Transplantation immunology Flashcards
What is autografting?
Transfer of living cells, tissues and organs from one part of the body to another
What is allografting?
Transfer of living cells, tissues and organs from one individual to another (SAME SPECIES)
What is xenografting?
Transfer of living cells, tissues and organs from one individual to another (DIFFERENT SPECIES)
Why is there a need for transplantation?
- Damaged organs
- Non-functional organs
How do organs become damaged?
Disease or injury
Which cells are the main players in transplantation?
APCs and T cells
What are allo-antigens?
All antigens that differ between individuals of the same species
Which division can be made in the allo-antigen category?
- Histocompatibility Complex antigens
- Blood group antigens
Which two kinds of antigens do you have in the ‘histocompatibility Complex antigens’ category?
- MHC antigens/Human Leukocyte Antigen
- Minor histocompatibility complex antigens
What kind of graft rejection reaction is caused by MHC antigens? What is the main cause of graft rejection?
- Fast and strong
- Differences in HLA
What kind of graft rejection reaction is caused by minor histocompatibility complex antigens?
Slow and weak
What is a calcineurin inhibitor?
Tacrolimus
What is the main immunosuppressive drug?
Tacrolimus
What is a pro of tacrolimus?
Low level of rejection
What are 5 problems with tacrolimus?
- Narrow therapeutic window
- Nephrotoxicity
- Neurotoxicity
- Incidence of diabetes
- A specific (infections)
In what way is tacrolimus better than cyclosporin?
Better kidney function
What two types of rejection are there?
Cellular rejection and antibody-mediated rejection
What mismatched cells can be recognized by CD8 cells?
All nucleated cells
What mismatched cells can be recognized by CD4 cells?
Antigen presenting cells and activated CD4 cells
How are minor allo-antigens presented?
They are taken up and presented by recipient HLA molecules to recipient T cells, like all other peptides
What are minor-allo antigens?
All non-MHC proteins that differ in amino acid composition between toe donor and recipient outside of MHC due to mutations or genetic polymorphisms
Does presentation of red blood cell antigens require T cell help?
No, they immediately activate B cells
What types of antibodies do you have if you are blood group A?
Anti-B
What type of antibodies do you have if you are blood group B?
Anti-A
What type of antibody do you have if you are blood group AB?
None against blood groups
What type of antibody do you have if you are blood group O
Both Anti-A and Anti-B
What is the most important allo-antigen recognition pathway?
Direct allo-recognition, of intact foreign HLA molecules on donor APCs by recipient T cells
What is cross-reactivity in allo-recognition?
When T cell receptors can recognize peptides presented by intact foreign HLA molecules, causing an immune response
What is peptide-independent binding?
When the recipient TCR recognizes the donor MHC but not the peptide
What is peptide-dependent binding?
When the recipient TCR recognizes only the peptide but not the donor MHC presenting it
What is foreign peptide:self MHC binding?
When the recipient TCR recognizes a foreign peptide on the recipient (own) MHC
What is indirect allo-recognition?
When a donor peptide is taken up by a recipient APC and presented to the recipient TCR (through self-MHC)
What is the semi-direct recognition pathway?
When an APC of the recipient presents a donor peptide on a donor HLA to a recipient TCR
How can donor matching be tested in the lab?
Mixed lymphocyte reaction with T cell activation or cytokine production as read-outs
What are two signs of kidney transplant rejection?
A rise in creatinine and descreased urine production
What is done after creatininine and urine tests to prove kidney rejection?
Biopsy and histology
What are measurable signs of liver rejection?
Rise in serum aminotransferases (ASAT, ALAT), alkaline phosphatase, bilirubin
How is heart rejection tested?
Biopsy. There is no other biochemical way.
What is a 4th target for organ transplant rejection?
Injury
What happens when there is a blood group mismatch?
Blockages of capillaries, hyperacute rejection within minutes or hours. Causes severe damage by antibodies of the recipient
What is hyperacute rejection?
Blood group mismatch causes severe damage to the transplant, causing organ loss within minutes or hours
What causes the severe damage to the transplant in hyperacute rejection?
Immediate lysis of donor cells due to ABO or donor HLA specific antibodies
Can there already be pre-existing anti-donor HLA antibodies?
Yes, due to pregnancy, blood transfusions or earlier transplantations
What are the 2 requirements for organ transplantation?
- ABO system compatibility
- Negative cross match (except for liver)
How does tissue injury play a role in rejection?
Reactive oxygen species, cellular damage, imflammatory cytokines, immune cell attraction and attachment of immune cells to inflamed endothelium
Why can’t cardiac death donors donate?
Stopped circulation leads to lack of oxygen supply to the organ
Why can’t brain dead donors donate?
Cytokine storm
How can tissue injury be minimized?
Machine preservation
What is the type of rejection based on?
The type of immune cells involved and how quickly rejection occurs
What type of rejection can take weeks or years?
Humoral rejection: B cell-mediated (antibody-mediated) rejection
How can humoral rejection be detected?
C4d staining in capillaries
What is CMV seropositivity a risk factor for?
Antibody-mediated rejection
How can you treat acute cellular rejection?
High doses of methylprednisolone, otherwise T cell depletion
How can you treat acute antibody-mediated rejection?
Plasmapheresis (antibody depletion), IVIg, otherwise Rituximab (anti-CD20) therapy
What is rituximab?
Anti-CD20 therapy, so B cell depletion
What are signs of chronic kidney rejection?
Increase of serum creatinine, proteinuria, hypertension
What are two reasons chronic organ rejection happens?
- Low levels of immune attack against the organ
- Chronic calcineurin inhibitor (Tacrolimus) nephrotoxicity
What is needed for improved immunosuppressive therapy?
Something as effective or more effective as Chronic calcineurin inhibitors (i.e. Tacrolimus), but less nephrotoxic
What Class I HLAs are mostly looked at in transplants?
A and B
What Class II HLAs are mostly looked at in transplants?
DR
Why is strict stem cell matching important?
Because there is a huge risk of rejection but also that the new immune system also attacks the recipient body
What are two clinical consequences of mismatching in solid organ transplant?
- Host versus graft (HvG) -> rejection
- Graft versus host (GvH) -> GvHD
In what setting can you get host versus graft and thus rejection?
Usually HLA mismatching in solid organ transplants
In what setting can you get graft-versus-host and this graft versus host disease?
In hematopoetic stem cell transplation when the stem cells differentiate into immune cells that attack the recipient immune system due to HLA mismatching
What can cause sensitization before transplantation?
Pregnancy, previous transplants and blood transfusion
What is sensitization in transplantation?
Formation of anti-HLA antibodies such as against paternal HLA molecules during pregnancy, making it more difficult to find a suitable donor
What happens when anti-HLA antibodies encounter a mismatched organ?
Hyperacute rejection
What has reduced the incidence of hyperacute rejection?
Serological crossmatching
What causes de novo antibody formation after transplantation?
Humoral alloimmune responses
What can de novo antibody formation after transplantation lead to?
Acute humoral rejection and chronic transplant dysfunction
What are 5 reasons to do a renal biopsy?
- Provides a diagnosis (toxicity, rejection, viral, donor disease)
- Guides treatment (changes in more than half of the cases)
- Predicts prognoses
- Reveals pathogenesis
- Validates outcome (as endpoint result in clinical trials)
What are 6 pitfalls in nephropathology?
- Morphology not specific
- Sample size
- Sample location might not show primary lesion
- Chronic changes can obscure origin or pathology
- Differences in pathologist experience
Sampling error (might miss lesion)
Name 4 examples of clinical information that is important to know when looking at nephropathology?
- Anti-donor HLA antibodies
- Original disease
- Drug therapy
- Time post transplant
What is the Banff classification?
Standardized grading system to grade severity and type of rejection
What is needed for an accurate classification according to Banff?
A minimum of 7 glomeruli and 2 arteries, but depends on the disease
What are the two main types of rejection in the Banff classification?
Antibody-mediated rejection and T-cell mediated rejection
What are the three levels of TCMR (histologically)
-bTCMR (borderline)
-I Tubulo-interstitial
-II Vascular rejection
What can be found in AMR? (cells)
Antibodies, monocytes, neutrophils, and NK cells
What is needed for an AMR diagnosis?
Microvascular inflammation +
C4d+ and donor-specific antibodies (DSA+)
What morphological change is found in AMR?
Microvascular inflammation
What is BK nephrology?
Nephropathology caused by a polyomavirus, characterized histologically by enlarged nuclei (caused by viral replication in the nucleus)
What is being done to improve diagnosis of transplant rejection?
microRNA profiling
What 3 types of immunosuppression are there?
Induction therapy, maintenance therapy and anti-rejection therapy
When is induction therapy given?
Shortly before and after the transplant surgery to fully knock out the immune system
What type of induction therapy is given in a standard kidney transplantation?
Signal 3-blocking antibody (cytokines)
What is blocked by the induction therapy used in The Netherlands?
Anti-CD25, which blocks the IL-2 receptor
Why not use signal 1 antibodies?
A lot of side effects due to complete T cell depletion (infection susceptibility)
What are 3 standard maintanence drugs given?
Tacrolimus (chronic calcineurin inhibitor), mycophenolate mofotil (MPA/MMF) and prednisolon
What does Tacrolimus do?
Blocks downstream of signal 1
How does prednisolon work?
It works anti-inflammatory and immuniosuppressive by inhibiting mRNA expression when interacting with corticosteroid receptor, mimicing cortisol. It inhibits T cell growth and differentiation.
What is the standard immunosuppressive regimen in kidney transplantation in The Netherlands?
- High dose immunosuppression: Induction with Anti-CD25 (basiliximab), Prednisolon, Tacrolimus and MMF
- Taper down prednisolon for 3 months, also tacrolimus and MMF
-Tacrolimus and MMF only, no more prednisolon
What are 3 additional immunosuppressive therapies in case of rejection?
- Methylprednisolon (always, high dose intravenously)
- Alemtuzumab (T and B depletion)
- IVIg (little evidence that it works)
What are 3 major adverse effects of immunosuppressive drugs?
Infections, malignancies and cardiovascular disease
Which immunosuppressive drug needs to be monitored closely and why?
Tacrolimus due to the small therapeutic window and interactions with other drugs
How can drugs be monitored?
Measuring trough levels
Which drug affects antiviral immunity the most?
Prednisolon
