Flashcards in Lecture 18: Fetal Transplant Deck (59)
What is the biggest barrier igniting rejection?
MHC (system that allows us to discriminate between self and non self)
What tests can be done to determine donor/recipient compatibility?
detect recipient antibodies that might cause rejection of transplanted organs
What antibodies would you react with donor to test compatibility?
serum antibodies (lymphocytotoxic - would only have them if you were pregnant or had a prior transplant)
What is mixed lymphocyte culture?
basically a transplant in vivo (classic way to measure compatibility)
What are the best predictors of graft survival?
MHC Class 2 (DR) matches
What is the best way to determine whether potential organ recipients have MLC antibodies present in their serum?
incubate it with a panel of lymphocytes of known HLA specificity in individual wells. Then add complement so that the lymphocytes that have bound antibody will lyse
What are the steps of a mixed lymphocyte culture?
1) take cells from recipient and mix them with irradiated donor cells (so the donor won't respond to recipient by multiplying)
2) mix the two lymphocyte cultures
3) Look to see if recipient cells proliferate (sign of INCOMPATIBILITY; not a good donor)
True or false: in graft rejection, both donor and host DCs get involved
What are the 2 main ways the mammalian immune response prevents engraftment of tissue? (2 routes of allorecognition)
1) DIRECT: activation of the immune system by foreign MHC marker itself (w/o any MHC processing - HERESY)
2) INDIRECT: alloantigens are phagocytized, processed, and represented in context of Class II MHC by APCs
Why is the DIRECT allorecognition route considered a heresy?
It doesn't obey the MHC restriction concept of antigen presentation since the recipient is recognizing MHC as antigen
(CD4+ T cells react with foreign MHC, treating it like peptide)
Which method of allorecognition involves recognizing grafted antigen presented by recipient MHC?
indirect (normal way)
Which method of allorecognition involves recognizing MHC as pathogen?
What happens after direct and indirect activation of the immune system by allorecognition?
Classic CD4, Th1 response occurs
What are MANDATORY participants in ALL forms of cellular rejection?
CD4 T cells
What kind of Th response occurs during graft rejection?
TMMI (lots of IL-12 secretion)
leads to clonal expansion of CD8-alloantigen specific T cells (driven by IL-21)
True or false: donor dendritic cells take up alloantigen
FALSE, only host DCs do
What occurs in the lymph node after grafts?
Th1, Th2, and Th17 responses
APCs present peptide to T cells to generate a Th1 response
B cells present peptide to generate a Th2 response which will generate graft specific antibody
Th17 is generated and produces IL-17 for a chronic response (lots of IL-23 to promote this)
Which cytokines help promote the Th2 response in the lymph node?
IL4 and 21 - help produce alloantigen specific B-cell
What role do NK cells play in graft rejection?
try to kill graft right off the bat
What are the 4 important points summing up the cumulative effect of the graft rejection response?
1) activated macs mediate destruction
2) CD8 antigen specific graft cytolysis
3) Th17 mediated inflammation
4) antibody mediated, graft destruction by complement and/or Fc receptor activation of cell death mechanisms
What determines how severe the rejection to the graft is?
the ratio of Th1, Th2, Th17 cell activation countered by Tregs
Would a more dominant Th17 have a better or worse (more severe) response?
WORSE (recruits more neutrophils to the area)
Name 7 ways the immune system kills grafted tissue:
1) NK cytotoxicity against non-self MHC
2) NK antibody mediated cytotoxicity via Fc receptors (ADCC)
3) Th1 activated macrophage killing
4) Th1 amplified CD8 cytotoxicity
5) Th2 driven graft antibody
6) Complement mediated cytotoxicity
7) Th17 activation by DC
Hyperacute rejection is defined as __________ rejection, occurring within ___________ post transplantation.
accelerated; 48 hours
patient has pre-existing antibodies to graft (ex: antibodies to donor blood group antigens so antibodies bind vascular endothelium of graft, initiating inflammatory response that occludes blood vessel)
What is the pathology of hyperacute rejection?
widespread vascular injury brought about by alloantibody mediated endothelial damage
When do acute rejections occur?
within 3 weeks (after a CD4 cell reaction to direct or indirect alloantigen response)
What does a hyperacutre rejection look like?
ischemic and white (no blood flow, platelets agglutinate)
What defines acute rejections?
sudden appearance of effector cells in the graft
What determines the vigor of acute rejetion?
MHC Class II (DR)
What technology helps with determination of acute rejection?
microarray (shows gene expression profile)
What unknown fact have microarrays elucidated about predicting severe rejection?
if B cells are present
What is chronic rejection?
repeated, slow attrition of graft
Are chronic rejections caused by the same mechanisms acute rejections are?
NO; chronic via unknown mechanism
What is the pathology of chronic rejection?
intimal thickening that leads to graft ischemia
What is the ultimate goal to prevent graft rejection?
Name 4 strategies to prevent rejection:
1) optimally match MHC (especially DR)
2) block t-cell response to alloantigens
3) provide inhibitory second signals (CTLA-4), Tregs (CD4, 25) or cytokines (IL21, 23, 10, TGFb to override Th1, 17 and CD8)
4) INDUCE TOLERANCE BY MANIPULATING TREGS
Graft vs. Host disease (GvH) is unique to what?
bone marrow transplantation (or inadvertent transfusion of immunocompetent cells into an immunodeficient host)
What needs to happen before bone marrow transfusion occurs?
host needs to be essentially immunologically bankrupt (need to wipe out host's T cells)
How do you set up an assay to test for compatibility of bone marrow?
recipient cells are the stimulators and donor cells the responders ----- effectively the opposite of how you would set it up for a solid organ transplant
Why don't xenotransplants work?
a 1,3 GT gene which higher primates develop antibodies against
What can help blunt the autoreactivity to xenotransplants?
insert Human Decay Activating Factor (DAF) to activate complement and break it down so it wont cause inflammation
What is the rate of first trimester failure?
True or false: trophoblast (fetal tissue) does not express HLA-A B or C
True (it is downregulated)
What kind HLA is expressed on trophoblast tissue?
non classical HLA-G that expresses an inhibitory motif for maternal NK cells
What is special about the HLA-G?
it expresses inhibitory motif for maternal NK cells
What prevents the expression of cytokines that would promote cytotoxic T cells?
In the non-pregnant uterus, NK cells ___________ (increase or decrease)
In the gravid uterus, what happens to NK cells?
convert to markedly different NKs and make up 70% of all lymphocytes
What is special about the NKs in the pregnant uterus?
they do NOT express CD16 (the Fc receptor necessary for antibody-directed cytotoxicity)
they have regulatory and tolerogenic functions that prevent immune cytotoxic attack
also help with angiogenesis
what other immune cells are upregulated in the pregnant mom?
yd T cells, macs, paterna antigen specific CD4, 25 Tregs
these secrete IL10 and TGFb to tone down immune response
What two cytokines strongly promote the presence of Tregs?
IL-10 and TGFb
What does progesterone do in terms of maternal pregnancy?
suppresses Th1 type response
The pregnant mom has suppressed _____ response but normal ____ response
True or false: during pregnancy, mom has increased numbers of paternal MHC antigen specific maternal Tregs circulating
What else does progesterone do to the surface of the uterine endometrium to subdue immune response?
displays decay accelerating factor (DAF) to inhibit complement mediated death
What is the best characterization of the mom's immune system state during pregnancy?
dominant Th2 but suppressed Th1, Th17, and cytotoxic responses
What happens if the dominant Th2 converts to Th1 bias with dominance of IFNy at the fetal/maternal interface?
inability for successful implantation or fetal resorption
Why can the Th2 bias be harmful?
leads to exacerbation of maternal diseases dependent on TMMI (like Tb)