Transplantation Immunology Flashcards
Tests before kidney transplantation
Compatibility
- HLA (A, B, DR)
- ABO (blood Ag’s)
Pathogens
HIV, HepB/C, AMV, HTLV, Syph, EBV
Most common type of transplantation
allogenic
(from genetically different individuals)
Allogenic immune responses after transplantation are caused by ______
Genetic differences (MHC, ABO) between donor and recipient
What is a hyperacute reaction?
What two things can cause it?
An immediate response to either ABO or MHC expressed by endothelial cells
- Preexisting AB’s to A/B antigen = acute rejection
- Preexisting _AB’s to MHC_I or II from pregnancy, blood transfusion, or transplantation
What needs to be tested before blood transfusion or organ donation
ABO blood antigens
RBC’s dont express ____
They do express ______
Dont express MHC
Do express CHO antigens (ABO)
Antibodies to blood antigens A or B can cause ______ or _______.
What kind of reaction is this?
Complement fixation/rapid RBC clearance or hyperacute rejection
Type 2 HS reaction
All blood types/genotypes express __ enzyme
H
A antigen ends in ____
GalNAC
All ABO antigens are connected to _____ at its base
A ceramide
Blood types are inherited from…
both parents
Minor blood group antigens
The most important one is ____, due to…
Other minor blood group antigens such as ___, __, and ___ are less _____
Rhesus: C, D, E
RhD is morst important because it has high immunogenicity
Kell, Duffy, MN are less immunogenic
TImeframe for acute rejection
Occurs within WEEKS
Acute rejection caused by what?
This is similar to what kind of reaction?
How can this be prevented?
effector CD4+ TH1 cells or CD8 Tcells responding to HLA differences between donor and recipient
Like a Type 4 HS reaction
Immunosuppressive drugs or anti-T-cell antibodies
Accelerated acute rejection (AAR) ocurs within…
Mediated by what?
days
mediated by sensitized memory T cells from previous exposure or grafts
What happens during acute rejection?
Alloreactive CD8 T cell responds to antigen on parenchymal cells = damage to parenchymal cell and interstitial inflammation
Allorecognition occurs when (2 ways)
- TCR recognizes an allogenic MHC whose structure resembles the MHC-foreign epitope complex
- TCR recognizes structure formed from allogenic MHC + bound peptide
Direct vs Indirect allorecognition
Direct = CD4 and CD8 bind directly to donor DC
Indirect = Donor DC death produces membrane vesicles that contain the allogenic complexes –> get internalized and presented by recipients DC to CD4/CD8 cells
After transplantation, __________ migrate to the recipient’s _____ to activate T cells (which mediate rejection)
Donor’s dendritic cells
Spleen
What is a Mixed lymphocyte reaction test?
It measures ____ and ______
How is it read?
Co-culture of donor + recipient blood cells, measures T-Cell proliferation and T-cell cytotoxicity
More proliferation = More mismatch
Chronic rejection occurs ______ after transplantation
_______ occurs, leading to ______
Months to years after transplantation
Thickening of vessel wall leadds to ischemia
Which HLA’s are most important in matching kidney transplant?
A, B, DR
______ that differ in amino acid sequences give rise to ________________ between donor and recipient
Polymorphic self proteins
minor histocompatibility antigen differences
2 types of alloreactions
- Transplant rejection = recipient’s T cells attack transplant
- GVHD = When hematopoietic cells are transplanted the T cells in the transplant attack the recipient’s tissues (in Soviet Russia, graft attacks you!)
*there is also Graft-versus-Leukemia against leukemic or tumor cells (a type of GVHD)
Three conditions for GVHD to occur
- Graft must have immunocompetent T cells
- There must be an MHC mismatch
- The recipient must not be capable of rejecting the graft
- During GVHD, T cells circulate in blood to ________
- Alloreactive cells interact with _______ and proliferate
- _______ and ______ enter tissues inflamed by the conditioning regimen and cause further tissue damage
Secondary lymphoid tissues
Dendritic Cells
Effector CD4 and CD8 T-cells
Pros and cons of BMT
- Pros
- Can cure lots of diseases
- Lots of donors
- Simple procedure (marrow from iliac crests… local anesthesia, 30 minutes)
- Cons
- GVHD
- Non-functional T cells due to MHC mismatch
- Failed reconstitution (graft failure)
Alternative stem cell sources to minimize GVHD
- Autologous marrow (obtained before radiation)
- Umbilical cord blood cells (lots of CD34+ hematopoietic cells)
- Isolated stem cells free of T cells
Donor cells kill recipient tumor cells based on _______
MHC1 differences
Haploidentical transplant in which the recipient has only one of two ___________ of the donor.
Donor hematopoietic cells inhibit _____
Recipient hematopoietic and leukemia cells inhibit ______
inhibitory HLA-C
Donor = inhibit ALL donor NK cells
Recipient = inhibits only SOME donor NK cells
GVHD has ____ stages/grades
These are based on what tissues?
4 stages
Skin, Liver, and GI tract
____ are the xenoplantation donor of choice
3 problems with this procedure?
Solutions?
Pigs
Problems:
- humans have antibodies to pig endothelial CHO
- human complement attacks pig cells
- Zoonoses
Solutions
- Transgenic pigs expressing DAF
- Transgenic pigs that dont express the reactive antigens
- Germ free pigs
What is the advantage of xenotransplantation?
MHC molecules differ between species = human T cells dont recognize
Therefore T cell response is mild
___________ make allogenic transplantation possible, and also treat __________
Four Examples?
Immunosuppressants, Autoimmune diseases
- Corticosteroids
- anti-lymphocyte proliferation drugs
- microbial immunosuppressives
- Immunosuppressive antibodies
Short and long term sides from immunosuppressive drugs
Short = susceptibility to infection
Long = higher incidence of cancer
Immunosuppressive targets for:
- Belatacept
- Alemtuzumab
- rATG
- Basiliximab
- Anti-CD3 mAB
Belatacept = CD28
Alemtuzumab = CD52
rATG= immunodepletion
Basiliximab = IL-2
Anti-CD3 mAB = TCR/CD3 complex
Target for:
- Tacrolimus, Cyclosporin
- Methotrexate, Mycophenolate, Cyclophosphamide, Azathioprine
- Ca–> calcineurin
- DNA replication
Anti-CD52 is efficient at…
depleting leukocytes before organ transplantation
Prednisolone mechanism
Side effects?
induces IkB-alpha = inhibits NFkb activation
Side effects = cortisol sides
Corticosteroid effects (5)
- Reduces cytokine-mediated inflammation
- Reduces NO
- Reduces PG’s/LT’s
- Reduces emigration of leukocytes from vessels
- Induces apoptosis in lymphocytes and eosinophils
Annexin/Lipocortins suppress
PLA2
Cyclosporine A derived from _____
Targets ____
Blocks _____
a cyclic decapeptide from soil fungus
Targets calcineurin
blocks NFAT activation
Fk506 (a.k.a.___) definition
Targets ____
blocks _____
macrolide from soil actinomycete
Targets calcineurin
blocks NFAT activation
Rapamycin definition
Blocks ___, which is required for ______
macrolide from soil bacterium
Blocks mTOR, required for cell proliferation (inhibits IL-2 signaling)
Mechanism of Anti-CD3 monoclonal antibody (2 effects)
it is used to treat what?
- depletes T cells
- Promotes phagocytosis or complement-mediated lysis
*used to treat acute rejection
Calcineurin is a ________ that activates ______ and is inhibited by _____/_____
ST kinase
activates NFAT
inhibited by CsA or tacrolimus (FKBP)
calcineurin is a ______ protein, required for _______
calcium-binding protein
required for T, B, and granulocyte activation
effect of CsA or FK506 in granulocytes
reduced calcium-dependent exocytosis of granules
Nonspecific cytotoxic drugs target _______ cells
Examples? (with mechanisms)
dividing cells
Azathioprine = inhibits DNA replication (all dividing cells)
Cyclophosphamide = cross links DNA (bladder damage sides)
Methotrexate = Inhibit Thymidine synthesis (prevents DNA rep)
Uses and limitations for antibodies specific to human T cells
Used to deplete T cells or to suppress their functions
Limitation = the non-human antibodies can induce formation of antibodies to the anti-Tcell antibodies (yo dawg)
This reduces the effectiveness of the anti-Tcell Ab’s
