Chapter 15

Question 1

What is graft?

Answer 1

• tissue or organ that is transplanted from a donor to a recipient

Question 2

What is hyperacute rejection?

Answer 2

• recipient receives an organ from donor with a different blood group
• IgG antibodies bind to graft vasculature -> complement activation
• rejection of the tissue
• also due to anti-HLA class I antibodies
  
  • donor and recipient have to be compatible
  • flow cytometry cross match test

Question 3

What is acute rejection?

Answer 3

• immune response to cells of graft
• T cell attack
  
  • cell death

Question 4

What is graft-versus-host reaction (GVHR)?

Answer 4

• during hematopoietic stem cell transplant
  
  • chemo
  • then patient is infused intravenously with healthy stem cells from a donor
  • reconstitution of hematopoietic system
• T cells in graft attack recipients tissues = GVHR leading to graft-versus-host disease

Question 5

Why are organs from living donors more effective in providing successful transplantations, than
organs from deceased donors?

Answer 5

• death is usually caused by stress -> organ inflamed
• deprivation from blood = ischemia
  
  • further stresses the organ
  • damage to organ if too long

Question 6

What happens if donor’s and recipient’s HLAs are not a match?

Answer 6

• DCs of donor (from graft) travel to spleen
  
  • activate alloreactive T cells of recipient
• recipient T cell activation
  
  • target allogeneic HLA (from donor)
  • acute rejection
  • death of epithelial cells in graft by CD8 T cells
• called direct pathway of allorecognition
• type IV hypersensitivity
  
  • takes a few days to develop -> can be prevented

Question 7

What is a chronic rejection of transplanted organs?

Answer 7

• concentrated attack after a few months / years
• attack vasculature -> thickening walls -> narrowing lumen
  
  • ischemia -> graft death
• type III hypersensitivity reaction
  
  • IgG for graft’s HLA class I
  • immune complexes deposited in blood vessels of graft
  • CD40-expressing B cells and CD40 ligand T cells arrive to site

Question 8

What is the indirect pathway of allorecognition?

Answer 8

• recipient’s DCs endocytose allogeneic HLAs from dead DCs of graft (which die by apoptosis)
  
  • those peptides are produced on HLA class I and II -> activate naive T cells in secondary lymphoid tissues
  • chronic graft rejection

Question 9

What is the role of immunosuppressive drugs?

Answer 9

• interfere with T-cell activation and differentiation
  
  • prevent alloreactions
• different types
  
  • depletion of lymphocytes and monocytes -> the day before transplantation
  • interfering with signals generated by TCR upon recognising antigen or signal from co-stimulatory receptor
  • interfering with signals generated by IL-2 receptor on T cell
  • effect on activated naive T cells that are proliferating

Question 10

What are the risks of immunosuppressive drugs?

Answer 10

• highly susceptible to infections
• exposure to pathogens has to be reduced
• high risk of malignancies (carcinomas of skin and genital tract, lymphoma)

Question 11

How are antibodies used for immunosuppression?

Answer 11

• leukocytes coated with rabbit antibodies (rATG) -> complement activation
  
  • cells phagocytosed
• other ab used (humanised rat): alemtuzumab (anti-CD52)
  
  • CD52 found on surface of lymphocytes
• anti-CD3 monoclonal antibody prevents signal 1 from TCR
• another way: binding high-affinity IL-2 receptors on partially activated alloreactive T cells -> prevents binding of IL-2
  
  • IgG1 ab = basiliximab is used
  • bind to CD25 (IL-2R)
• used the day before (induction therapy) and a few months after

Question 12

What is the role of prednisolone?

Answer 12

• from prednisone (pro-drug)
  
  • when activated becomes prednisolone
  • reduces inflammation
    
    • prevents lymphocytes from entering secondary lymphoid tissues and inflammatory sites
  • used with combination of other drugs
  • part of the maintenance therapy

Question 13

How are corticosteroids used for immunosupression?

Answer 13

• prevent actions of NFkB
  
  • transcription fator for inflammatory response
• corticosteroids cross cell membrane and bind with a receptor in cytoplasm -> become a transcription factor
  
  • production of inhibitory regulator of NFkB transcription
• many adverse side effects
  
  • used only to treat rejection

Question 14

How is T cell activation suppressed by drugs?

Answer 14

• by cyclosporin and tacrolimus
• bind to calcineurin
  
  • which activates transcription factor for IL-2 gene
• usually calcineurin activated by Ca2+, but here drugs prevent binding

Question 15

How is T-cell co-stimulation inhibited?

Answer 15

• by belatacept -> soluble form of CTLA4 (CTLA4 -Fc fusion)
  
  • binds to B7 on donor APC and prevents binding of CD28 (recipient T cell) to generate a signal
  • no activation