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Cancer, Autoimmunity and Transplant Immunology > Different types of rejection and animal models (SGTs) > Flashcards

Different types of rejection and animal models (SGTs) Flashcards

1
Q

what is recognised in acute rejection?

A
  • direct recognition of in tact donor HLA (MHC)
  • male vs female H-Y antigen - minor histocompatibility antigen polymorphism
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2
Q

what is the effector mechanism of acute rejection?

A

CD4 Th1 cells, CD8 T cells

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3
Q

what is the pathology of acute rejection?

A

T cell, NK cell and macrophage infiltration into the graft
- necrosis of tissue
- fibrosis

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4
Q

what is the speed of acute rejection?

A

7-21 days, depending on the tissue

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5
Q

why does acute rejection occur?

A

donor MHC incompatibility

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6
Q

how can acute rejection be prevented?

A

immunosuppression

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7
Q

what is recognised in chronic graft rejection?

A
  • Donor MHC – driven by indirect T cells recognising fragments of donor MHC presented by recipient MHC
  • Minor antigen differences
  • Damage during chronic rejection leads to epitope spreading = autoimmunity e.g. cardiomyosin autoantibodies in heart transplant
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8
Q

what are the effector mechanisms of chronic rejection?

A
  • Lesions contain T cells and macrophages – T cell response
  • Humoral responses – antibody deposition on endothelium
  • Complement-fixing antibodies cause damage
  • Can sometimes be just antibodies or just T cells alone
  • Some antibodies mask MHC from being recognised by T cells = can protect from rejection
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9
Q

what is the pathology of chronic rejection?

A
  • T cell and macrophage infiltration in the blood vessels – perivascular cuff around blood vessels: transplant vasculopathy
  • Intima and media endothelial layers have underlying inflammation
  • Smooth muscle cells that form the media penetrate through the intima and hyper-proliferate - concentric intimal thickening of vessels
  • these cells enter vessel lumen and close it
  • This impairs blood flow to the graft organ – hypoxia and collapse of graft
  • gradual decrease in graft function
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10
Q

how fast is chronic rejection?

A

Accounts for most grafts that are rejected after 1 year (can be months)
- If patient stops taking immunosuppression after years – rejection can occur

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11
Q

why does chronic rejection occur?

A

Donor MHC but why later?
- Insufficient immunosuppression can lead to a response later on
- Donor DCs killed in periphery – specificity of T cells are induced by indirect recognition via recipient DCs entering the graft

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12
Q

how can chronic rejection be prevented?

A

immunosuppressives

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13
Q

how can alloantigen contribute to chronic rejection?

A

Incidence increases with acute rejection episodes
Incidence increases with inadequate immunosuppression
Incidence increases with HLA mismatch
Lesions associated with chronic rejection contain immune
cells
Correlates with the presence of antibodies to HLA
and complement deposition on endothelium

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14
Q

what is recognised in hyperacute rejection?

A
  • donor MHC/HLA expressed by donor endothelium
  • ABO blood-type incompatibility/mismatch
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15
Q

why do people naturally have antibodies against blood group antigens?

A
  • Enzyme generates A or B or AB or lack of enzymes by default generates O
  • If you have A, you naturally generate antibodies to B and vice versa, if you have O, you naturally have anti-A and anti-B
  • These antibodies are generated by interactions with microbiome – specifically their glyco-structures
  • Forms IgM antibodies as these are against carbohydrates
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16
Q

what are the effector mechanisms in hyperacute rejection?

A
  • Mainly induced by preformed antibodies against donor MHC and ABO
  • leads to complement fixation
  • No T cell infiltration found in these grafts
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17
Q

what is the pathology of hyperacute rejection?

A

Complement fixation by antibody sticking to endothelium – leads to inflammation and lysis of endothelium:
- Neutrophil recruitment which cause damage
- Rapid breakdown of intima – leads to oedema – plasma from blood enters graft – causes damage
- Stimulation of endothelial cells to secrete Von Willebrand procoagulant factor
- Results in platelet adhesion and aggregation – intravascular thrombosis, lesion formation and graft loss/necrosis
- Thrombin produced – closes the vessels to the graft

18
Q

how fast is hyperacute rejection?

A

Occurs within minutes to hours, sometimes within 48 hours of re-vascularisation
- Preformed antibody ready to bind to target within minutes, leading to complement fixation

19
Q

why does hyperacute rejection occur?

A

Prior sensitisation:
- Recurrent/pre-existing anti-donor antibodies against HLA or ABO blood group antigens
- Patient may be sensitised to MHC antigens due to prior transplants, blood transfusions or pregnancies
- Anti-MHC generated sensitisation – tend to be IgG1,3
- In pregnancy: can get sensitised to the MHC of the father – semi-allogeneic foetus in the mother
- ABO incompatibility – transplant across blood groups can cause hyperacute

20
Q

how can hyperacute rejection be prevented?

A

By checking for ABO compatibility – screen blood typing and only do a transplant with matched donor and recipient
- transplants are always ABO matched

Tissue typing for MHC e.g. for renal

Induction of immunosuppression provided at time of transplant e.g. plasma cell-depleting antibody, or plasmaphoresis: removal of preformed antibodies
- Memory cells are in the spleen – can undergo splenectomy to remove memory B cells
- IvIG = donor antibody cocktail to inhibit recipient preformed antibodies
- anti-CD20 B cell removal

21
Q

how can MHC antibodies be tested for to prevent hyperacute rejection?

A

cross-match techniques between donor graft cells and recipient sera:
- Test for pre-existing donor-specific HLA antibodies using sera
- Screen recipient and donor for MHC: Take donor cells, put recipient antibody on, add complement and see if they kill the donor cells
- Cytolytic functional test of antibody
- Or use beads bound to MHC and see if antibody binds – but doesn’t shown function of antibody

22
Q

if patients are MHC-mismatched, can a transplant still happen?

A

MHC matching doesn’t happen for heart because there are so few donors, so accept whatever you get
- sometimes there is no choice – patient may have had sensitisation in the past – but better to risk transplant rejection than not at all

23
Q

when can transplants across ABO barriers occur?

A

Can transplant across ABO barriers in infants below age of 4 as they are immunodeficient in adaptive so won’t have preformed antibodies
- This children have poor antibody responses, so won’t recognise ABO difference

24
Q

what is an example of a transplant across an ABO mismatch?

A

Hyperplastic left-heart syndrome - the left side of the heart fails to develop correctly in utero
- Kids born with this condition are unable to survive outside ITU
- >50% of hyperplastic left heart infants die while waiting for a heart
- Only option is a heart transplant
- need to match size and ABO
- AB antibodies not generated for first 6 months so
- ABO incompatible graft can be transplanted in neonates
- Presence of ABO incomp. graft may tolerise
- First patient – blood group O – transplanted at 23 days of age with a blood group AB heart

25
Q

what is the best animal for xenogeneic transplants?

A

Pig proposed to be the best xeno match to humans
- Size
- Physiology
- Pathogen transference
- Ethical use

26
Q

what is disconcordant?

A

Discordant (distant) species-Humans have pre-formed
anti-pig antibodies that can lead to hyperacute rejection

27
Q

what is recognised in xenogeneic rejection?

A

Alpha-gal epitopes (pig version of ABO)
- Human anti-pig IgM antibodies are directed against a1-3 galactose (a Gal) epitopes

Donor MHC e.g. pig MHC is foreign

28
Q

what recognition pathway is involved in xenogeneic rejection?

A

Indirect pathway – donor DCs with donor MHC and co-stim interactions – all of this is from pig, so will not effectively stimulate T cells
- This is recognised as foreign
- Pig MHC peptides presented by recipient DCs with co-stim

29
Q

what effector mechanisms are involved in xenogeneic rejection?

A

Antibody response initially
- antibody inhibition therapies can result in T cell response which recognise the pig graft
- Involves both cellular and humoral mechanisms
- NK cell driven
- akin to acute allograft rejection
- Indirect pathway may predominate due to
incompatibility of costimulatory/adhesion molecules between species

30
Q

what is the speed of xenogeneic rejection?

A

minutes to a few weeks (hyperacute to acute)

31
Q

why does xenogeneic rejection occur?

A

Human sensitisation to aGal is likely to take place through recognition of aGal expressing micro-organisms
that colonise the gut

32
Q

how can xenogeneic rejection be prevented?

A

Genetic editing of the pig organ to be similar to human
- Alpha-gal K/O pigs – remove enzyme that generates the alpha-gal epitope (alpha 1-3 galactosyltransferase) – removes risk of hyperacute rejection – but not completely efficient
- Also K/I CD155 to inhibit complement
- Human thrombomodulin K/I to remove platelet thrombosis
- K/O of MHC class I and class II
- Generate Decay Accelerating Factor (DAF) Transgenic pigs – inhibits the formation of the MAC complex
- Pig contains endogenous retroviruses in their DNA – perturbance of system could lead to pig retrovirus crossing into human: use CRISPR/Cas9 to K/O retroviruses from genome of pig
- immunosuppression

33
Q

what small animals are often used for study of transplantation?

A

mouse and rat

34
Q

what transplants can be modelled in small animals?

A
  • Skin, heterotopic heart, orthotopic kidney, liver, lung, small bowel, vessel, islet, composite tissue, bone marrow, limbs, hemiface
  • Can use TCR-transgenic T cells. + gene knockout etc.
  • Can be used to look at concordant and non-concordant xenograft rejection
  • Mice can be used in “humanised models”.
35
Q

what kinds of rejection can be induced in small models?

A
  • concordant between mouse and rat to avoid hyperacute rejection
  • disconcordant e.g. hamster to rat, evolutionary distance induces hyperacute rejection
  • Chronic – give immunosuppression to overcome acute rejection, and then see changes in the graft that are consistent with chronic
  • Lower immunogenicity of graft with congenic mice to avoid acute, but small response can lead to chronic rejection
36
Q

how can small animal transplant models be humanised? what can this be used for?

A

humanised models: remove IL-2b chain to deplete mouse lymphocytes
- reconstitute with human PBMCs
- But T cells will cause GVHD in mice within 50 days – so short time to do this
- Or put in human BM cells – knock in to mouse human proteins to enable graft to take – enables human haematopoiesis in the mouse
- Can do human skin graft
- Can do human blood vessel graft into mouse descending aorta – vascular changes consistent with chronic rejection, hyperplasia within 30 days
- Can do human islets – put in bloodclot and place under kidney to see response to islets

37
Q

what are the strengths of small animal models for transplantation?

A
  • less ethical issues
  • well defined MHC - whole genome is sequenced
  • inbred so high reproducibility
  • amenable to genetic modification
  • constant source of donor cells for further assays
  • can manipulate cells ex vivo and examine function via injection in vivo
  • inexpensive
  • statistically robust due to large sample size - short gestation
  • well defined models for all rejection types
  • availability of reagents and gene databases
  • more resilient to surgery
38
Q

what are the cons of small animal models for transplantation?

A
  • Young age of immune system (memory cells limited)
  • Environment (IVC) very clean – impact of memory.
  • Different pharmacokinetics of drugs to humans.
  • Evolutionary distant – drugs, biologics may not recognise human molecules and vice versa, molecules may have different function, molecules may be missing (IL-8, CD1a, b and c), MHC class II not on mouse endothelium
  • Frequently difficult to perform due to size – rat less so
  • Significant period of training in techniques required
  • Rejection different to humans – kidney allografts frequently accepted, liver grafts too
  • Inbred mice may harbour immune defects, difficult to assess which strain is more representative of human response
  • Short life span, so can’t look at long term effects
39
Q

what large animal models can be used to study transplantation?

A

non-human primates

NIH minipigs - bred like lab mice

40
Q

what transplants can be modelled in large animals?

A
  • Skin, heart, kidney, lung, small bowel, islet, pancreas, composite tissue.
  • Often used to look at concordant and non-concordant xenograft rejection due to clinical potential of pig to human
  • Potential source of transplantable cells and organs (pigs)
  • Humans (Brain-stem dead patients used to test pig organ transplants)
41
Q

what are the strengths of large animal models for transplantation?

A
  • Need to define MHC but now can be done – NIH minipigs inbred and typed like mice.
  • Evolutionary similar – drugs, biologics may act similarly in humans
  • Normally surgeons can perform transplants without too much training
  • MHCII can be induced on vascular endothelium
  • Genetic alteration of pig is now feasible (but primate life cycle to long to attempt)
  • Pigs easy to breed (outbred) (imnipigs not so easy)
  • MHC class I 90% homology between human and baboon
  • Homologous immunoglobulins between macaques and humans
  • The ABO system, haemoglobin and coagulation homologous between humans and baboon
  • have more memory cells as they are kept in more normal environment
42
Q

what are the cons of large animal models for transplantation?

A
  • Expensive
  • Complex to interpret – Genetically distinct (but maybe not NIH minipigs)
  • Ethics complex and controversial – need a lot of in vitro and small animal data to justify their use
  • Extensive post-operative care.
  • Limited reagents to assay immune responses
  • Young immune system (significant thymic output still present) but older animals can be used (Minipigs)
  • Pharmacokinetics - similar size and physiology but still different to humans. Transition to humans normally involves blood concentration of reagent.
  • Most large animals are outbred making it difficult to repeat experiments and most using donor-recipients
  • mismatched at a different number of MHC loci. (Now achievable but difficult to achieve known MHC donor-recipient pairs)
  • less statistically robust, with small sample size
  • CD40L blockade for tolerance induction was good in NHPs, but not good in humans as CD40L is expressed on human platelets – led to thrombosis

Cancer, Autoimmunity and Transplant Immunology (15 decks)

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