome inhibitor - stop production of Ab from plasma cells
If complement involved - complement inhibitors eg eculizumab
IVIG - reduce production of ig globally
drug toxicity in kidney - biopsy
calcineurin inhibitor - acute tubular injury
see by vacuolation of tubular cells - not m,any lymphocytes - so not inflammation, just alteration of cytoplasm
rx - reduce immunosuppressive drug
infection on biopsy in transplant patient
Get opportunistic infection - related to immunosuppression
BK nephropathy - reactivation of BK virus
Treatment - reduce immunosuppressive drug
vascular disease in transplant biopsy
a lot are hypertensive - hypertensive fibrous intimal thickening
Mx - BP control
post transplant lymphoproliferative disease on biopsy
Often related to EBV virus -> malignant transformation of B cells
rx - reduce immuno suppressive drug, chemo
recurrent glomerulonephritis after transplant - biopsy
Recurrence of what cause kidney to fail initiallt
Treatment - would be the treatment would give in the native kidneys
