Transplants

sophie_connor
Mind Map by , created over 6 years ago

Immunology Mind Map on Transplants, created by sophie_connor on 05/23/2013.

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Created by sophie_connor over 6 years ago
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Transplants
1 Why transplant?
1.1 Cure for organ specific disease
1.2 Skin
1.2.1 Burns victims
1.2.2 Temporary grafts of non-viable tissue
1.3 Blood
1.3.1 Transfused from living donor
1.3.2 ABO and Rh matching required
1.3.3 Complications extremely rare
1.4 Pancreas
1.4.1 From cadaver
1.4.2 Islet cells from organ sufficient
1.5 Kidney
1.5.1 From live donor or cadaver
1.5.2 ABO and MHC matching useful
1.5.3 Immunosuppression usually required
1.6 Bone marrow
1.6.1 Needle aspiration from living donor
1.6.2 Implanted by IV injection
1.6.3 ABO and MHC matching required
1.7 Liver
1.7.1 From cadaver
1.7.2 Surgical implantation complex
1.7.3 Resistant to hyperacute rejection
1.8 Heart
1.8.1 From brain dead donor
1.8.2 MHC matching useful but often impossible
1.8.3 Risk of coronary artery damage
1.9 Lung
1.9.1 From brain dead donor
1.9.2 Procedure recently developed
2 History: skin transplantation
2.1 Early experimentation had little success
2.2 Skin grafting was attempted on burnt patients in WW2
2.3 Skin could be grafted from one part of the body to another
2.4 Skin could not be grafted from one individual to another unless they were identical twins
2.5 Athymic children have no lymphocytes so could not make immune responses and could accept any skin graft
3 Genetic basis of transplant rejection
3.1 Inbred mouse strains means all genes are identical
3.2 Transplantation of skin between strains showed that rejection or acceptance was dependent on the genetics of each strain
3.3 Skin from inbred mouse grafted onto the same strain of mouse is accepted
3.4 Skin from inbred mouse grafted onto a different strain of mouse is rejected
3.5 Mouse grafted with different skin, rejected and lymphocytes taken and injected into a new mouse
3.5.1 Same graft transplanted to injected moues is again rejected but much faster: secondary rejection
3.5.1.1 If injected mouse is grafted with a different skin, primary rejection occurs
3.6 Rejection response shows all hallmarks of an adaptive immune response
3.6.1 Property of lymphocytes
3.6.2 Specific
3.6.3 Escalating response
3.6.4 Memory
3.6.5 Primary rejection: slow (naive)
3.6.6 Secondary rejection: fast (memory)
3.7 Isograft: twin to twin
3.8 Autograft: me to me
3.9 Allograft: person to person
3.10 Xenograft: species to species:
4 Role of T cells in graft rejection
4.1 CD4 T cells are important for rejecion
4.2 Anti CD4/CD8 is used to determine levels after grafting
4.3 A mouse with no CD4 cells (nude mouse) will tolerate a skin graft
4.3.1 A mouse with CD4 T cells will undergo actue skin rejection after a skin graft
4.4 CD8 T cells will tolerate the graft only if they are sensitised by CD4 T cells
5 Transfusion vs. Transplantation
5.1 Transfusion
5.1.1 Transfer of blood
5.1.2 Ab mediated reactions
5.2 Transplantation
5.2.1 Transfer of tissue or organ
5.2.2 T cell mediated reactions
5.2.3 Transplantation antigens
5.2.3.1 ABO: limited polymorphism
5.2.3.2 MHC: high polymorphism
5.2.3.2.1 Recipient immune system destroys MHC in graft
5.2.3.3 non-MHC antigens: limited polymorphism
5.2.3.4 Xenoantigens: high polymorphism
5.2.3.5 Alloantigens: molecules that are recognised as foreign on allografts
5.2.3.6 Alloreactive: lymphocytes that interact with alloantigens
6 MHC
6.1 In mice MHC is called H2
6.2 Rapid graft rejection between strains segregated with antigen-2 encoded as part of MHC halotype
6.2.1 A set of genes inherited as a unit
6.3 Inbred mice identical at H2 did not reject skin grafts from each other
6.3.1 MHC genetics in mice are simplified by inbred strains
6.4 In humans, only monozygous twins have identical MHC
6.4.1 The human population is extensively outbred
6.4.2 MHC genetics in humans is extremely complex
6.4.2.1 MHC is polygenetic: many genes encode different MHC
6.4.2.2 MHC is polyalleic: many gene alleles at each locus
6.4.2.3 MHC is polymorphic: many variations in amino acid sequence
7 Transplant rejection
7.1 The failure of a recipient's body to accept transplanted tissue of organ as the result of immunological incompatibiilty
7.2 Association with inflammation and lymphocyte infiltration
7.3 Autograft acceptance
7.3.1 Grafted epidermis
7.3.1.1 Day 3-7: revascularisation
7.3.1.1.1 Days 7-10: healing
7.3.1.1.1.1 Days 11-14: resolution
7.4 First set rejection
7.4.1 Grafted epidermis
7.4.1.1 Days 3-7: revascularisation
7.4.1.1.1 Days 7-10: cellular infiltration
7.4.1.1.1.1 Days 11-14: thrombosis and necrosis
7.5 Second set rejection
7.5.1 Grafted epidermis
7.5.1.1 Days 3-4: cellular infiltration
7.5.1.1.1 Days 5-6: thrombosis and necrosis
7.6 Hyperacute rejection
7.6.1 Occurs within hours after transplantation
7.6.2 Immediate graft rejection
7.6.3 Primary mechanism: humoral mediated rejection
7.6.3.1 Preformed antibodies from previous transplants or multiple pregnancies
7.6.3.2 Caused by transplanting organ with incompatible blood type
7.6.4 Prevented by selecting donors with compatible blood types
7.6.5 Outcome is irreversible and untreatable
7.6.5.1 Transplanted organ must be removed
7.6.6 Example: kidney graft
7.6.6.1 Pre-existing antibodies are carried to graft
7.6.6.2 Antibodies bind to antigens of renal capillaries and activate complement
7.6.6.3 Complement split products attract neutrophils which release lytic enzymes
7.6.6.4 Neutrophil lytic enzymes destroy endothelial cells; platelets adhere to injured tissue, causing vascular blockage
7.7 Acute rejection
7.7.1 Occurs within weeks/months after transplant
7.7.2 Class I and II antigens on the cells of the transplanted graft activate cellular mediated rejectionn
7.7.3 Treatable and reversible
7.7.4 Example: skin graft
7.7.4.1 Skin graft with Langerhans cells
7.7.4.2 Langerhans cells migrate to local lymph node where they activate effector cells
7.7.4.3 Effector cells migrate to graft via blood
7.7.4.4 Graft destroyed by effector cells
7.7.4.5 Initiation of graft rejection involves migration of donor APC from the graft to the local lymph node
7.8 Chronic rejection
7.8.1 Develops over months/years
7.8.2 Combination of cellular and humoral
7.8.3 Results in diffuse scarring tissue and stenosis of vasculature of organ
7.8.4 Untreatable and eventually leads to graft loss
7.9 Problems with pre-existing antibodies
7.9.1 Allotransplants
7.9.1.1 Natural antibodies to ABO blood group antigens
7.9.1.2 Anti-MHC antibodies raised during previous transfusion, transplant or pregnancy
7.9.1.3 Solution: test recipient serum for ABO compatibiilty and negative crossmatch
7.9.2 Xenotransplants
7.9.2.1 Natural antibodies to Gala1-3Gal epitope present in non-primate mammals
7.9.2.2 Solution: agalactosyl transferase knockout pig
7.9.3 Sensitisation
7.9.3.1 'Passenger' leukocytes drain out of the graft and into the recipient lymph nodes
7.9.3.1.1 Recipient CD4 lymphocytes recognise MHC II
7.9.4 Effector
7.9.4.1 Allospecific T cells differentiate into mature helper and cytotoxic T lymphocytes
7.9.4.1.1 Alloreactive effector cells migrate back to the graft: MHC disparate graft is destroyed
7.9.5 CD8 T cells lyse endothelial cells
7.9.5.1 CD4 T cells can recruit and activate macrophages-graft injury by a delayed type hypersensitivity reponse
7.9.5.1.1 Antibodies activate complement and injure graft vasculature
7.10 Recognition of alloanigens in grafted organs
7.10.1 Direct recognition: donor APCs migrate to local lymph node and stimulate alloreactive recipient T cells
7.10.1.1 Donor MHC/peptide complexes are directly recognised by recipient TCR
7.10.2 Indirect recognition: recipient APCs process and present peptides derived from graft
7.10.2.1 Fragments of donor cells can be processed and presented by recipient APC and presented to T cells
7.11 Allorecognition
7.11.1 Sequences of donor MHC II molecules are frequently found in self MHC peptide grooves
7.11.2 This is thought to play a role in the later stages of the rejection process (chronic rejection)
8 Minor antigen incompatibility
8.1 Complete MHC matching does not ensure graft survival
8.2 Responses to minor antigens are much less potent than responses to MHC because the frequency of the responding T cells is much lower
9 Strength of the response
9.1 MHC II differences
9.1.1 High strength
9.1.2 Present on APCs and present peptides to CD4 T cells
9.2 MHC I differences
9.2.1 Mid strength
9.2.2 Present on all nucleated cells and highly polymorphic
9.3 Minor Histocompatibility complex antigens
9.3.1 Low strength
9.3.2 Minor polymorphisms
10 Alloreactive T cells
10.1 High precursor frequency
10.2 High determinant density
10.2.1 To activate antigen specific T cells- 10-100 MHC molecules are needed to present antigenic peptide
10.2.2 All foreign MHCs can act as ligands for the alloreactive TCR meaning there are more ligands for TCR
10.2.3 High concentration of ligand could stimulate a broader range of T cells with lower affinity
10.3 Multiple binary complexes
10.3.1 Donor allogenic MHC bind different spectrum of cellular peptides
10.3.2 Foreign MHC + self peptide could resemble self MHC and foreign peptide
10.3.3 Numerous different clones are activated by the allogenic MHC/peptide complexes
10.4 Foetus is a natural allograft tolerated by the mother
10.4.1 Trophoblast cells of the placenta lack expression of MHC molecules
10.4.2 Secretion of TH2 inducing cytokines
11 Tissue typing
11.1 Differences in MHC antigens are responsible for most intense acute graft rejection
11.2 Screens recipients and donors for their MHC type
11.3 Aim: to match donor to recipient
11.4 Serological techniques
11.4.1 Microtoxicity test
11.4.1.1 Cells from recipients and potential donors are tested against a series of different antibodies anti MHC I and II in the presence of complement
11.4.1.2 Cytotoxicity is assessed as uptake of dye by the lysed cells
11.4.2 MHC typing
11.4.2.1 Anti-MHC antibodies attach to MHCs on lymphocyte
11.4.2.1.1 Complement and trypan blue dye added
11.4.2.1.1.1 Cell damaged by complement takes up dye
11.4.3 Cytotoxic cross match
11.4.3.1 Presence of anti-donor antibodies is detected by the ability of the recipient serum to lyse donor cells
11.4.3.2 Cannot distinguish between MHC I and II antibodies
11.4.3.3 Cannot distinguish between IgM and IgG
11.4.4 Flow cytometric cross match
11.4.4.1 Presence of anti-donor MHC antibodies is detected by the ability of recipient serum to bind to donor cells
11.4.4.2 Very sensitive, rapid, specific technique
11.4.5 Mixed lymphocyte reaction (MLR)
11.4.5.1 In vitro model of direct T cell recognition of allogenic MHC
11.4.5.2 Predictive test of cell mediated graft rejection
11.4.5.3 Donor cells irradiated
11.4.5.3.1 If recipient cells lack MHC II sharing with donor then recipient cells will be activated and proliferated
11.4.5.3.1.1 Radioactivity of donors will be incorporated into cell nuclear DNA
11.4.5.3.1.1.1 Graft will be rejected
11.4.5.4 Time consuming
11.5 Molecular technqiues
11.5.1 Restriction fragment length polymorphism
11.5.1.1 Cleave DNA with restriction enzymes
11.5.1.1.1 Separate fragments on agarose gel
11.5.1.1.1.1 Probe with labelled cDNA
11.5.1.1.1.1.1 PCR
11.5.2 Sequence specific oligonucleotide typing (SSO)
11.5.2.1 Amplify group of alleles
11.5.2.2 Sequence specific oligonucleotide probes used to detect polymorphic sequences in the amplified DNA
11.5.3 Advantages
11.5.3.1 Accuracy
11.5.3.2 Cell type, viability, surface expression are unimportant
11.5.3.3 DNA probes are easier to make than continuous screening for allo-antisera
11.5.3.4 Easy to assay large batches
11.5.3.5 Reproducible
11.6 Test for MHC antigens
11.6.1 Serological detection
11.6.1.1 Measures difference between donor and recipient antigens
11.6.1.2 Monoclonal antibodies used for defining MHC antigens
11.6.2 Dectection of transplantation antigens by mixed leukocyte reaction
11.6.2.1 Leukocytes from donor and recipient are cultured together for several days
11.6.2.2 See if recipient lymphocytes will react against donor MHC antigens
11.6.2.3 Reaction intensity depends on degree of MHC differences
11.6.2.4 Lengthy procedure
11.6.3 Genotyping of transplantation epitopes
11.6.3.1 Type epitopes on MHC molecules rather than entire molecule
11.6.3.2 Typing on genomic level
11.6.3.2.1 Detects differences between amino acids
11.6.3.3 More accurate than serological
12 Transplant promises
12.1 Improvement in quality of life
12.2 Highly successful surgical treatment
13 Bone marrow transplant
13.1 Provides a functional immune system
13.1.1 Individuals with SCID
13.2 Replaces a defective haemopoeitic system
13.2.1 Cure patients with life threatening disorders such as thalaseemia
13.3 Restoring haemopoeitic system of cancer patients
13.3.1 Chemotherapy can destroy system
13.4 10% donor bone marrow is enough to restore system
13.5 Haemopoietic stem cells find their own way to bone marrow after IV injection
14 Immunocompromised host
14.1 Immunocompetent lymphoid cells are transplanted in an immunological incompetent host
14.2 Host appears foreign to the graft
14.3 Pre treatment with chemotherapy
14.3.1 Eliminates malignancy
14.3.2 Provides immune supression to prevent rejection of new stem cells
14.3.3 Creates space for new stem cells
14.4 Conditioning
14.4.1 Total body irradiation or chemotherapy can cause extensive damage to host tissue
14.4.1.1 Allows translocation of microbial products
14.4.1.1.1 Stimulates secretion of pro-inflammatory cytokines
14.4.1.1.1.1 Activated macrophages produce chemokines that activate neutrophils which increase inflammation
14.4.1.1.1.1.1 Increases expression of MHC and adhesion molecule on host, enhancing their antigen presenting capacity
14.5 Induction
14.5.1 Activation of donor T cells
14.5.1.1 Drain GVHD target organs
14.5.1.1.1 IFN production
14.5.1.1.1.1 MHC on APC and antigen presentation
14.5.1.1.1.1.1 CD8/CD4 expression and NK cells
14.5.1.1.2 Symptoms of GVHD
14.5.1.1.2.1 Pruritic rash often on palms, soles and ears progressing to total body erythroderma
14.5.1.1.2.2 Gastrointestinal symptoms: anorexia, nausea, diarrhoea and abdominal pains, liver dysfunction and selective epithial damage or target organs
14.5.1.1.2.3 Clinical result: severe immunodeficiency and immunocompetence

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