Intro to transplantation Flashcards
Question
Answer
syngenic
transplantation between genetically identical individuals
allogenic
transplantation between genetically dissimilar individuals of same species
xenogeneic
transplantation between different species
minor histocompatability antigen
normal proteins on cell surface that are polymorphic in nature
evidence that graft rejection is caused by lymphocytes
occurs 7-14 days after first transplant-role of lymphocytes
rejection occurs more rapidly second time-role of memory (3-7 days later)
rejection of distinct graft 7-14 days-specific response (the ability to reject a graft rapidly can be transferred to a naive individual by lymphocytes from a sensitized individual)
evidence for role of MHC in grafts?
transplant between genetically identical individuals not rejected
transplant between genetically non-identical individuals is rejected
EXCEPT–> graft from inbred parental strain (MHCb) is not rejected by MHCa/b
BUT graft from MHCa/b is rejected by a mouse with strain MHCa
direct alloantigen recognition
allogenic APC presents allogenic MHC**activates CTLs
indirect alloantigen recognition
self APCs present allogenic MHC proteins**activates CD4 T cellscan also have allo-antibodies produced by alloreactive B cells in indirect pathway
high probability that T cells recognize allogenic MHC due to?
T cells are selected to have low affinity -allogenic MHC not negatively selected - may be high affinityself MHC restricted T cells are able to recognize foreign MHCallogenic MHC with bound peptide may mimic self MHC and peptide complex
what triggers costimulation expression in transplantation patients?
induces inflammation, taking a tissue and placing into recipient
Treatments aimed at blocking costimulation for less inflammation?
hyperacute rejections
within minutes
thrombosis of graft vessels followed by ischemic necrosis
host circulating antibodies are specific for antigens on graft endothelial cells (IgG usually, and are present prior to transplantation due to previous transplantations, blood transfusions or multiple pregnancies)
complement activation leads to endothelial cell injury, thrombosis and vascular occlusion occur
how to prevent hyperacute?
cross-match with antibodies
every donor and recipient are matched for blood type and potential recipients are tested for antibodies against the cells of the prospective donor
acute rejection
within days to weeks
rejection stimulated by alloantigens in the graft
mechanism:-acute cellular rejection (CTL and CD4)-microvascular endothelialitis (inflammation within the endothelial cells)
acute antibody-mediated rejection characterized by transmural necrosis of graft vessel walls
acute rejection treatable?
YES!
chronic rejection
months to years after transplant
refractory**
T cells and antibodies against alloantigens
immune response results in fibrosis of graft tissue and gradual narrowing of vessels-
graft arteriosclerosis
immunosuppressive drugs for T cells used in transplantation
azathioprine, rapamycin, cyclosporine, anti-IL-2R, anti-TCR (OKT3, thymoglobulin)
rapamycin
targets mTORC1
Interfers with signaling from
IL-2 receptor
azathioprine
no proliferation
cyclosporine
Interfers with signal transduction from TCR
CTLA4-Ig
inhibits CD28 B7 interaction
thymoglobulin, OKT3
no TCR activation
side effects of immunosuppression
malignancy- T cells have the ability to survey the body and eliminate tumor cells (transformed cells) that have formed, so if we suppress T cells then have resulting malignancy in some cases
infections
drug toxicity= side effects of immunosuppressive drugs
non T cell targets for immunosuppression
alloantibodies and alloreactive B cells
anti-inflammatory drugs
inhibitors of leukocyte migration
strategy to minimize alloantigenic effects?
cross-matching-testing for preformed antibodies against donor HLA
why do people develop anti-A and anti-B antibodies for blood group antigens?
normal gut flora has similar epitopes
lewis antigen
fucosylation at additional terminal sites of blood group antigen
rhesus antigen
Rh15% of population has deletion or other alteration in RHd allele
Can ABO-incompatible transplant be done?
yes, more likely to be successful in children
mechanisms that can take up the antibodies against antigen A and B or reduce B cell population that is producing antibodies
GVHD
graft versus host disease
reaction of mature grafted T cells to alloantigens of the host
usually against minor histocompatability antigens
acute less than 100 days (epithelial cell death in the skin, liver and GI tract)
chronic greater than 100 days (fibrosis and atrophy without acute cell death)
treated by immunosuppression
hematopoietic stem cell transplant
transfer allogenic pluripotent hematopoietic stem cells from bone marrow to a recipient
patient treated with radiation beforehand to deplete bone marrow to make room for the transferred cells
can cause GVHD
example of immunologic cross reaction
allogeneic MHC molecules containing peptides derived from the allogeneic cells of the donor may look like self MHC molecules plus bound foreign particles
how do you distinguish between acute and chronic rejection in transplantation? and what is the next step in treatment for both?
Get biopsy of tissue
acute–> endotheliallitis
chronic –> fibrosis
if it is acute–> back of immunosuppressive drugs
if chronic–> increase immunosuppressive agents
how is GVHD different from acute rejection?
in acute rejection the recipient is attacking the donor graft tissue
whereas in GVHD donor is affecting recipient
why are the skin and intestinal tract targeted in acute GVHD?
T cells recognize MHC/antigen
Skin in intestinal tract may have more MHC on their suface and makes them targets
Inflammation can also propagate GVHD b/c it upregulates MHC expression
methods employed to maintain graft tolerance
immunosuppressive agents
reduction of immunogenicity
tolerance induciton- (co-stimulatory blockage, hematopoietic chimerism, transfer of T-regs)
