(18) Transplant Immunology Flashcards
Define Allogenic.
Individuals of the same species who are genetically Different
What allogenic traits in humans are major determinants of transplant success or failure?
- MHC class I and MHC class II genes
- Blood Group antigens
Define Autograft (isograft).
Graft of tissue from one site of an individual to another
*No rejection expected
Define Syngeneic Graft.
Graft between genetically identical patients (isograft)
*No rejection expected
Define allogenic graft (allograft)
Graft between two genetically different patients
*graft WILL be rejected unless appropriate immunosuppressive drugs are used
Define zenograft.
Graft between to individuals of different species
Differentiate Transplant Rejection and Graft vs. Host disease as far as when they occur.
Transplant Rejection:
- Solid tissue grafts are destroyed manly be T cells specific to alloantigens on grafted tissue
Graft vs. Host Disease:
- Bone marrow is transplanted into a recipient and T cells from donor marrow attack the host SKIN and GI tract mainly
***GVHD can also occur in SOLID tissue transplant IF MATURE Naive T cells are left inside the tissue
What is the most common type of tissue transplant?
- what is the role of MHC?
- Primary targets of alloreactivity?
- Cells involved in rejection event?
Blood Transfusion = MOST COMMON
- NO MHC I or II on RBCs so no worries there, ALSO MEANS NO T CELL INVOLVMENT IN REJECTION!!!!
- Main means of alloreactivity = A and B blood group antigens
What is the universal Donor blood type?
- universal recipient?
- WHY IS THIS?
Universal Donor = O, Rh- antigen
Univseral Recipient = AB , Rh+ antigen
- people with O can’t receive A or B because during development there cells were never desensitized to A and B sugar structures
- Same goes for Rh
What is a major difference between the immune response to A or B antigens vs. Rh antigens?
A and B antigens:
- many bacteria encountered by humans have structures similar to A and B group antigens, this means that in people with O blood they will NOT ONLY have reactive B cells to A and B in there repertoire BUT they will ALSO HAVE BEEN ACTIVATED at some point previously
Rh antigens:
- Humans don’t encounter things similar to this antigen so encountering the antigen once will be NBD because we don’t have any antibodies against it
What is hyperacute transplant rejection and what causes it?
- how long before donated tissue is killed
What is it:
Rejection mediated by pre-formed antibodies that are specific for alloantigens that are expressed on grafted tissue
What causes it:
- VASCULAR ENDOTHELIUM HAS THE SAME A,B,O blood groups expressed that were expressed in the donors blood
- PRE-formed antibodies to A or B intiate complment
- Phagocytes come in and recognize their Fc’s and complement receptors
- Inflammatory Mediators cause platelet aggregation inside tissue and it dies within 48 hours
What two forms of tissue rejection are primarily CTL mediated?
- Acute Transplant Rejection
- Minor Histocompatibility Rejection
Acute Transplant Rejection
- Which Cell is Mediating?
- What antigens cause it?
- How long does it take, and why?
Cells:
- CTL’s specific for alloantigens in the grafted tissue
Antigens:
- Alloantigens that are the product of POLYMORPHIC GENES
- Since MHC class I and II are the most polymorphic genes in the genome it makes sense that they are THE CTL TARGET during transplant rejection
Time:
- Takes 11-15 days (w/o drug admin) because the response has to be primed after the tissue is introduced into the body
What is the difference between first set and second set acute transplant rejection?
- Time?
- Cells responsible?
- Why does it occur?
1st set:
- This is typical acute transplant rejection where the MHC’s are incompatible and it takes the host 11-15 days to mount an immune response
- Response mediated by CTLs
2nd set:
- This occurs if the donor donates a SECOND ROUND of the same tissue
- Response can be mounted in 4-7 days
- MUCH quicker because CD8 repertoire has already been built up in the 1st round
- CTL mediated
T or F: in 2nd set Acute Rejection the tissue never even has a chance to become vascularized before it is killed
True, it the 1st round your body will allow it to become vascular before it kills the tissue, in set 2 it won’t even let this happen
What/whose APC’s are used to initiate the acute transplant rejection response?
APCs from the DONOR will migrate to 2˚ lymph tissue where it will present via MHC class I to the RECIPIENT’S Naive CD8+ cells
Since these are DONOR APCs they will be presenting a lot of donor specifc proteins (T cells in the host were never desensitized to the way that these proteins are presented on MHCs)
**Note the Recipient’s APCs can also participate in the response by taking up Donor tissue
What are the MHC loci that are the MOST important in assuring compatibility in a transplant?
- how do we ensure proper matches?
- HLA-A
- HLA-B
- HLA-DR
- Serological and DNA techniques be used to determine HLA haplotype
LONG TERM SUCCESS IS SUPER DEPENDENT ON THE DEGREE OF HLA MATCH
Is it possible to have a good HLA match and still see transplant rejection?
- if so how?
- How long would this take?
Yes - MHC is not the sole determinant even though its the most important
How:
Minor Histocompatibility Antigens can facilitate this response
How long:
30-60 days for response to be mounted (w/o giving any drugs)
Where in the genome are minor histocompatibility antigens found?
Encoded within the MHC locus
What is super unique about Liver Transplantation?
- IT DOES NOT REQUIRE HLA cross-matching
- Blood types DO have to match to prevent hyperacute rejection
What matching is required for corneal transplantation?
- are anti-inflammatories used?
- NO matching required because the tissue isn’t even vascularized
- Don’t even need to use anti-inflammatories
Why is it amazing that a fetus can live inside a mother without being rejected by the mom’s immune system?
- what are some possible explanations for this?
The fetus is technically and ALLOGRAFT because it contains HLA’s from the father in addition to the mother’s
No one knows why it isn’t destroyed, possible explanations:
- Placenta is fetal tissue and does not express MHC molecules, therefore it may serve as a partial barrier to the mom’s T cells
- Placenta and Uterine epithelium produce TH2 cytokines that down regulate cell-mediated immune response
What is the most important of the Rh factors?
RhD
What is the risk of an Rh- mother carrying an Rh+ baby?
- what disease could result?
If the mother is exposed to fetal blood she will mount an an immune response against that blood.
Disease:
- Erythroblastosis Fetalis - Hemolytic disease caused by IgG crossing the membrane
Is there a risk for an Rh+ mother carrying an Rh- baby?
- what disease could result?
No risk here, the mom lack Rh specific Abs altogether
Why is IgG attack on the fetus not a concern until the 2nd pregnancy usually?
- In the birth of the 1st baby the Rh- mother will be exposed to a lot of the baby’s Rh+ blood during parturition and will result in her mounting an immune response to RhD
- Since the 1st baby is out those antibodies will only be around to be encountered by a 2nd baby
What is given to protect the second Rh+ baby that is born to an Rh- mother?
- what does it do?
RhoGAM - Preparation of anti-RhD IgG antibodies given to the mother following the birth of the 1st child
*anti-RhD Abs rapidly bind and cause destruction of RhD+ RBC’s preventing the mother from making an anti-RhD response
What mediates the formation of petechial lesions in a child with Erthroblastosis Fatalis?
Macrophage Mediated TNF-alpha production
What are some characteristics of a child born with Erythroblastosis Fatalis?
- Enlarged Spleen and Liver from macrophages attacking RBC’s marked by Abs
- Immune complex disease is seen in these babies because of all the antigen released when the RBCs are lysed
- Petechial lesions are also often observed
Who do you give RhoGAM to and why?
RhoGAM is given to ANY Rh- mother that gives birth because we don’t know until after the baby is born if they’re Rh+ or Rh-
**Start giving this at the beginning of the 2nd trimester
What is the major cause of morbidity and mortality following a bone marrow transplant?
Graft vs. Host Disease
**Note: GVHD can take place in Solid Organ transplant but the incidence is MUCH lower than bone marrow transplant
How does Graft vs. Host Disease play out? (step by step)
- Donor T cells were - selected for self-reactivity for DONOR not recipient
- Some donor T cells migrate to 2˚ lymph of the Recipient, and get activated by RECIPIENT APCs these Donor T cells then proliferate
- CD4 or CD8 effector cells attack the Host tissue
**This disease is Super Devastating because the Tissue is attacking the entire host, opposed to normal solid tissue rejection where just the transplanted tissue is killed
**What are the 3 primary problems caused by Graft vs. Host Disease?
- Inflammation of the skin - MACULOPAPULAR SKIN RASH
- Bile duct inflammation in the liver - HIGH SERUM BILIRUBIN
- Damage to intestinal tract - DIARRHEA
T or F: most organ transplants are mismatched at 1 or more HLA loci
True, this means we must give immunosuppressants to prevent rejection
What is the important action of Corticosteroids that prevents transplant rejection?
- Inhibits the function of NFkB, which is involved in cytokine expression
**Don’t forget it also blocks GATA-3 and HAT while upregulating HDAT
What is the primary cytotoxic drug given to prevent graft vs. host?
Methotrexate
What is the primary cytotoxic drug given following a solid organ transplant?
Azathioprine
GO BACK AND REVIEW IMMUNOSUPPRESSIVE DRUGS
GO BACK AND REVIEW IMMUNOSUPPRESSIVE DRUGS
What is the overall task of Cyclosporin A?
Prevent IL-2 expression by blocking calcineurin which is an NFAT phosphatase that leads to IL-2 transcription
What is the job of Tacrolimus?
Same deal as Cyclosporin A (calcineurin inhibitor)
What is Rapamycin, what does it do?
Interferes with IL-2 receptor signaling
T or F: RBC’s express MHC class I and MHC class II molecules
False, RBC’s are not nucleated and don’t express MHC class I (or II), No Need for MHC I because no nucleus means CTLs can’t carry out their effector functions on these cells anyways
T or F: Hyperacute rejection can be mediated by anti-HLA antibodies
True, if a patient has mounted a response against another HLA via a previous pregnancy, (blood transfusion?) or graft tissue you can run the risk of Hyperacute organ transplant rejection
How do we assess how sensitized someone has become to a particular HLA as a result of previous exposure, that has caused them to make anti-HLA abs. that could cause Hyperacute rejection?
Panel-reactive Antibody (PRA) - this tests the sera of the Host against a panel of population sera and determine the Percentage of Positive reactions
***Note: this is just an antibody test for Hyperacute rejection
A and B mismatch isn’t an issue during pregnancy, so why is Rh?
- A and B are sugars that will only elicit IgM response
- Rh is a protein that can elicit a class switching IgG response when mixed with the mothers blood (this is because a T-DEpendent response is mounted)
