Mim: Transplants

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sources for HPC

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bone marrow
stimulating stem cells with growth factor (causing them to leave the BM to the peripheral blood and then isolating peripheral blood with apheresis)
umbilical cord blood

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barriers to organ transplant

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1. not enough available organs
2. immune response/non-self-recognition

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autograft

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from self

this would be if you had some of your own BM harvested, frozen, and then re-introduced later

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syngeneic graft

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if you have a genetically identical twin you can do this

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allogeneic graft (or "allele different")

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this graft is from a genetically different person of the same species

could be from family or someone unrelated

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xenograft

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from another species

usually recognized and destroyed immediately

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allorecognition

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the ability of an individual organism to distinguish itself from someone else

this can result in graft rejection

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hyperacute rejection

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your body starts rejecting a graft while you are on the OR table

this means you've already been sensitized to human tissue of this type and have antibodies in you that are ready to attack it

your immune response begins immediately and the organ is destroyed in a short time

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acute rejection

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this takes days-weeks

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accelerated acute rejection

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where an individual is already sensitized and has memory cells from a previous reaction- these become activated upon contact with the new graft and you see lymphocyte infiltration and complement C4d deposition in tissues

takes place over a week (potential to be faster than just an acute rejection)

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chronic rejection

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this is "slow" rejection

taking months to years

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laws of transplantation

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graft from donor that is genetically identical to recipient will be accepted

if you do this with an allogenic mouse, the graft will be rejected in ~2 weeks ("1st Set Rejection")

if you give a 2nd graft from same allogeneic mouse, the mouse will reject it again- but this time the rejection will be swifter and stronger. ("2nd Set Rejection") Only takes ~1 week

if the 2nd graft is from a different mouse (but still allogeneic) it will be rejected in ~2 weeks since the mouse has not been exposed to it before

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1st set rejection

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graft transplant from an allogeneic mouse (genetically different but same species)

graft will be rejected in ~2 weeks

immune cells infiltrate around day 7-10
see necrosis, damage, and blood clots ~ day 10-14

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2nd set rejection

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giving second graft from the same allogeneic mouse

rejection is swifter and stronger as a result of immunological memory

only takes ~1 week

a mouse or human can produce this kind of rejection if sensitized by pregnancy or blood transfusion as well

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directions of allorecognition

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immune response can be bi directional

1. Recipient's immune system rejects graft (can take several forms depending on timing of response)

2. the graft itself can carry immune system cells that ay attack the recipient causing graft vs. host disease

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graft versus host disease (GvHD)

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graft itself carries immune system cells or immune products from the donor and these may attack the recipient

usually a problem of hematopoietic progenitor cell transplant

passenger leukocytes in solid organ grafts may cause gvhd

can be acute or chronic

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Solid organ rejection: 1st set rejection

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non sensitized patient receives a solid organ graft

graft is initially accepted but is then rejected by immune response

rejection mediated by T cells

vascular endothelium is primary target

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solid organ rejection: 2nd set rejection

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sensitized through prior transplant or transfusion or pregnancy

may lead to loss of graft function, reduced graft survival and/or hyper acute rejection

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Dealing with ABO differences

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Blood Transfusion: try to match ABO and Rh

Solid Organs: try and select donors that are ABO matched for educe risk of rejection

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major histocompatability complex differences and why this makes transplants so complicated

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genes controlling acceptance/rejection are mapped to MHC class 1 and 2 genes

because they have so many alleles, tissue selection in regards to a donor becomes difficult bc donors will look foreign unless you can manage to match up some alleles

also, a transplanted organ's MHC's can look like your own MHC carrying a pathogen. If this is what your body sees, you will activate memory cells that previously responded to pathogens and they respond to the new organ via the foreign MHC presenting its's own peptides
-> your response to this is stronger than to a pathogen alone because of cross-reactivity and the activation of multiple T Cells which now target the new tissue

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direct cellular recognition

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also, a transplanted organ's MHC's can look like your own MHC carrying a pathogen. If this is what your body sees, you will activate memory cells that previously responded to pathogens and they respond to the new organ via the foreign MHC presenting its's own peptides
-> your response to this is stronger than to a pathogen alone because of cross-reactivity and the activation of multiple T Cells which now target the new tissue

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minor histocompatibility complex issues

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a patient's APCs can pick up graft fragments from a transplant, and in these fragments may exist proteins that seem suspicious to a recipient

if a female receives graft from male, the Y chromosome might looks sketchy

if any of these are picked up and presented to T Cells, they will be recognized as foreign and an immune response will be mounted

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methods for preventing an immune response

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1. Match histocompatibility molecules and ABO blood group
2. Monitor Sensitization
3. Suppress immune response
4. Use less immunogeneic tissue
5. Induce specific tolerance

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differences in MHC matching in transplantation of different tissues

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1. Blood- separate components used for transfusion so you're not exposed to WBC's that could express MHC

2. HPC: precise HLA matching is important to prevent immune response since you need to generate a new immune system for the person

3. Platelet Transfusion- you will be exposed to platelets carrying foreign MHC molecules. If you're getting a lot of these transfusions you need to be matched up with someone who has similar MHC alleles to you to prevent sensitization and overreaction

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preventing immune response: solid organs (kidney, liver)

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relies more heavily on immune suppression than HLA matching

Kidney- selected by HLA type to prevent rejection

Liver- low HLA expression, more resistant to rejection so HLA matching not usually used

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limitations to immune suppression

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toxic drugs
increased susceptibility to infection
failure to reconstitute an immune system after an HPC transplant
cost
patient compliance

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testing for sensitivity

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crossmatch- this involves taking patient serum and incubating it with the cells of a donor organ to see if there is reactivity

newer protocol involves removing reactive antibodies from the recipient