Graft Flashcards
Why do kidney transplants fail?
clot, infection, side effects of medications (eg. calcineurin inhibitors–effectively block T cell activation but nephrotoxic), donor kidney disease, recurrent disease, REJECTION is the most common
What is allogenic graft?
graft between two individuals of same species–most common kind
When doing a biopsy diagnosis, what is the sign of acute T-cell mediated rejection? What about acute antibody-mediated rejection?
T cell: interstitial inflammation and tubulitis Antibody: capillary inflammation, positive C4d stain (complement from classical pathway)
A 55 year old woman complains of inflamed, stiff and painful joints and is treated with daily prednisone therapy. Prednisone acts by which of the following mechanisms to ameliorate these symptoms of rheumatoid arthritis? A - Activates phospholipase A2 B - Decreases intracellular concentrations of lipocortin C - Inhibits COX-1 D - Inhibits lipoxygenase E - Reduces the expression of COX-2
Prednisone increases the synthesis of lipocortin - a protein that inhibits phospholipase A2 and thereby inhibits the cleavage of arachidonic acid from membrane phospholipid and reduces expression of COX-2.
Rituximab is an anti-CD20 antibody. How does this function as a immunosuppressant?
inhibits B cell proliferation
What is second set rejection? In models, how can this be transferred adoptively to a naive mouse? What is the major antigenic target for rejection?
Second graft from same donor is rejected more rapidly = MHC-specific. this is because donor MHC is the major antigenic target
Give T cells from immunized mouse
Why might complete MHC matching not insure graft acceptance?
donors and recipients may be differing at minor loci, leading to slow graft rejection
What are two models of cross-reactive recognition?
- peptide-dominant binding (most common): peptides bound to allogenieic (nonself) MHC molecules fit well with the TCR, even when the allogeneic MHC molecule doesn’t fit very well with the TCR
- MHC-dominant binding: the allogeneic MHC molecule may provide a better fit to the TCR, giving tight binding that is less dependent on the peptide molecule that is bound to the MHC molecule
How does mixed luekocyte reaction help you figure out whether there are differences in Class I or Class II?
CD4 activty bc of Class II, CD8 because of Class I
What is the direct versus indirect pathway of allorecognition?
Direct: initiated by host T cells that recognize the foreign HLA of the graft (on GRAFT APCs). CD8’s recognize the foreign Class I MHCs, and kill graft cells. CD4’s reocgnize the foreign Class II MHCs, IFNy -> inflammation
Indirect: initiated by host T cells that recognize graft peptides after uptake and presentation by HOST APCS: CD4+ T cells enter graft and recognize graft antigens, DTH type inflammatory
The human leukocyte antigen (HLA) system or complex is a gene complex encoding the major histocompatibility complex (MHC) proteins in humans.
What is hyperacute antibody mediated rejection? Difference between acute, chronic?
immediate, within minutes to hours:
preformed anti-donor antibodies exist in the recipient, so endothelial injury and thrombosis due to Ig/complement being deposited in the vessels walls
in acute, anti-donor antibodies are generated AFTER transplant–> small vessels may show thromboses,
in chronic: developed in almost everybody, primarily affects vasculature components; antibodies found in circulation but not readily within graft. unclear
How do we prevent rejection?
1 ) for kidney, match all the polymorphic HLA alleles (both inherited alleles of HLA-A, -B, and -DR)
2) immunosuppression via standard triple therapy: steroids (reduce overall inflammation), cellcept (inhibits lymphocyte proliferation by inhibiting gunaine nucleotide synthesis in lymphocytes), tacrolimus: inhibits calcineurin, preventing T cell function
What is graft-versus-host disease (GVHD)? what immune system comonent causes it?
Immunocompetent donor T cells recognize the RECIPIENT’S HLA antigens as foreign, likely directed against minor histocompatibility genes.
you see sloughing of skins, mucosal alteration, usually probably because of excess donor cytokine release, and maybe CD8+
How can we prevent GVHD? Why isn’t this the strategy we use always?
depletion of donor T cells before transfusion would eliminate it, but is associated with leukemia recurrence, graft failure, EBV related lymphoma
why? they have a lot of value
donor T cells aid the engraftment of HSCs, preventing recipient’s residual immune system from rejectin the graft
donor T cells have a graft versus tumor effect, so infusion of allogeneic T cells is used to treat leukemias resistant to chemo
