Transplantation Immunity Flashcards
what needs to match b/w donor and recipient to have it last
MHC
tissue compatibility testing
need to test tissue to determine if it is compatible with recipient
GVHD stands for
graph vs host disease
what is GVHD
the transplant rejects the donor
what is definition of transplantation
Transfer of living cells, tissues, and organs (a graft) from one part of the body to another or from one individual (donor) to another (recipient or host).
what is definition of transfusion
is a special case of transplantation and the most frequent.
examples of live transplant organs
skin
bone marrow
kidney
blood
what is autogenic or autograft
from one part of your own body to another
will autogenic graft be accepted without immunotherapy
yes - it is yourself
examles of autogenic grafts
skin
stem cell
vein
blood
syngeneic or isograft describe
identical twins - one idential person to another
syngeneic accepted without immunotherapy
yes
another name for syngeneic
isograft
another name for autogeneic
autograft
allogeneic or alograft
one individual in species to another individual in species
most common form of transplant
allogeneic
another name for allogeneic
allograft
allogeneic accepted without immunotherapy?
no - rejected
xenogeneic transplant
from a member of a different species
another name for xenogeneic
xenograft
xenogeneic accepted without immunotherapy?
no
ex of xenogenic transplant
heart valve - like pig
exampel of allogeneic transplant
blood, cornea, heart, lung, liver, kidney, bone marrow
to prolong transplant survival, what needs to happen
they are screened and matched at MHC and test that recipient does not have pre-existing antibodies that would recognize the tissue
if the donor has antibodies against the tissue when does rejection happen
before the transplant is even finished
what leads to most rapid form of transplant rejection
blood group different
need to match blood for
successful transplant
what are the three targets of alograft rejection
Blood group (ABO) antigens
MHC I and MHC II
Minor histocompatibility antigens
what is universal donor
O-
what is universal recipient
AB+
what are the two different ways MHC I and II can be recognized during transplant rejection
direct and indirect mechanism
we can never get rid of TCR that have receptors that bind to
somebody else’s MHC cells
direct mechanism
being directly recognized
donor APC migrate to secondary lymphoid tissue and stimulate alloreactive recipient T cells
indirect mechanism
MHC molecules taken up like foreign antigen by receipient APC, processed, and presented on recipient MHC to recipient T cells
direct allorecognition
APC carried over in the transplanted tissue that are directly recognized by CD4 or CD8 T cells
T cell activation
indirect allorecognition
shedding of MHC from donor DC, aquired by recipient APC, processed, prseented on recipient MHC to the alloreactive T cell
indirect allorecognition allows for production of
antibodies against foriegn MHC molecule
how are antibodies against foreign MHC possible in indirect
alloreactive CD4, B cells may have receptor specific, if the b cell is specific, i will be taken up and processed and b cell will recruit help from CD4 T cell to generate antibody against the alloreactive MHC molecule
is it possible to perfectly match MHC
no - there are so many possible polymorphisms
where is it most important to get MHC match
class II
most importnat MHC to match for
class II -especially MLH -DR
what do you want to match in order of importatnce for MHC for transplant
DR
A
B
why isn’t it 100% acceptance for transplant with completely MHC match
there will always be a minor mismatch, it won’t be profound rejection reaction but can still give rise to rejection
what are minor histocompatibility antigens
polymorphic proteins - AA sequence from particular proteins may differ
examples of proteins that make minor histocompatiility issues
stress induced proteins
Y chromosome proteins
describe Y chromosome proteins
female could reject male tissue even if they are HLA identical, female doesn’t have any male protein so she can’t handle
review pg 18
pg 18
if individual has antibodies aginast ABO blood groups you can use their serum to ____ the mismatched RBC
agglutinate
what technique do you use tot test for ABO blood type
agglutination
what is agglutinate
RBC clump together
assay used to detect difference in MHC class II is
mixed lymphocyte reaction
describe mixed lymphocyte reaction
mix donor and recipient, if they are mismatched at MHC class II then alloreactive cells in recipient will proliferate - extent of proliferation. differences detected are usually HLA-DR
to tell if recipient have attack of donor, have to stop them proliferating so you know if it is donor vs. recipient, how do you do this?
irradiate the donor cells - so you make it so they can’t divide
when you add thymidine at end of MLR what will not encorporate the thymidine
donor cells b/c they were irradiated
if there are no differneces at MHC II (what we want), that means what happened in mixed lymphocyte reaction
no reaction - the recipient did not proliferate
when you add thymidine what happens if donor and recipient had same MHC II
no reaction so 0 cpm
if recipient and donor do not share same MHC II what happens
recipient clls not tolerized, so when they are incubated the recipient cells are going to react against donor cells and will proliferate
add thymidine to MLR when the MHCII doesn’t match, what hapesn
radioactivity DNA, lots of cpm (pg 22)
what is major downside to MLR
takes a long time - several days
what does MLR stand for
mixed lymphocyte reaction
how is typing of MHC done usually
sequening or other molecular means, it’s much faster
microcytotoxicity test, how do you do it
buy antibodies against all the HLA alleles, and add to donor and recipient cells (seperately), if they bind it indicates the cells express the HLA allele, you add complement and the cells are lysed.
why can you do Microcytotoxicity test in class I but not II
if you take peripheral blood from tissue, all would express class I but just tiny bit would express class II
do donor and recipient both express HLA A 2? explain how you do it
add antibody then add complement, the ones that take it up will be lysed, add dye, the cells that do not express allele wil not be lysed, so see which cells killed by adding stain and it will be taken up by lysed cells. so blue = dead cells
what is advantage of Microcytotoxicity assay
it’s fast
what is major disadvantage of Microcytotoxicity assay
don’t have enough antibodies to distinguish from al the HLA-A and HLA-B alleles
difference in HLA - where is it?
AA that lie in peptide binding route
describe HLA-A immobilized probe array typing system
primers for the alpha 1 and alpha 2 regions - have PCR products from potential donor and recipient.
PCR
see what alleles both have
HLA-A identifies
HLA-A locus, it’s identifying the locus
an asterisk (*) means
it has been defined by sequensing
review pg 28
28
tissue crossmatching - describe
detects if recipient has pre-existant antiodies capable of recognizing donor cells
fastest rejection possible
tissue crossmatching- if recipient already has antibodies against donor
how do you analyze for tissue crossmatching
peripheral blood cells from donor, add from recipient, i didn’t catch the rest read pg 29
why would a person have pres-existing antibodies against donor cells?
pregnancy
blood transfusion
prior transplantation
what is classical test to match MHC I
microcytotoxicity assay
MHC II classical test to match
mixed lymphocyte reaction
purpose of typing donor and recipient is to avoid
rejection
hyperacute rejection, how quicly
minutes-hours
what is the most rapid form of transplant rejection
hyperacute
what is cause for hyperacute rejection
pre-formed anti-donor antibodies + complement
accelerated rejection, how quickly
2-4 days
what is cause for accelerated rejection
reactivation of sensitized t cells
what is most common kind of rejection
acute rejection & chronic rejection
acute rejection, timing
about a week (minimum, can be a month to siix months)
what is cause for acute rejection
primary activation of t cells
what is time frame from chronic rejection
months to years
what is the cause of chronic rejection
antibody and cell mediated rejection. not well understood
what kind of response from accelerated rejection
memory response
if somebody is getting second transplant what kind of rejection do you really need to look out for
accelerated rejection
hyperacute, what type of hypersensitivty response
type II HSR (IgG against cell surface)
acute and accelerated what type of HSR
type IV
chronic, what type of HSR
II, III, IV
hyperacute graft rejection mediated by
antibody
describe steps in hyperacute graft rejection - 4 steps
Pre-existing antibodies enter the donor organ cells.
C’ is activated.
PMNs are attracted and destroy endothelial cells
Platelets adhere to denuded areas, coagulation is activated,and vessels are occluded
____ can participate in acute rejection, but require CD4 t cell help
antibody
induction of antibodies in acute vascular rejection, that person is at risk for what in another transplant
hyperacute rejection
most important participate in acute graft rejection
CD8 T cells
what form of rejection is controlled by immunosuppressive therapy
acute graft rejection
acute graft rejection, describe steps
donor APC migrate out of transplant to lymph node
there they stiulate alloreactive t cells in recipient (esp CD8)
the t cells migrate to transplant and kill cells in transplant
all transplants will eventually succumb to
chronic graft rejection
chronic graft rejection occurs despite
immunosuppressive therapy
what kind of transplanation can the transplant reject the recipient
bone marrow transplantation
at least 50% of pts who get bone marrow translant have some form of
GVHD
prior to bone marrow transplantation have to make space for bone marrow cells, have to do what
ablate the bone marrow
conditioning regimen prior to bone marrow transplant includes
radiation, chemotherapy, immunosuppressants, antivirals
where is inflammation due to the conditioning regiment for bone marrow transplant
GI, skin, liver
where is GVHD likely to affect
GI, skin, liver (quickly dividing cells)
describe GVHD
T cells in transplant attack recipients tissues
symptoms of GVHD
rash, jaundice, diarrhea
why can’t we get rid of t cells from bone marrow before transplant to prevent GVHD?
there is higher risk of transplant failing if you get rid of t cells from donor
higher risk of leukemia relapse
higher risk of fungal infections
higher risk of EBV lymphoproliferative disease
why does it help get rid of leukemia to keep the t cells in bone marrow
the t cells in bone marrow will attack the leukemia
how do you mobilize stem cells from bone marrow to prepare for bone transplant
inject chemotherapeutic drugs into bone marrow, so it puts stem cells into circulation
vast majority of recipients have to immunosuppressed, why
you won’t be able to find the perfect match, there are way too many variants
for immunosuppressive therapy, how do they prevent activation and proliferatin of t cells
Inhibitors of IL-2 production
Cyclosporin A, FK-506 (Tacrolimus)
Inhibitors of IL-2/IL-2R signal
IL-2 antagonist mAbs (anti-CD25 Abs)
Rapamycin (Sirolimus) inhibits IL-2R signaling
blocking IL-2/IL-2R blocks
clonal expansion
to remove actively dividing cells for immunosuppressive therapy use what
cytotoxic drugs
to deplete peripheral t cells for immunosuppressive therapy what do you use
anti-CD3 mAb, anti-CD4, anti-CD2
what do you use to inhibit inflammatory response for immunosuppressive therapy
corticosteroids
why do neutrophil numbers seem to go up with corticosteroids
they are inhibiting the things that make WBC stick to the cell walls, so it seems like there is more when you draw blood
what does CTLA4 bind to
CD80 or CD86
review pg 44
44
how does CTLA4-IG prevent delivery of signal 2 to naive t cells?
make fusion protein, it makes it a soluble protein you can inject into recipient
see page 45
blocking what prolongs graft survival
CD28
CD40L
what is the most probable source of xenotransplantation
pigs
what is the downside to pig transplants
we have natural antibodies to them
we do not get strong what kind of response against the pig MHC
TCR
why do we have heterophilic antibodies against pig antigens?
we do not have Galactose-a-1,3-galactose so our b cells are not exposed to them so reactive ones are not deleted
when enzyme do humans lack that most mammals have
Galactose-a-1,3-galactose
how much of our IgG is reactive against Galactose-a-1,3-galactose
1%
what has happened to pigs to decrease rejection
took out the gene to make the Galactose-a-1,3-galactose but they just an alternative pathway to make it. we now make triple transgenic pigs -
what is hDAF, hMCP and hCD59
complement regulating proteins
what is hDAF
decay accelerating factor
hMCP
membrane complement protein
what does hCD59
prevents insertion of MAC
what is autograft
frm one part of individual to another
what are syngeneic grafts
b/w twins
most common form of transplant
allogeneic transplant
what is allogeneic transplant
from one individual to another of same species
review pg 49
49
indirect
llows generation of alloantibody
type IV HSR
cytotoxic T cell or macrophage activation
review pg 50
50
