3.4 Transplantation Flashcards
Types of grafts – allografts are most commonly used in solid organ transplants
Autograft: Within the same individual
- Coronary artery bypass graft – ____, ________, _____
- Reconstructive surgery – skin grafts, jaw reconstruction from ________ , hair etc.
- Bone marrow transplant – bone marrow stem cells are aspirated and purified, then irradiated to remove malignant or deficient bone marrow cells, followed by recolonization with purified stem cells
Isograft: Between genetically identical individuals of the same species i.e. identical twins
Allograft: Between different individuals of the same species
- Solid organs (kidney, liver, heart, lung, pancreas)
- Small bowel
- Free cells – bone marrow, pancreas islets (endocrine cells)
- Temporary – blood, skin (burns)
- Immunologically privileged sites – cornea
- Framework – bone, cartilage, tendons, nerves
- Composite – hands, face
Xenograft: Between individuals of different species – e.g. prosthetic grafts, materials such as plastic or metal
left internal thoracic artery, radial artery or saphenous vein;
fibula
Donors – donors can be living or dead
- Living donors: ___, ___________, _________
- Deceased donors: solid organs (kidney, heart, pancreas, lungs, liver) and others (cornea, heart valves, bone, skin, composite)
o Types of deceased donors –
Brain dead, heart-beating (DBD – donor after brain death) e.g. road traffic accident, massive cerebral haemorrhage
- Circulation maintained by artificial ventilation
- Confirmation of brain death
- Harvest organs and cool to _____________ – to ensure optimum quality of donated organs
Non-heart beating donors (DCD – donor after cardiac death)
- Circulation stopped for an extended period
- Heart stopped before organ harvest
- Longer period of warm ischaemia time – may lead to more complications such as slower function in the post-operative period
- Suitable for _______
bone marrow, kidney (in healthy patients, rare and minor risks only), liver (lobe);
minimise ischaemic damage;
kidney
Brain dead, heart-beating donors – stringent criteria is used to conform brain death
- There must be an irremediable structural brain damage with a known cause
- Apnoeic coma must not be due to ___________, ___ or , ____, _______
- Demonstration lack of brain stem function – pupils both ________, corneal reflex absent, no eye movements with cold caloric test, no cranial nerve motor responses, no gag reflex, no respiratory movements on disconnection (with _______________)
- Potential donors are also assessed for viral infection (, __, ______ etc.), malignancy, drug abuse and disease of organs
- Removed organs are rapidly cooled and perfused in specific fluids – the time limit from organ harvesting to transplant depends on the organ
o The absolute maximum cold ischaemia time for kidney is _________ (ideally < 24 hours), and is much shorter for other organs
o Cornea – ________, longer with cryopreservation
- Consent is important from the family before organ donation
depressant drugs, metabolic or endocrine disturbance, hypothermia or neuromuscular blockers;
fixed to light;
PaCO2 >50 mmHg;
HIV, HBV, HCV;
60 hours;
96 hours
ABO blood group – A and B proteins are present on the surface of red blood cells and endothelial lining of blood vessels in a transplanted organ
- Naturally occurring anti-B antibodies in A patients and vice versa, and O patients have both anti-A and anti-B
- Organ transplantation across different blood group barriers without specific management can lead to _______________
o e.g. heart transplant from a group B donor to a group A recipient – recipient serum contains naturally occurring anti-B antibodies
o Circulating, pre-formed, recipient anti-B antibody binds to B blood group antigens on donor endothelium
Activation of complement – complement mediated lysis, opsonisation, increased permeability
Other cells rapidly recruited – e.g. phagocytes (release of mediators and granzymes)
Disruption of endothelium – activation of platelets, inflammation and thrombosis - In recent years, it has become possible to remove the antibodies in the organ recipient with good outcomes
hyperacute rejection;
Human leukocyte antigens (HLA) – discovered after first failed attempts at human transplantation
- Cell surface proteins with a highly variable portion – variability of HLA molecules important in defence against infections and neoplasia
- Foreign proteins are presented to immune cells (T cells) in the context of HLA molecules being recognised by the immune cells as “self”
Classes of HLA
o Class I region (Expressed on all cells) – A, B, C genes encoding for various forms of the α chain which associates with the _______________ encoded for on different chromosome
o Class II region (expressed immune cells but also can be upregulated on other cells) during injuries –_______________, each contain an A and B gene encoding for α chain and β chain respectively, associating form
Class II HLAs
o HLA-A, HLA-B and HLA-DR are the most important in organ allocation
- Highly polymorphic – many alleles for each locus (for example: A1, A2, A3 etc.)
o There are 372, 661 and 401 HLA-A, HLA-B and HLA-DR1 alleles respectively - HLA haplotype and genotype – each individual has 2 alleles for each loci
o Donation is more favourable in related individuals – increased probability of matching in a smaller pool of HLA alleles
o For any given HLA type, amongst siblings, there is – 25% ______________, 50% __________ and 25% ___________ - In the case of a mismatch, the recipient’s immune system mounts a reaction against the donor’s HLA, as if it were an infection/cancer
o Results in rejection – destruction of the graft by cellular and antibody-mediated immune processes, eventually resulting in graft failure - HLA matching in organ allocation – number of mismatches can be from 0 to 6
o Minimising HLA differences between donor and recipient improves transplant outcome
o HLA matching is important in graft survival ____________ transplantation, controversial in liver transplant and not important in ___________________
invariant β2-microglobulin chain;
DP, DQ and DR regions;
2 haplotype match; 1 haplotype match; 0 haplotype match;
kidney and bone marrow ;
heart and lung transplant
Acute T-cell mediated rejection – results from recognition of donor HLA antigens by CD4+ TH cells
- Activation of CD4+ TH cells lead to a production of cytokines – help for CD8+ Tc cells, B cells, and the recruitment and activation of macrophages and neutrophils
o Similar to a ________________
o Biopsy of a graft undergoing acute T-cell mediated rejection – infiltration of ___________
o Presence of T cells can be illustrated by immunostaining with CD3
Type IV hypersensitivity response;
interstitium, tubules and sometimes blood vessels by macrophages and lymphocytes
Acute antibody-mediated rejection – production of antibody against graft HLA and/or AB antigen
- Antibodies can be present before transplantation (recipient has seen the antigen before – e.g. previous transplantation, transfusion) or arise after transplantation (from the graft)
o Antibodies fixed to the graft will activate _________________
o Hyperacute rejection – refer to above - Biopsy – neutrophils in peritubular capillary between tubules, positive immunostaining of ______________ (suggests complement activation)
Antibody activates complements and macrophage
- Activates complement: classic complement activation, complement mediated lysis, opsonisation, increased permeability
- Other cells rapidly recruited: phagocytes via ____________
- Disruption of endothelium: platelets activated, inflammation, thrombosis, ischemia of organs
complement and macrophages;
complement fragment C4 in the peritubular regions;
Fc receptors ;
Diagnosis of rejection
- Kidney, liver, pancreas – graft dysfunction detected by regular blood tests (e.g. creatinine, liver function, amylase)
o If detected, ________________ is needed to distinguish rejection from other causes of graft dysfunction such as drug toxicity
- Heart – no good test for dysfunction, ______________
graft biopsy and histological interpretation;
regular endomyocardial biopsies
Prevention and treatment of rejection
- Prevention – maximise _______________ and suppressing the immune reaction of the recipient by immunosuppressive drugs
o Standard, lifelong administration after transplantation
- Further immunosuppressive drugs are added if graft rejection is diagnosed
- Immunosuppressive drugs – can target T cell activation and proliferation or B cell activation and proliferation
- Anti-T cell drugs target different points on the pathway – common drugs include __________________
- Anti B-cell drugs – bortesomib (______________ inhibitors) has anti T cell actions but causes plasma cell apoptosis
HLA compatibility;
calcineurin and corticosteroids;
proteasome
Immunosuppression
Modern transplant immunosuppression – usually 3 components
- Induction agent to deplete immune cells before transplantation (example: ________ Campath will deplete T cells)
- Baseline immunosuppression – variable, commonly involving a signal transduction blockade, usually a CNI inhibitor (Tacrolimus or Cyclosporin, sometimes ____________ Rapamycin)
o +/- antiproliferative agent – MMF or Azathioprine
o +/- corticosteroids
- Treatment of episodes of acute rejection – depends on type of rejection on biopsy
o Cellular – steroids, anti-T cell agents
o Antibody-mediated – IVIG, plasma exchange, anti-C5
- Balance between prevention of rejection and long-term side effects such as infection, tumours and drug toxicity (________________ associated with substantial cardiovascular risks)
Post-transplantation infections
- Increased risk for conventional infections – bacterial, viral, fungal
- Opportunistic infections – normally relatively harmless infectious agents give severe infections because of immune compromise
o Cytomegalovirus, BK virus, Pneumocytis carinii
Post transplantation malignancy
- Skin cancer
- ________________ disorder – EBV driven
- Others – common malignancies
anti-CD52;
mTOR inhibitor;
hypertension and hyperlipidaemia;
Post-transplant lymphoproliferative
