Transplantation and the Immune System Flashcards
(123 cards)
1
Q
What are the three types of transplantation reject reactions that can occur?
A
Hyper acute rejection
Acute rejection
Chronic rejection
2
Q
What is hyper acute rejection?
(4)
A
This is antibody mediated rejection
It should never occur -> it only happens if we have not crossmatched the organ transplant -> any antibodies present should have been noted before the transplant ever happened
It is caused by pre-formed antibodies alrady present in the recipient
It is an untreatable reaction - it is irreversible but it should be preventable
3
Q
What is acute rejection?
(4)
A
It occurs when living donor cells from the donated organ travel to lymph nodes in recipient tissue and cause an immune response
It is the direct pathway of rejection
It is treatable with anti-rejection medications
It can happen weeks to months after transplant
4
Q
What is the process that occurs to acute rejection?
(6)
A
APCs present in donor tissue prior to transplant are in ischemic/inflammatory conditions (either from cadaver or surgery etc)
It is caused by the direct recognition of foreign MHC on APCs
These conditions prime the APCs to move to nearby secondary lymphoid organs as soon as theyre transplanted
These APCs come out at the paracortex of lymph nodes
These APCs display mismatched MHC molecules class (MHC from donor) which the recipient CD4 cells recognise as foreign
These CD4 cells respond and cause rejectinon by activating T cells etc etc
5
Q
What primes the donor APCs to move to secondary lymphoid organs as soon as they are transfused?
A
Low oxygen/ischemic conditions either because the donor organ is from a cadaver or from the surgery where the organ was removed and blood supply lost etc
Surgery in general is an inflammatory process which also primes these APCs
6
Q
Is acute rejection reversible?
A
Yes -> we can prevent r reverse the affects of acute rejection through the use of anti-rejection drugs such as Cyclosporin A or Tacrolimus
This allows us to transplant those who arent a complete match
7
Q
What is chronic rejection?
(6)
A
This is a form of rejection which happens months to years after transplant
It is caused by the indirect recognition of foreign MHC on APCs
It happens when the donor APCs die in the recipient
The APC degraded products are processed by recipient APCs
The fragments/epitopes from the mismatched donor MHC molecules of donor APCs can be incorporated in MHC class II of recipient cells
These antigens are then displayed by APCs to T cells etc etc
8
Q
Compare the treatmet of acute vs chronic rejection
A
Acute rejection is easily treated
Chronic rejection is much harder
9
Q
When might a transplant be considered?
A
To replace diseased, damaged or worn-out tissue
10
Q
What are the three requirements for a transplant tissue
A
Transplant tissue must perform their normal tissue function e.g. a transplanted kidney must produce urine
The health of both the recipient and the donor (living donor)/transplant (cadaveric donor) must be maintained during the surgery e.g. have to keep the tissue viable and donor alive
The immune system of the recipient must be prevented from destroying/rejecting the transplanted tissue
11
Q
How is the preferred method for keeping hearts viable?
A
We used to keep them refrigerated but now we know that hearts are actually more viable when kept warm
12
Q
For what conditions is transplantation actually considered the treatment of choice?
A
Burns
Trauma
Infection
Chronic disease
-> it saves ad extends many thousands of lives
13
Q
For how long have we been transplanting patients?
A
66 years
14
Q
Give a quick run down on the history of transplantation
(6)
A
5th centrury BC -> an autographic nose reconstruction requiring skin from another body site
In 1908 there was the first transplantation in cats
In WWII frozen skin samples were used to treat burn victims
In 1954 there was the first kidney transplant between identical twins
In 1961 there was the first non-twin living kidney transplant of mother to daughter
In 1964 we had the first heart transplant
15
Q
Comment on the first kidney transplant in cats
A
1908
Not mentioned how genetically similar the two cats for
The cat had urine output for 21 days
16
Q
Comment on the use of frozen skin grafts in WWII
A
These were less like transplants and were more used like gauze
Similar research ongoing in Brazil whereby fish tissue is used -> more like a dressing
17
Q
Why were the first organ to organ transplants done in twins?
A
This was because identical tins have a very high chance of sucess
This is pretty much an autograft
18
Q
Why would a mother/daughter transplant have a higher chance of success than strangers?
A
The child will be haploidentical to the mother
- half identical
- certainly better than a complete stranger who you might only share one allele with
19
Q
Write a note on our progress in anti-rejection drugs
(2)
A
We have yet to achieve selective suppression of the response to transplanted tissue
We have nonspecific suppression through the use of a variety of drugs and Abs which bring about widespread inactivation of the immune system
20
Q
What causes immune responses against transplanted tissue?
(2)
A
They are caused by genetic differences betwee ndonor and recipient e.g. HLA molecules
In particular the immune responses are provoked by alloantigens of HLA i.e. molecules that vary between members of the same species (alloreactions) -> immunogenetics is the study of this
21
Q
Why is nonspecific suppression to prevent rejection not ideal?
A
This leaves our patient (our already sick patient) extremely immunocompromised
This also leaves our patient at risk of developing cancer
Even at a maintenance level immunosupression increases the chance of cancer when taking them for long term
Especially increases the chance of carcinomas
It also prevents the bodys ability of surveillance
22
Q
Why does HLA play such a role in transplant rejection?
A
This is because the HLA locus is the most polymorphic gene i.e. there is a huge degree of ariability in the gene between persons
23
Q
What are the 2 types of alloreaction that can occur in clinical transplantation?
A
Transplant rejection (recipient vs donor)
Graft-versus-host reaction (GVHR) - GVHD (donor vs recipient)
24
Q
In general what is transplant rejection?
A
This is when a kidney is transplanted, the recipients T cells attack the transplant
25
In general what is graft versus host disease
When haematopoietic cells are transplanted, the T cells in the transplant attack the recipients tissues
26
How do we carry out a haematopoietic stem cell transplant/bone marrow transplants?
(4)
Recipients are put on myeloblative therapy
This kills of recipient immune system/cells to make room for the transfusion/transplantation of donor bone marrow
When donor cells are transplanted the Donor T cells will start to take over
These T cells will attack host tissues and cause graft versus host disease
27
Why dont we prevent graft versus host disease by removing the donor T cells before transplantation?
This is because the T cells can actually be beneficial to some patients
Graft versus leukaemia/Graft versus disease affect
In leukaemia patients the donor cells will actually attack any remaining leukaemic cells -> better outcome for the patient
Double edged sword
28
What kind of hypersensitivity is a rejection reaction?
These types of reactions are examples of type II, III and IV hypersensitivity
29
What are the different kinds of transplants?
Liquid transplants like a blood transfusion
Solid transplants like a kidney transplant
30
What are the four types of graft?
Autograft
Isograft
Allograft
Xenograft
31
What is an autograft, give an example of when they are used?
A transplant from one site to another on the same individual e.g. burn victim
From one part of the body to another
These are used for burn victims -> we are able to take a section of skin and expand it to increase the surface area
32
What is an isograft?
Its a transplant between genetically identical individuals e.g. twinz or within inbred strains
Also called a syngeneic transplant e.g. identical twins
First successful kidney transplant in 1954
33
What is an allograft?
A transplant between different members of the same species e.g. a mr smith to a mr jones
Also called an allogeneic transplant
Its a transplant between two genetically different individuals of the same species
34
What is a xenograft
A transplant between members of different species e.g. monkey to man
35
What animal is considered the most suitable donor species for humans, why is this?
Pigs
Their organs are of similar size
Pigs are already farmed, slaughtered and consumed by humans in large numbers
If person consumes pig they will have a degree of tolerance against pork antigens -> not all but toleragenic to some degree
36
What are some issues with pigs as xenotransplants?
(4)
Hyperacute rejection due to antibodies against alpha-Gal (a form of XNAs)
Most people have XenoAbs to porcine due to infection by common bacteria
Pig tissue cannot inhibit human complement cascade
Endogenous retrovirus that infects pigs also a concern
37
What is a XNA?
A xenoreactive natural antibody
38
What is the main XNA that causes hyperacute rejection associated with pigs transplants?
alpha-Gal
galactose-alpha1,3-galactose
39
What induces xenoantiodies against pigs in humans?
Humans produce antibodies against pig antigens
They are induced to do this when they are infected with common bacteria whose surface Carbohydrates resemble those of pig cells
40
What are some ways we try and make pig xenografts work?
We genetically modify pigs to exclude certain antigens such as alpha Gal
Weve began making chimeric animals where by weve added human stem cells to pig foetuses to grow human cells and tissues -> these studies have been limited due to ehtical reasons -> these animals were only allowed live for a few weeks
41
Why cant pig cells inhibit human complement?
Pig cells lack CD59
They done have complement regulatory molecules on cells as well
42
Comment on the use of primate organs in xenografts
Theres was limited success with primate organs
There was also more ethical issues associated with these than pigs
43
What antigens are important in organ and haematopoietic cell transplantation?
The ABO blood group antigens
HLA class I
HLA class II
44
What is tissue typing?
The use of molecular assays using sequence-specific primers to establish whch HLA alleles are expressed by the recipient and potential donors (tissue typing)
This has become common in recent years, especially in HSCT
There is higher specificity with molecular methods vs antisera methods
45
When was the first clinical transplant to save a llife carried out?
1812
46
How many people will need a blood transfusion in a life time, why?
1 in 4 people:
- trauma
- surgery
- childbirth
- disease
47
What are the four properties of blood that have led to its extensive use in transplants?
It is readily donated by healthy individuals at regular intervals without compromising their health
The procedure is simple and inexpensive
Transfused blood componentns are usually needed only in the short term. More stringent demand is placed on transplanted organs which need to function for years
Erythrocytes do not express either MHC class I or class II molecules
48
What kind of hypersensitivity reaction would an ABO mismatch transfusion reaction be?
It is a type II hypersensitivity which resultls in complement fixation and rapid clearance of the RBCs
49
How many blood groups are there?
There is now 46 blood groups and there is an additional one being considered for formal registration
50
How many genes are responsible for red cell antigens, why is this significant?
There are over 50 genes that determinered cell antigens
DNA-based methods are being considerd to type donors for all the different polymorphisms to enable more preise and selective matchgin
51
What is the most frequently transplanted kidney, how many are transplanted?
80% of all transplants are kidneys
Since the first transplant in 1950s there has been over 500,000 kidneys transplanted over the world
Since donors can live with one kidney the procedure is carried out much more frequently
the procedure has been really optimised, it has the best organ survival after being removed
52
After kidneys, what are the most commonly transplanted organs?
Livers, then heart, then lung then pancreas
53
Hyperacute rejection
54
How is ABO involved in hyperacute rejection?
ABO antigens are expressed on endothelial cells of blood vessels - this is a crucial factor in the transplantation of the highly vascularised organs
If a type O recipient were to receive a kidney graft from a type A donor, then anti-A Abs in the recipients serum would bind to blood vessels throughout the graft
By fixing complement throughout the graft's vasculature IgG Abs cause a very rapid rejection - hyperacute rejection - most devastating form of rejection for organ grafts - extreme form of type II hypersensitivity
55
How does ABO hyperacute rejection occur?
Healthy kidney is grafted into the patient
Preexisting antibodies against donor blood group antigens
Antibodies against donor blood group antigens bind vascular endothelium of graft, initiating an inflammatory response that occludes blood vessels
Graft becomes engorged and purple-colored because of haemorrhage
56
How do we avoid ABO hyperacute rejection?
We type and crossmatch for the ABO blood group antigens
57
Other than ABO blood group antigens, what other antigens can cause hyper acute rejection?
Pre-existing alloantibodies to HLA class I and class II to a lesser degree
58
Where are HLA class I molecules expressed other than red cells?
Vascular endothelium
59
Why does HLA class II cause hyper acute rejection to a lesser degree than HLA class I
Class II is only expressed on donor APCs compared to Class I being expressed on all nucleated cells
60
How do we prevent HLA incompatible hyper acute rejection, why is this so important to do?
It is avoided by assessing HLA compatibility using a cross-match test
Impossible to reverse hyperacute rejection
61
How did we used to carry out a HLA compatibility cross match?
Traditionally it was done by detecting antibodies in the recipients serum that triggers complement-mediated lysis of the prospective donors lymphocytes (same as ABO)
The lymphocytes from a peripheral blood sample were separated into T cells (MHC I) and B cells (MHC II) to determine if antibodies are present against MHC I or MHC II
This is known as CDC screening for DSAs, this has since been replaced with flow cytometry
62
What are the two ways of carrying out CDC screening for DSAs?
We can detect either C1q -> complement or against bound antibody
If lysis occurs then DSA is present in patients serum
63
How do we carry out CDC screening for DSAs
We culture lymphocytes and separate them into donor T and B cells
Donor cells are mixed with recipeint plasma
If antibodies present in plasma they will bind to the MHC molecules
AHG is then added, this will bind to anti-MHC antibodies - crosslinking
This mediates complement? and lysis occurs
64
What is the new method of HLA crossmatch screening for DSAs
Flow cytometry (FCXM)
We use it to examine patient Ab binding to the prospective donor's lymphocytes - this allows detection of all isotypes, not just those that fix complement
65
What is FXCM
A standard technique for evaluating the compatibliity of potential kidney transplant recipients and donors
Recipient serum is incubate with donor lymphocytes and the latter are analysed in a flow cytomter for the presence of bound IgG antibodes - Luminex assay for FC, which does not rely on the procurement of donor cells, has been more recently developed
66
What is Luminex FCXM for detection of DSA?
It makes use of luminex beads expressing different HLA alleles
Each bead are single allele beads (very specific)
Any DSAs present in plasma will bind and coat the beadds
We then add FITC conjugated rabbit anti-humanIgG
67
How can we modify a FCXM to determine if a DSA is complement fixing or not?
We can determine if the DSA is complement fixing antibody by addinf in complement before adding anti - DSA specific antibody
DSA -> C1q ->fluorophore-conjugated anti-human C1q
68
Why do we preform multiple crossmatches, when are they done?
Patient is originally typed
Since recipients anti DSA status can change they must be recrossmatched after any recent exposure e.g. blood transfusion or previous transplant
We will always crossmatch just before actual donor organ transplantation
69
What are the four ways a person can become sensitised against HLA
Pregnancy
Blood transfusion
Previous organ transplant
Infectious agents
70
How can pregnancies cause anti-HLA sensitisation
Mother and father usually differ in HLA class I and class II type
During gestation cells of the foetus are not exposed to maternal immune system
During trauma of birth maternal circulation is exposed to fetal cells and stimulates the production of antibodies against paternal HLA
Risk of sensitisation increases with successive pregnancies i.e. multiparous women
71
How can blood transfusions cause anti-HLA sensitisation
In routine blood transfusion, patients are matched for ABO type but not HLA type
Infusion of HLA-incomaptible leucocytes (expressing class i and II) and platelets can generate antibodies specific for donor HLA allotypes
Multi-transfused patients tend to develop panel reactive antibodies (PRA)
72
What is a PRA?
A group of antibodies in a test serum that are reactive against any of several known specific antigens in a panel of test leukocytes or purified HLA antigens from cells
73
How can previous organ transplants cause sensitisation against HLA
Many patients who have had previous organ transplants tend to have a greater percentage PRA
This makes it more difficult to find another donor for another donation
74
How can certain infectious agents cause anti-HLA sensitisation
Some microorganisms can elicit MHC cross-reactive antibodies
Molecular mimicry
75
Inflammation during the transplant process can affect both the recipient and the donor, how exactly is the recipient affected?
First off the patient is already sick - history of disease - immune complex deposition is probably already occuring - leadds to organ failure e.g. with the kidney, ischemia etc
Treatments such as dialysis are inflammatory -> interaction of dialysis membranes with serum proteins causes inflammation
The inflammation of the patient is exacerbated by surgery, removal of organ and introduction of donor tissue (reprofusion injury)
This leaves recipients immune system primed to direct an immune response against the transplanted tissue
76
Inflammation during the transplant process can affect both the recipient and the donor, how exactly is the donor affected?
In the case of cadaveric organs the donor will usually have died in a violent or stressful manner - all round inflammation, possible damage to donor tissue
The procedures used to harvest the organ and transport them add to the stress
Ischemia casuse damage to blood vessels and tissue of the organ by activating the endothelium and the complement system, infiltration with inflammatory leucocytes and the prodution of cytokines
77
What are the five effects of donor organ harvesting on transplant rejection
Donor organ procurement causes ischemia and reperfusion injury
Danger signals are released by inflamed tissues
Mature donor dendritic cell picks up on danger signals through its multiple receptors
Dendiritc cells travel to lymph nodes where they activate T cells
Effector T cells move from lymphoid tissue to donor organ and destroy any inflammed tissue -> cycle repeats
78
What are danger signals also called
DAMPS - Danger associated molecular patterns?
79
Give some examples of Danger signals released by donor tissue upon transplantation
Microbial contaminants (if infected)
Heparan sulfate
Hyaluronan
Uric acid
HMGB1
HSPs
80
Give some examples of receptors expressed by dendritic cells that pick up on danger signals
Scavenger receptors
TLR2
TLR4
RAGE
81
What does RACE stand for?
Receptor for Advanced Glycation Endproducts
82
What cells release DAMPS?
Stressed or apoptotic cells
Could also be from infectious microbes that got in during surgery
83
What hapens when DCs recognise DAMPS?
Immature DCs undergo cell activation - activtion of NF-KB - gene regulation etc to become mature DC
mature DC then travels to lymph node
84
What histological findings would there be in a glomerulus of a kidney in early stages of hyperacute rejection as well as ischemic injury
Neutrophils infiltration
Neutrophils seen in the interstitium
Associated with ischemic injury or rejection
85
How do we reduce ischaemia affects on donor tissue?
By carrying our donation and recipient srgeries at the same time
Done for related donors but also now extended to family members etc etc
86
What kind of hypersensitivty is acute rejection?
Type IV hypersensitivity
87
Compare hyper acute rejection to acute rejection
Hyper-acute:
- pre-formed antibodies
- avoidable through crossmatch
- not curable
- often anti-HLA
- can happen within minutes, process begins on operating table
Acute rejection:
- T cell mediated
- several days to develop
- Can be monitored and treated
- MHC mediated
88
Why do we often see acute rejection?
Cant perfectly match donors - HLA too polymorphic
so we have some degree of rejection
Most organ transplants are performed acoss some HLA class I and/or class II difference
89
What exactly happens in acute rejection?
CD8+ cells respond to class I differences and CD4+ T cels respond to class II differences (present on donor APCs)
Effector CD8 and CD4 cells produced can attack and destroy the transplant
90
How do we treat acute rejection?
we condition patients before hand and maintain immunosuppression of recipient after surgery
We carefully monitor the patients
Can switch drugs if needed or change treatment i.e. additional drugs or anti-T cell antibodies etc
We can usually decrease levels of immunosuppressant as immune reaction will wane with time
91
What exactly is the direct pathway of allorecognition?
Acute rejection
Whereby recipient T cells are stimulated through the interaction of their TCRs with allogeneic HLA molecules expressed on donor DCs
92
Why might we see a Memory response in acte rejection
Many alloreactive T cell clones have a memory phenotype meaning that they were originally stimulated and expanded by pathogens that are cross-reactive with allogeneic HLA
93
What is the MLR reaction
The mixed lymphocyte reaction
94
What is the mixed lymphocyte reaction?
A method of assessing the extent to which a patients T cells will respond to transplanted tissue
5 days culture (downfall)
Proliferation and cytotoxicity measured
This is the flow crossmatch using 5 day cell culture we talked about in labs
95
What is chronic rejection, process, when etc
A form of type III hypersensitivity caused by IgG antibodies specific for the allogeneic class I molecules of the graft
Occurs months or years after transplantation
Characterised by reactions in the vasculature of the graft that cause thickening of the vessel walls and a norrowing of their lumina -> ishcaemia caused loss of function and death of graft
Reponsible for the failure of more than half of all kidney and heart grafts within 10 years of transplantation
96
In your own words what is chronic rejection
Anti-MHC class I antibodies which bind to graft
Characterised by reactions in the vasculaure
97
How exactly does grafts chronic rejection damage grafts?
Immune complexes are deposited in the blood vessel walls of the transplanted kidney
These complexes recruit inflammatory cells, CD40+ B cells and T helper cells expressing CD40L
Damage to graft enables immune effectors to enter the tissue of the blood vessels walls and to inflict further damage
98
What is the drug of choice for chronic rejection and why?
Rituximab
CD40+ B cells and CD40L + T helper cells are responsible for rejection
Binding of C40 to its ligand is a form of costimulation which results in cytokine production
Rituximab targets this
99
What is the indirect pathway of allorecognition
Another name for chronic rejection
100
Explain how exactly chronic rejection/indirect pathway of allorecognition occurs
Donor tissue is a source of donor APCs
Donor-derived APCs die by apoptosis in the draining lymphoid tissue -> can be weeks to months after transplant
Membrane fragments from these dead cells are taken up by the recipients DCs and process in the endocytic pathway
These fragments are then presented to a CD4+ T cell in MHC class II
These CD4+ cells stimulate the alloreaction through sub cellular sensitisation
Host APCs are activated etc
CD4+ T cells initiate an AB response to APC membrane proteins
CD4+ T cells provide help to B cells specific to other alloantigens aswell -> epitope spreading
Overall the T cell respose and B cells response causes gradual impairement of the function of the transplant
CD4+ cells can also contribute to acute rejections but are less numerous than those produced by the direct pathway -> i.e. CD4+ can be stimulate through either method in acute rejection
101
What are antibodies produced against in chronic rejection?
Antibodies are produced against membrane fragments of the APCs not against actual HLA
102
What is epitope spreading in chronic rejection?
This is whereby CD4+ T cells stimualte both B cells specific to APC membrane molecules as well as B cells specifiic to other donor tissues
103
Why can we not detect the B cells involved in epitope spreading of chronic rejection during crossmatching?
This is because the B cells are nairve
-> havent produced any antibodies yet => therefore no reaction upon crossmatch
-> these are only activated due to infection by certain microbes etc -> cross reactivity
104
What are the drugs of choice for Antibody mediated chronic rejection?
anti-CD5 monoclonal antibody Eculizumab
Tocilizumab
105
What is Tocilizumab and how does it work?
An IL-6 receptor antagonist
Used in the treatment of chronic, active AMR (cAMR) with positive donor specific antibodies and transplant glomerulopathy resistant to traditional treatment with IVIG and rituximab
This prevents B cell activation
Inhibits differentiation of T helper cells into TH17 (inflammatory cells)
-> you want these cells switched off, dont want this active
Decreases acute phase reactants such as CRP and ESR
106
Talk about cross-priming/presentation
This is whereby recipient DCs acquire and process intact donor HLA molecules from donor cell debris and instead of processing it though the enodgenous pathway it processes it through the cytosolic pathway
- some material shuttled over to cytosolic pathway upon endocytosis of donor HLA
Antigens are processed into class 1 MHC and used to activate cytotoxic lymphocytes
its basically the crossover beween cytosolic and endogenous pathways of antigen processing - both of which are indirect pathways of AMR which cause chronic rejection
107
What is the transfusion effect?
The phenomenom whereby Tregulator cells suppress CD4 and CD8 effector T cells and thereore improve clinical outcomes after kidney transplantation
These Tregs are more active in patients who received a blood transfusion sharing an HLA-DR allotype previously to their kidney transplantation -> done by accident not on purpose
Exposure to donor cells in non-inflammatory context encourages tolerance to donor allantigens -> occurs due to absence of co-stimulation
108
Compare direct vs indirect allorecognition
Direct:
- Donor cell expressing MHC
- MHC peptide recognised by recipient T cell receptor
- T cell activated by intact donor MHC protein
Indirect:
- recipient APC expressing MHC proteins
- peptide from MHC recognised by recipient T cell receptor
- T cell activated by peptide from donor MHC protein
109
What is direct allorecognition
(A) In direct pathway allorecognition, MHC
Class Il and Class I alloantigen is
recognised as intact protein on the surface
of donor antigen presenting cells (APC) by
recipient CD4 and CD8 T cells respectively
110
What is indirect allorecognition?
(B) In indirect allorecognition, graft
alloantigen (typically MHC antigen) is
internalised by recipient APC [typically a
dendritic cell (DC)], processed and
presented as peptide fragments in the
context of recipient MHC, for self-restricted
recognition by recipient T cells. Although in
theory both CD4 and CD8 T cells can
recognise processed alloantigen via the
indirect pathway, indirect pathway CD8 T
cell responses are not considered
relevant for the rejection of vascularised
allografts
111
What is semi-direct allorecognition
(C) In semi-direct allorecognition, MHC
alloantigen (both dasses) can be acquired by
recipient DC but, rather than presentation
as processed allopeptide, is re-presented
as conformationally intact protein — cross-
dressing — e.g. trogocytosis, exosome
uptake and tunneling nanotubes
112
What is cross-dressing?
Semi-direct allorecognition whereby recipient DCs dress themselves with the donor HLA molecules
113
Compare histology of acute rejection of kidney vs chronic rejection of kidney
Acute = lymphocytic infiltrate, particularly surrounding the tubules, glomeruli are not as affected
Chronic = intimal damage to blood vessels, less obvious mononuclear cell infiltrate, progressive deposition of material in the interstitial space, thickening of the interstiital space which causes damage to the tubules, blood vessels and glomeruli
114
How has organ transplantation developed over the years
First successful transplant was a kidney from an identical twin - no alloreactivity but not everyone has a twin
Two approached proved successful
- selection of a donor as closely matched in terms of HLA to the recipient as possible (not always possible)
- use of a bettery of immunosuppressive drugs
- Tend to use a comination of both
After success of transplantation between living relatives methods were developed to transplant kidneys from unrelated cadaveric donors
Over 500,000 kidney transplants have been performed worlwide and statistical analysis shows both graft performance and long-term health of the recipient increase with the degree of HLA match
115
Why was clinical transplantation pioneered with kidney transplants
Dialysis -> patients can live on dialysis for a while -> not as high risk if graft does reject, wont die etc
Everyone has 2 kidneys, only need 1, healthy relatives often act as donors, immunogenic differences smaller within families, the better the match the better the clinical outcome
116
Other than kidneys what other organs are frequently transplanted in Ireland
Corneal transplants
Livers
Hearts
117
When trying to HLA match donors to recipiens which organs are easiest and which are hardest to match
Corneal transplants really successful
- 90% success without HLA matching or immunosuppressives
Bone marrow other end of spectrum
118
Why are corneal transplants so successful?
The eye has evolved an immunosuppressive environmen in its anterior chamber -> aqueous humor contining TGFBeta
This maintains sufficient protection against pathogens
The cornea also lacks vasculature - the less blood the less antibodies
119
What happens when antigens are introduced into the eye?
They are carried to the spleen by DCs where they generate a response skewed towards Tregs and the production of IL-4 and TGFBeta
This active and systemic state of tolerane to foreign antigens in the eye is called anterior chamber-associated immune deviation (ACAID)
120
Talk about liver transplants
HLA type or cross-match are not assessed before liver transplantation
ABO type is the only factor selecing donor selection
Cyclosoprin A and Tacrolimus markedly improve transplant success -> NFAT inactivation
This is a large organ which can be split in two and one half transplanted to two or more recipients etc
121
What factors contribute to liver transplant success
Very low expression of class I and no class II molecules on hepatocytes
Daily exposure of hepatocytes to the digestion products of intestinal proteins may also contribute to the distinct immunobiology of the transplanted allogeneic liver
122
Talk about heart transplants
Only cadaveric donors obviously -> very complicated -> failure of graft is fatal
Cyclosporin A and tacrolimus again
50% 10 year survival rate
Hearts only remain viable for a few hours in ice-cold buffer
HLA matching is often not done due to limited supply of these organs and urgency of procedure
-> we could probably improve this success rate if hearts could survive outside the body for longer
123
Patients needing a transplant outnumber the available organs, coment on this
Significant shortage of 4:1 in Ireland
3-5 year waiting list for kidneys
Approximatel 20 patients die per day on waiting list
Patients are chosen on various criteria including severity of disease and HLA match wit organ
Some countries now starting opt-out policy rather than opt-in
Unsatisfied demand has resulted in fluorishing and unregulated trade of human organs
