W15 - Transplantation Flashcards
What is the range of half-life for adult kidney transplants?
List the following from highest to lowest half life:
- Living donor (1-year conditional survival)
- Living donor
- Deceased donor (1-year conditional survival)
- Deceased donor
Half life ranges from 10-15 years
Living donor (1-year conditional survival) > living donor > deceased donor (1-year conditional survival) > deceased donor
Name 3 ways to improve transplant outcome?
- Improved surgical technique
- Improved pre- and post-transplant patient management
- Drug levels, infections, CVS disease, diabetes, etc. - Better understanding of transplant immunology
- Prevention, diagnosis + treatment of graft rejection
END RESULT => improved patient survival and graft survival!
Describe phase 1 to phase 3 of immune response to transplanted graft
Phase 1 = recognition of foreign antigens
Phase 2 = activation of antigen-specific lymphocytes
Phase 3 = effector phase of graft rejection
What are the 2 protein variations in clinical transplantations that are important?
- ABO blood group
- HLA (Human Leukocyte Antigens)
What are the 2 major components to organ rejection?
- T cell-mediated rejection
- Antibody-mediated rejection (B cells)
Describe HLA class I and II - where are they expressed?
HLA class I (A, B, C) => on ALL cells
HLA class II (DR, DQ, DP) => on APCs, but can also be upregulated on other cells under stress
HLA classes are highly _________, meaning that there are hundreds of _____ for each locus.
HLA classes are highly polymorphic, meaning that there are hundreds of alelles for each locus.
ex: A1, A2, A3 => A372 and up
What is the important interaction in T cell mediated rejection?
T cell TCR interacts with highly vairable HLA with its antigen => interaction => T cell becomes ACTIVATED!
Which 3 HLA are used for matching donor and recipients in organ transplantation?
HLA-A
HLA-B
HLA-DR
How are HLA mismatches written?
What is the max # of HLA mismatches?
For example: 1:1:0
(in the order of HLA-A, HLA-B, HLA-DR)
max 6 mismatches
Minimising HLA differences between donor and recipient improves transplant outcome - T or F? explain
True - The more mismatches you have the worse the outcome
In terms of HLA matching for organ transplantation, explain chances of MM for A) parent to child and B) sibling to sibling
A) Parent to child
>=3/6 MATCHED
B) Sibling to sibling
25% - 6 MM
50% - 3MM
25% - 0MM
How does HLA disparity cause rejection?
- T cell mediated
- Antibody mediated
A lot of the immunosuppressive medications developed to use for transplanted organs target T cell activation. Name 4 targets for these drugs. Give drug names for each.
- block calcineurin involved in downstream signalling of TCR = calcineurin inhibitors (tacrolimus)
- block MTOR signalling = Siromilus or steroids
- block cytokine signalling = anti-CD25 antibodies
- blocks TCR = OKT3 (used in acute rejection!)
Describe the 3 steps to T cell mediated rejection
- T cell - APC interaction
- T cell activation, inflammatory cell recruitment
- effector phase (organ damage) = cytotoxic T cells and monocyte/macrophages will tether, roll, arrest, and diapedesis into the endothelium of the graft = interstitial inflammation = tubulitis
Describe the 3 phases of antibody-mediated rejection
Phase 1 - B cells recognise foreign HLA
Phase 2 - Proliferation and maturation of B cells with anti-HLA abs production
Phase 3 - Effector phase; antibodies bind to graft endothelium = INTRA-VASCULAR DISEASE
What does this histo slide show in terms of rejection in transplanted solid organ?
Arteritis
macrophages under the epithelial layer = likely T cell mediated rejection
What do you see in this histo slide of a transplanted kidney?
right circle = lots of immune cells stuck in glomerulus = glomerulitis
left circle = lots of immune cells stuck there = capillaritis
=> ab-mediated rejection
antibody mediated rejection of transplanted, solid organs happens _______
intravascularly
anti-HLA antibodies are/are not naturally occuring, anti-A or anti-B antibodies are/are not naturally occuring?
anti-HLA antibodies ARE NOT naturally occuring, anti-A or anti-B antibodies ARE naturally occuring
Pre-formed anti-HLA abs = give 3 examples where they arise from?
- Previous transplantation
- Pregnancy
- Transfusion
A and B glycoproteins - where do you find them in donor organ?
Donor RBCs
endothelial lining of blood vessels in transplanted organ
Group A
Group B
Group AB
Group O
What abs does each have in their plasma?
Group A = anti-B
Group B = anti-A
Group AB = none
Group O = Anti-A, anti-B
Describe 3 times when screening for anti-HLA abs is done
- Before transplantation
- At time of transplantation
- After transplantation
Name and briefly describe 3 types of assays used for screening for anti-HLA abs
- Cytotoxicity assays = does recipient serum kill donor lymphocyte in prescent of complement = lymphocytes remain viable if NO ab binding
- Flow cytometry = does recipient serum bind to donor lymphocyte (using IF labelled anti-human Ig)
- Solid phase assays = does the recipient serum bind to recombinant single LA molecules attached to a solid support such as beads?
Give a few drugs that inhibit ab-mediated rejection of transplanted organs
- Remove abs with plasma exchange
- Intravenous Ig
- Anti-CD40/anti-CD20
- BAFF inhibitors
- Proteosome inhibitors
How do you detect rejection in kideny transplant?
- Monitor transplant function (creatinine) => if creatinine becomes elevated, take biopsy to cofnirm and classify rejection
- screen for antibodies
Describe treatments for T cell and ab-mediated kidney rejection
T cell => steroids (methylprednisolone), OKT3/ATG
ab-mediated => IVIG, plasma exchange, anti-CD20
What agents are used as induction agents (3) and baseline immunosuppression (3) for kidney transplant
Induction agent
- OKT3/ATG
- anti-CD52
- anti-CD25 (anti-IL2R)
Baseline immunosuppression
- CNI inhibitor +
- MMF or Aza
- with or without steroids
The most important antigenic determinant of rejection in current clinical practice for kidney transplantation is…
A) ABO blood group
B) Human Leukocyte Antigen/Major Histocompatibility Complex
C) Minor Histocompatibility Complex
B) Human Leukocyte Antigen/Major Histocompatibility Complex
A potential donor is described as being 1:1:0 MM. What does this mean?
1 MM A locus; 1 MM B locus; 0 MM DR locus
The main effector cells (2) in T cell mediated rejection are…
T cells (mainly cytotoxic) and monocyte/macrophages
A patient has an episode of acute T cell mediated rejection 2 months post-transplantation. What additional drug would most commonly be administered?
Steroids - methylprednisolone
Whih cell is injured in the effector phase of ab-mediated rejection of transplanted kidney?
Endothelial cells
(Remember, it’s INTRAVASCULAR damage)
