Transplantation medicine Flashcards
(167 cards)
1
Q
What is an autograft?
A
Transfer of living cells, tissues or organs from one part of the body to another
2
Q
What is an allograft?
A
Transfer of living cells, tissues or organs from one individual to another individual of the same species
3
Q
What is a xenograft?
A
Transfer of living cells, tissues or organs from one individual to an individual of another species
4
Q
What is an allo-immune response?
A
Immune response to non-self-antigens from members of the same species
5
Q
What are the main players in allo-immune responses?
A
- APCs
- T-cells (can lead to cellular rejection & activate B-cells)
6
Q
What are allo-antigens?
A
All antigens that differ between individuals of the same species
7
Q
What are important groups of allo-antigens in organ transplantation? (3)
A
- Major histocompatibility complex antigens
- Minor histocompatibility complex antigens
- Blood group antigens
8
Q
What type of rejection will a mismatch in major histocompatibility antigens cause?
A
Fast and strong rejection
9
Q
What type of rejection will a mismatch in minor histocompatibility antigens cause?
A
Chronic rejection -> slow & weak
10
Q
Where are the MHC-antigens encoded?
A
P-arm of chromosome 6
11
Q
Why are there so many MHC mismatches between individuals?
A
Highly polymorphic gene locus with various alleles -> lot of variety in population
12
Q
Which two types of minor allo-antigens can be identified?
A
- All proteins that differ in amino acid composition between donor and recipient (for instance due to genetic mutations, polymorphisms)
- Y-chromosome encoded proteins (if transplanting from man to woman)
13
Q
How do proteins that differ in amino acid composition cause rejection?
A
They are presented in MHCII to T-cells -> these cells recognize the small differences from self-antigens
14
Q
Why do blood group antigens cause rejection?
A
T-cell independent B-cell activation due to recognition of repeated sugar structures by BCR
15
Q
Which three pathways can lead to allo-antigen presentation? Which of these three is most important in organ rejection?
A
- Direct allo-recognition = most important
- Indirect allo-recognition
- Semi-direct allo-recognition
16
Q
What is direct allo-recognition?
A
Recognition of intact foreign molecules on APCs of donor
17
Q
Which cells get activated by direct allo-recognition?
A
T-cells -> cross-react with intact foreign HLA-molecules -> T-cell activation
18
Q
Which two forms of direct allo-recognition are there?
A
- Direct activation of TCR by intact foreign MHC, without peptide -> stronger response
- Activation of TCR by non-self peptide being recognized in non-self MHC
19
Q
What is indirect allo-recognition?
A
Recognition of donor HLA peptide by recipient HLA-molecule on recipient APC (very small response)
20
Q
What is semi-direct allo-recognition?
A
Recognition of intact donor HLA + peptides on recipient APC
21
Q
How do APCs acquire donor HLA with donor peptide in case of semi-direct allo-recognition?
A
Cleaving HLA off at the membrane and taking over the loaded HLA-complex from the donor cell
22
Q
What kind of reaction is induced by allo-antigen stimulation?
A
Recipient T-cells primed by donor HLA in recipient organs migrate to graft & cause damage to cells expressing donor HLA
23
Q
T-cell rejection due to allo-antigen presentation is most important [early/late] after transplantation. Why?
A
Early -> during late stage, recipient APCs replace donor APCs, leading to an absence of donor APCs to activate the direct pathway
24
Q
How can allo-immune responses be analyzed?
A
Cross-reactivity test
25
How does a cross-reactivity test for allo-antigen recognition work?
Blood from patient + blood/splenocytes from donor mixed -> then studying T-cell activation using flow cytometry for cytokine/activation markers
26
In which case is donor blood, and in which case are donor splenocytes used for a cross-reactivity test?
Blood = living donor
Splenocytes = deceased donor
27
How can you make sure you analyze only the recipient immune response in a cross-reactivity test?
Irradiating the donor cells before the test -> prevents them from proliferating and attacking recipient cells
28
What are clinical signs of kidney rejection? (2)
1. Rise in creatinine (decrease of eGFR)
2. Decrease in urine production
29
How is kidney rejection confirmed?
Kidney biopsy
30
What is unique about liver transplantation? (2)
1. Partial transplantation is possible (living donor retains part of their liver that will grow back)
2. No HLA matching required
31
What are signs of liver transplant rejection? (4)
1. Fever
2. Fatigue
3. Abdominal pain
4. Decreased liver function
32
What markers are used to show liver function? (3)
1. ALAT/ASAT (increase in case of liver damage)
2. Alkaline phosphatase (increases in case of liver damage)
3. Bilirubin (increases in case of liver damage)
33
True or false: troponins/NT-proBNP can be used to gauge rejection of transplant hearts
False; there are no good biochemical measurements for heart rejection
34
How are donor hearts checked for rejection after transplantation?
Regular biopsies
35
On which cells are ABO-blood group antigens present? (3)
1. Erythrocytes
2. Endothelial cells
3. Tubular cells (kidney)
36
What happens in case of ABO-incompatible transplant?
1. Blockages in capillaries
2. Hyperacute rejection
37
What is hyperacute rejection?
Organ loss in minutes/hours after transplantation due to severe damage by anti-ABO antibodies
38
True or false: all HLA-molecules are equally important for transplant rejection
False
39
Which HLA-molecules are generally most important for organ rejection? (3)
1. A1
2. B
3. DR
40
Reactions against HLA-mismatch can be caused by donor reactive antibodies. How can these antibodies be present before rejection? (3)
1. Induced by pregnancies
2. Induced by blood transfusion
3. Induced by earlier transplantation
41
How does the cross-reactivity test for HLA antibodies work?
Incubation of donor cells with patient serum -> in case of donor-reactive antibodies, lysis of cells will occur
42
Why is cross-matching for HLA antibodies not performed in heart transplantation?
Not enough time for cross-matching -> only HLA-typing
43
Why does the liver not require cross-matching or HLA typing?
Tolerogenic characteristics of the liver prevent rejection based on HLA-mismatch
44
True or false: a perfect HLA-match is required for succesful kidney/lung transplantation
False; match needs to be the best possible, but not perfect
45
All transplant organs have some degree of tissue damage. Why is this disadvantageous? (2)
1. Loss of organ function
2. Tissue injury leads to inflammatory injury
46
What does ischaemia reperfusion injury cause? (4)
1. Reactive oxygen species
2. Induction of cellular damage
3. Release of inflammatory cytokines & chemokines
4. Attraction & attachment of immune cells
47
How do BDD and CDC donors cause damage to the donor organs before removal?
BDD: cytokine storm, affecting donor organs
CDC: disturbance in blood supply, causing warm ischaemia
48
How is ischaemia reperfusion injury reduced?
Machine perfusion of organs
49
What happens during machine perfusion of organs?
Organs are supplied with oxygen, nutrients & temperature control
50
Which fluid is often used for machine perfusion of organs?
Donor blood
51
Which three types of organ rejection can be distinguished?
1. Hyperacute rejection
2. Acute rejection
3. Chronic rejection
52
Which cells are first activated in acute rejection? How?
T-cells, activated by donor APCs migrating to the lymph nodes
53
What is the effect of T-cell activation in acute rejection? (2)
1. Tc-cells cause direct damage to graft through lysis of cells
2. Th-cells induce antibody production by B-cells
54
How do antibodies produced by B-cells activated by Th-cells in acute rejection contribute to rejection?
Cause antibody-mediated rejection (AMR) -> complement-mediated lysis of target cells
55
Which processes of acute rejection take place in the lymph node, and which in the organ?
Lymph node: activation of Th- and B-cells by donor APCs
Organ: cytotoxic T-cells, antibodies & complement
56
What are risk factors for acute cellular rejection? (5)
1. Young age of recipients
2. Female gender (both donor & recipient)
3. High number of mismatches
4. Black recipients
5. Induction therapy
57
What are risk factors for antibody-mediated rejection? (5)
1. Female gender
2. Elevated pre-transplant PRA
3. CMV seropositivity
4. Previous implantation of ventricular assist device (VAD)
5. Retransplantation
58
What is the first-line treatment of acute cellular rejection?
High dose methylprednisolone
59
What is the second-line treatment of acute cellular rejection?
Anti-thymocyte globulin (alemtuzumab) -> depletion of T-cells
60
What is the treatment of antibody-mediated rejection? (3)
1. Plasmapheresis
2. IVIG
3. Rituximab (anti-CD20) -> depletion of B-cells
61
What is chronic rejection?
Slow deteroriation of organ function
62
What are the clinical signs of chronic rejection of the kidney? (3)
1. Increase in serum creatinine (decrease in eGFR)
2. Proteinuria
3. Hypertension
63
Which changes can be observed in chronically rejected kidneys? (3)
1. Interstitial fibrosis without evidence of any specific aetiology
2. Ischaemia/cell death
3. No massive infiltration of inflammatory cells
64
What is the major cause for kidney loss after transplantation?
Chronic rejection
65
What are hypotheses for the cause of chronic rejection? (2)
1. Continuous low-level inflammation in the organ
2. Chronic calcineurin inhibitor nephrotoxicity
66
What is the treatment for chronic rejection?
No treatment available to prevent organ damage -> only retransplantation can restore organ function
67
Which possibilies are currently studied to minimize/prevent chronic rejection? (6)
1. Calcineurin inhibitor minimalization
2. Using MMF instead of AZA
3. mTOR inhibitors to prevent SMC proliferation
4. ACE inhibitors to prevent hypertension
5. Statins to prevent hyperlipidaemia
6. Anti-oxidant vitamins to prevent oxidant stress
68
Which HLA-molecules are important for stem cell transplantation?
All HLA-molecules (A, B, C, DR, DP, DQ)
69
How are HLA-genes inherited?
One haplotype from both parents
70
What is a haplotype?
One string of HLA-molecules, located on the same chromosome and therefore inheritec as a block
71
Why are parents always haploidentical donors?
Children receive 1 haplotype from their parents -> parents always share at least 1 haplotype
72
What is the chance of siblings being haploidentical donors?
50%
73
What is the chance of siblings being HLA-identical donors?
25%
74
What are the consequences of HLA-mismatching in transplantation?
1. Host-versus-graft -> rejection of graft
2. Graft-versus-host -> reaction of graft cells to host (only in stem cell transplantation)
75
Which techniques can be used for HLA-typing? (2)
1. Low resolution: PCR with primers for HLA locus
2. High resolution: NGS/nanopore
76
HLA typing takes place in [recipient/donor/both]
Both donor and recipient are HLA-typed
77
HLA-antibody screening takes place in [recipient/donor/both]
Only in recipient
78
How often is HLA-antibody screening performed? Why is it performed multiple times?
When patients are placed on the waiting list and then:
For solid organ tranpslantation: every 3 months + every time there are immunizing events
For stem cell transplantation: within 30 days of stem cell transplantation + every time there are immunizing events
This is necesarry because patients can develop antibodies whilst on the waiting list, for instance due to blood transfusions, vaccines, etc.
79
How can flow cytometric crossmatching be performed?
Patient serum + donor blood/spleen + anti-IgG-FITC -> shows IgG binding to cells, proving reactivity of recipient antibodies to donor cells
80
Why is the use of splenocytes preferred over blood in crossmatching?
Donor spleen contains more B-cells
81
Why are renal biopsies performed after kidney transplantation? (5)
1. Provides diagnosis (in case of rejection)
2. Guides treatment
3. Predicts diagnosis
4. Reveals pathogenesis based on molecular & cellular mechanisms
5. Validates outcome (in clinical trials)
82
What are pitfalls in nephropathology? (6)
1 Diverse pathogenic mechanisms may produce similar morphological response
2. Small size of biopsy
3. Primary lesions not always easy to find
4. Progression to end-stage disease results in non-specific chronic changes that obscure original pathological processes
5. Experience of pathologist very influential
6. Sampling error
83
Which information is important for renal pathologist to be able to interpret pathology? (7)
1. Donor source
2. Time post-transplantation
3. Initial kidney function
4. Current renal function
5. Drug therapy
6. Original disease
7. Anti-donor HLA antibodies
84
Which groups of diseases are commonly found in transplanted kidneys? (4)
1. Rejection
2. Drug toxicity
3. Viral infection
4. Donor disease
85
What is the Banff classification?
Classification for transplant kidneys
86
What is the advantage of the Banff classification?
Standardized; allows for multi-centre trials
87
What is the minimum of features that has to be present to judge a kidney biopsy according to the Banff classification?
7 glomeruli & 2 arteries
88
What are the types of rejection in the Banff classification?
1. Acute T-cell mediated rejection (aTCMR) -> T-cells
2. Acute antibody mediated rejection (AMR) -> NK-cells, macrophages & monocytes, spurred on by antibodies/complement
89
What are the subtypes of aTCMR? (4)
1. Suspicious/borderline
2. Tubulo-interstitial
3. Endarteritis
4. Transmural inflammation/fibronoid necrosis
90
How many % of suspicious/borderline cases of aTCMR develop into rejection?
33%
91
What is the morphology of type 1 (tubulo-interstitial) aTCMR?
Lymphocyte infiltration
92
What does granulocyte infiltration in kidney biopsy point to?
Pyelonefritis (not characteristic of rejection)
93
What is the pitfall of diagnosing tubulo-interstitial aTCMR?
Looks similar to polyoma- or CMV-infections
94
What is BK-nephropathy?
Polyoma infection of the kidney
95
How can BK-nephropathy be distinghuished from tubulo-interstitial aTCMR? (2)
Histology: presence of plasma cells points to BK-nephropathy
Serology: polyoma antibodies
96
What is the morphology of type 2 (vascular rejection) aTCMR?
Inflammatory rejection in the arterial endothelium, presence of lymphocytes
97
What is the histological picture of aBMR? (4)
Acute tissue injury, seen as:
1. Tubular injury
2. Neutrophils in peritubular capillaries -> microvascular injury
3. Thrombi
4. Fibrinoid necrosis
98
How can immunohistochemistry be used to show aBMR?
Deposition of C3, C4b and antibodies in peritubular capillaries
99
True or false: calcineurin inhibitor toxicity can not be distinguished from rejection
False; calcineurin inhibitor toxicity leads to characteristic morphological changes
100
Which three regimens of immunosuppression are used in kidney transplantation?
1. Induction therapy
2. Maintenance therapy
3. Anti-rejection therapy
101
What is the goal of induction therapy in organ transplantation? Which drugs are used?
Prevention of activation of immune reaction
Drugs: basiliximab
102
What is the goal of maintenance therapy in organ transplantation? Which drugs are used?
Maintaining tolerance to graft
Drugs: tacrolimus, mycophenolate mofetil, prednisolon
103
What is the goal of anti-rejection therapy in organ transplantation?
Suppression of acute rejection
104
To which class of drugs does tacrolimus belong? What is its mechanism of action?
Calcineurin inhibitors -> block downstream signaling of the TCR
105
What is the mechanism of action of mycophenolate mofetil? What is its brand name?
Mechanism of action: blocking of nucleoside synthesis and therefore expansion of immune cells
Brand name: Cellcept
106
What is the mechanism of action of prednisolon?
Blocks transcription of inflammatory genes
107
At which points in the immune rejection are drugs in organ transplantation aimed? (5)
1. Signal 1: TCR activation
2. Signal 2: costimulation
3. Signal 3: inflammatory cytokines
4. Immune cell proliferation
5. Immune cells
108
Which drugs used in organ transplantation target signal 1?
Calcineurin inhibitors -> inhibit downstream signaling of TCR
109
Which drugs are part of the calcineurin inhibitors? (2)
1. Tacrolimus
2. Cyclosporine
110
What is the mechanism of action of mTOR inhibitors?
Blocking of immune cell proliferation
111
Which drugs belong to the mTOR inhibitors? (2)
1. Everolimus
2. Sirolimus
112
Why can azathioprine be used in organ transplantation?
It inhibits proliferation of inflammatory cells through blockages of the cell cycle
113
What is the mechanism of action of anti-CD52 monoclonals?
Deplete T-cells -> stops immune reactions
114
What are common side effects of immunosuppressive drugs used in organ transplantation? (4)
1. Reactivation of infections
2. Malignancies due to depressed immune activation
3. Cardiovascular disease
4. Hyperglycaemia due to steroids
115
What are side effects of prednisolone? (6)
1. Hypertension
2. Increased hair growth
3. DM
4. Increased cholesterol
5. Muscle weakness
6. Obesity
116
What are side effects of tacrolimus? (6)
1. Hypertension
2. Decreased hair growth
3. DM
4. Nephrotoxicity
5. Neurotoxicity
6. Increased cholesterol
117
What are side effects of cyclosporine? (6)
1. Hypertension
2. Increased hair growth
3. DM
4. Nephrotoxicity
5. Neurotoxicity
6. Increased cholesterol
118
What are side effects of azathioprine? (3)
1. Hepatotoxicity
2. Bone marrow toxicity
3. Abdominal complaints/diarrhoea
119
What are side effects of MMF? (2)
1. Bone marrow toxicity
2. Abdominal complaints
120
What are side effects of sirolimus/everolimus? (6)
1. Nephrotoxicity
2. Ulcerations in the mouth
3. Increased cholesterol
4. Hepatotoxicity
5. Bone marrow toxicity
6. Abdominal complaints/diarrhoea
121
How are infections prevented during immunosuppressive therapy? (5)
1. Vaccinations before transplantation
2. Anti-bacterial prophylaxis: cotrimoxazole for PJP
3. Anti-viral prophylaxis: valgancyclovir for CMV
4. Tapering immunosuppression
5. Life-style advice
122
How are malignancies prevented/managed under immunosuppressive medication? (2)
1. Population screening
2. Tapering immunosuppression
123
How can cardiovascular disease be prevented under immunosuppressive medication? (2)
1. Steroid-free regimen
2. Tapering tacrolimus (but: higher risk of rejection)
124
Why does tacrolimus require especially tight drug monitoring?
Small therapeutic window & high interindividual variance of metabolism
125
Why does MMF especially increase risk of viral infection?
Specifically inhibits antiviral immunity
126
Which groups of drugs can be used if a calcineurin inhibitor-free regimen is desired? (2)
1. Costimulation blockers
2. mTOR inhibitors
127
Which costimulation inhibitors are available in organ transplantation settings? (2) Which costimulatory mechanisms do they block?
1. Belatacept -> CD80/CD86 - CD28 interaction
2. Iscalimab -> CD40-CD154 interaction
128
What is the disadvantage of using belatacept?
Increases risk of lymphoma/EBV infections
129
Why is iscalimab not used in organ transplantation?
Severe side effects
130
Why is it desirable to use cellular therapies in organ transplantation? (3)
1. Less side effects than current therapies
2. Long-term effects -> cells may be around for a long time
3. Cellular therapy may create a balance between activation & suppression
131
Which immune cells with regulatory functions can be found within the myeloid lineage? (3)
1. Myeloid-derived suppressor cells
2. Regulatory macrophages (M2)
3. Tolerogenic DCs
132
Which immune cells with regulatory functions can be found within the lymphoid lineage? (4)
1. CD4+ regulatory T-cells
2. CD8+ regulatory T-cells
3. γδ T-cells
4. Regulatory B-cells
133
What is the main role of myeloid regulatory cells?
Tissue homeostasis by dampening immune responses through effects on the T-cell compartment
134
How are regulatory macrophages induced?
Costimulation of activated macrophages by regulating cytokines
135
What are tolerogenic DCs
DCs with a weak costimulation -> induce Tregs
136
What are mesenchymal stem cells (MSCs)?
Stem cells of connective tissues
137
Into which major cell types do MSCs differentiate? (4)
1. Osteoclasts
2. Adipocytes
3. Chondrocytes
4. Fibroblasts
138
From which kinds of connective tissue are MSCs currently harvested? (2)
1. Bone (hip replacement bone, bone marrow aspiration)
2. Adipose tissue
139
MSCs are [easily expanded/difficult to expand] after harvesting
Easily expanded -> harvesting of a few thousand MSCs can be cultured in to a large population
140
What is the immunomodulatory function of MSCs?
Suppression of inflammatory cell types via soluble and non-soluble signaling
141
What are important players in immunomodulatory functions of MSCs? (2)
1. PD-L1 = co-inhibition
2. IDO -> depletes L-tryptophan, which is needed for lymphocyte proliferation
142
In which environments are the immunomodulatory effects of MSCs strongest?
Inflammatory environments
143
Where do MSCs end up when they are injected intravenously?
Lung capillaries -> first capillary bed they encounter
144
How long do MSCs remain present after IV administration? How are they cleared?
~1 day, cleared through phagocytosis by macrophages
145
What hypothesis is used to explain why MSCs have immunomodulatory effects, even if they are cleared within 1 day?
Macrophages that clear them adopt a regulatory phenotype and induce a higher amount of Tregs
146
What are the advantages of using allo-MSCs vs. auto-MSCs? (2)
1. Allo-MSCs can be used clinically without delay required for expansion
2. Allo-MSCs could elicit anti-donor immune response, thus increasing graft loss
147
What are important markers of CD4+ Tregs?
Extracellular: IL-2R/CD25+
Intracellular: FoxP3
148
Why is it hard to isolate a population of Tregs for clinical use?
FoxP3 can only be stained for intracellularly -> cells are not viable anymore after staining
149
By which mechanism do Tregs regulate immune responses in the thymus?
Deletion of auto-reactive T-cells
150
By which mechanisms do Tregs regulate immunity in the periphery? (4)
1. Cell-cell contact: by competing for costimulating between effector T-cells and APCs
2. Secreting inhibitory cytokines
3. Cytotoxic molecules that kill effector T-cells
4. Metabolic disruption of inflammatory cells by competing for IL-2
151
What steps need to be taken to generate therapeutic Tregs?
1. Isolation of Tregs from patient blood (low numbers present)
2. Expansion in vitro
152
Which two methods for in vitro expansion of Tregs are there? What are their advantages?
1. Polyclonal stimulation -> all Tregs expanded
2. Antigen-specific stimulation -> stimulation of Tregs against desired antigens -> superior immunosuppressive properties
153
What are the changes that have been introduced into the field of transplant medicine since the introduction of calcineurin inhibitors? (3)
1. Low incidence of rejection
2. Transplantation of other organs than kidney has become possible
3. Allows for long graft and patient survival
154
What are the disadvantages of calcineurin inhibitors? (4)
1. Loss of kidney function
2. (Lethal) side effects
3. Not all allo-immunity sufficiently suppressed --> still chronic rejection
4. Aspecific blocking of the whole immune system
155
What is the mechanism of action of belatacept? What is the effect on T-cells? (4)
Blocking of CD80 & CD86, leading to:
1. No cell division
2. No cytokine production
3. Angergy
4. Apoptosis
156
What are the advantages of belatacept vs. cyclosporine (=calcineurin inhibitor)? (2)
1. Significantly better renal function
2. 40% lower risk of death-censored graft failure
157
What are the disadvantages of belatacept vs. cyclosporine? (3)
1. Rejection significantly higher
2. Risk of lymphoma increased
3. More expensive
158
What is the only situation in which belatacept is used over tacrolimus?
If a patient cannot tolerate tacrolimius
159
What are the reasons why development of new immunosuppressive medication for transplantation medicine has slowed? (3)
1. Newer drugs have not been proven beneficial over tacrolimus-MMF-steroids
2. Emergence of generics of original drugs has lowered cost of maintenance immunosuppression
3. Lack of acceptable/feasible clinical outcomes in research
160
Which three mechanisms are still being investigated/introduced for targeting in transplantation medicine?
1. IL-6 inhibitors
2. Imlifidase
3. CAR T-cells
161
Which two anti-IL-6 drugs are currently being investigated for use in transplantation medicine? What is their mechanism of action?
1. Tocilizumab -> blocks IL-6R
2. Clazikizumab -> catches free IL-6
162
Why is it advantageous to block IL-6 signaling in transplantation medicine?
IL-6 = inflammatory cytokine
163
What is the mechanism of action of imlifidase?
Enzyme that cleaves IgG, allowing for removal of antibodies against graft
164
What is the usecase of imlifidase in transplantation medicine?
Temporary removal of anti-graft antibodies gives a window for transplantation
165
What are the disadvantages of imlifidase? (2)
1. Antibodies are replaced over time
2. Risk of infection during this period
166
What is the promise of CAR T-cells in transplantation medicine?
Engineered CAR T-cell receptor to suppress immune responses against specific antigens (CAR Tregs)
167
