Fetal Transplant Flashcards
How can you determine if a donor is a good match to transplant recipient?
Detection of recipient antibodies that might cause rejection of a transplanted organ (ELISA, flow cytometry)
Determination of the degree of compatibility between the recipient and the donor (flow cytometry, DNA sequencing)
There are two ways to “type” or detect MHC or HLA specificities on mononuclear nucleated cells. The number of matched MHC loci, especially the Class 2 ones (also known as DR), between donor and recipient can be used to predict graft acceptance. The more loci matched the better, but MHC Class 2 (DR) matches are the most strongly predictive of graft survival.
Originally, the source of the antibodies used to detect HLA specificities were usually from women with multiple pregnancies who reacted to a paternal HLA antigen.
More recently, tailored monoclonal antibodies are available against specific MHC loci.
Tissue Typing Laboratories are now using flow cytometry, ELISA and molecular methods to decrease time of analysis and increase sensitivity
and decrease costs but you need to understand the fundamentals of detecting HLA antibodies.
The Mixed lymphocyte reactions (“In vitro”) transplants:
Mixed Lymphocyte Culture (MLC) - a transplant in vitro. The primary concept of this assay is that differences in the HLA (MHC) class I & II (particularly HLA-DR) antigens between the donors of the cells used in the assay will stimulate T lymphocytes to synthesize DNA and divide. The MLC is designed to quantitate the amount of cell division as measured by newly synthesized DNA in responder lymphocytes when exposed to irradiated stimulator lymphocytes. In a solid organ transplant scenario (eg. heart, kidney) the responder cells are the recipient cells and the stimulator cells are from a potential donor.
What determines hyperacute vs acute rejection?
Which is mediated by antibodies?
HYPERACUTE (within 24 hours)—Ab plays a critical role. secondary immune response bc body has memory against this tissue. that’s why Pre-test for Ab test is important
ACUTE: Defined by sudden (10-90 days) appearance of effector cells in the graft. Vigor depends upon DR mismatch, gender, intensity of immunosuppression
Describe mechanism of rejection involving naive and memory lymphocytes.
Alloimmune responses involve both naive and memory lymphocytes. In the graft and the surrounding tissues, dendritic cells of donor and host origin
become activated and migrate to T-cell areas of secondary lymphoid organs. There, donor antigen-bearing dendritic cells engage alloantigenreactive
naive T cells. Naive T cells are optimally triggered by dendritic
cells in secondary lymphoid organs, but antigen-experienced memory T and B cells (perhaps by past blood transfusions or pregnancy) may also be
activated by other “non-professional” APC such as endothelium of the transplanted organ.
The mammalian immune response has multiple effective pathways to
prevent engraftment of foreign organs. Describe the direct and indirect methods.
The MHC of the transplanted organ, especially the MHC on the “passenger” leukocytes carried into the recipient from the donor, function as alloantigens and are recognized by the immune system in two ways:
Direct - activation of the immune system by the foreign
MHC marker itself without any form of MHC processing or presentation. Large
numbers of CD4 T-cells will react with foreign MHC, possibly on the
process of the molecular mimicry.
Standard recognition by the “indirect” method - alloantigens are phagocytized, processed and represented in the context of Class II MHC antigens by antigen presenting cells to CD4 T cells.
What does intensity of rejection depend upon?
Would a reaction be more intense/destructive if Th17 were more dominant or if B cells were the dominant cell?
The intensity of rejection will depend upon the ratio of Th1, Th 2 and Th17 cell activation counter-balanced by T regulator inhibition. For example, if the dominant cell is Th17, the rejection might be more destructive (more neutrophils) than if B cells were the dominant cell.
Once either indirect or direct alloantigen activation of the immune system
occur, what immune response is initiated? What type of hypersensitivity reaction?
CD4 Th-cells are mandatory participants in all forms of cellular rejection.
IL-12 driven T Cell mediated Macrophage immunity (delayed
hypersensitivity) occurs early
Activation and clonal expansion of CD8-alloantigen specific T-cells
follows, driven by CD4 Th1 cells and IL-21.
Recent evidence strongly suggests that the Th17 cell and IL-23 may rewrite the story of rejection immunology.Th17 is a very pro-inflammatory cell and if it is the predominant cell in a
rejection episode, graft damage may be severe.
Th2 cells provide co-stimulatory signals, IL-4 & 21, for alloantigen
specific B-cells which then produce alloantibody
NK-cells participate in varying degrees in transplant rejection,
however, they are not mandatory for a successful rejection of a transplanted organ.
The cumulative effect is: 1) activated macrophage mediated graft destruction, 2) CD8 antigen specific graft cytolysis, 3) Th17 mediated inflammation and, 4) antibody mediated, graft destruction
either by complement and/or Fc receptor activation of cell death mechanisms.
Induction of T regulator cells- this highly dependent upon
individual “immune response” genes of the recipient and the
disparity of the MHC antigens between donor and recipient.
Graft arterial occlusions occur sometimes in the hyperacute response when antibodies against donor blood antigens bind vascular endothelium of graft, initiating an inflammatory response that occludes blood vessels.
How does a chronic mechanism differ from hyperacute reaction?
CHRONIC….insidious and caused by mechanisms probably different than acute rejection, usually caused by graft arterial occlusions, which results from the proliferation of smooth muscle cells and production of collagen by fibroblasts. This process, termed accelerated or graft arteriosclerosis, results in fibrosis which can cause ischemia and cell death. The major problem in solid organ transplantation today
fibroblast and fibrosis, collagen deposition in the vascular environment and also w/in tissue so whole lung thats supposed to be working for air exchange doesn’t work anymore and is just distinctive scar… chronic rejection is big problem .
The pathology of hyperacute rejection is characterized by widespread vascular injury brought about by alloantibody mediated endothelial damage.
What drug can wipe out acute rejection?
drug FK506- wipes out acute rejection)
Describe graft-vs-host disease. Given an example.
Please remember that this situation can occur when an Immunoincompetent host receives a transfusion!(if it is
Not depleted of lymphocytes first)
When bone marrow is transplanted the T cells in the transplant attack the recipient’s tissues.
radiate patient w v high dose to remove all lymphomas and all HSC. wipe out blood system. then repopulate patient w new bone marrow. or use umbilical cord blood. those are good sources of HSC. problem w this approach is sometimes bone marrow is v good source (niche) for memory T cells ..mature T cells that function effectively
if you don’t remove those memory T cells, they will go into the patient. then those T cells coming from bone marrow will start attacking the recipient tissues. for those T cells that is an allogenic condition… even though from whole organ system, that is allopathic for T cell coming here and that causes graft vs host.
What will transplantation of an A, B, or AB organ into an “O” individual result in?
a patient who is blood
group O normally has circulating antibodies to blood group A and B. antigens. These antigens are not only on erythrocytes, but are widely distributed on all tissue cells. Transplantation of an A, B, or AB organ into an “O” individual will result in an immediate reaction between the transplanted organ’s A or B determinants and recipient antibodies.
When might antibodies with reactivity to MHC antigens be present in patients prior to transplant?
Antibodies with reactivity to histocompatibility (MHC) antigens can also be present in some patients prior to transplant. These patients have
usually been sensitized by repeated blood transfusions or multiple
pregnancies.
What characterizes the acute reaction?
Acute rejection is defined by the sudden appearance of anti-donor organ
immune effector cells during the first three weeks after grafting. The
rejection sequence, especially early after grafting, is initiated when host recipient CD4 T-cells react with alloantigens, either directly or indirectly,
and mediate a TMMI-type response. Simultaneously, alloantigen specific
CD8 cells attack the graft, TH17 cells promote an inflammatory reaction
and B-cell alloantibody appears after alloantigen specific B-cells take up
residence within the graft.
The mix of cell populations, the vigor of their response, and
frequency of rejection is orchestrated by a complex interplay between MHC differences, especially between HLA- D
(MHC-II) loci of donor and recipient.
At what stage of rejection might you be most likely to see diffuse, widespread
arteriolar narrowing caused by intimal thickening of the vessel? Hyperacute, acute or chronic?
Chronic
What signals or cytokines might be able to override Th1 or CD8 responses to prevent rejection?
Provide inhibitory second signals (CTLA-4) or cytokines (IL-10 & TGF-beta) to override Th-1 and CD8 responses
What type of rejection will occur with a xenotransplant?
Non-primates, for e.g., pigs, have anatomically suitable organs for
xenografting but unfortunately have rich endothelial displays of the α-gal epitope. Thus the attempt to transplant these organs into humans is thwarted by hyperacute rejection.
