Immuno 13 - Transplantation Immunology Flashcards
autograft vs isograft vs allograft vs xenograft
Autograft: within the same individual*
Isograft: donor and recipient are genetically identical*
Allograft: donor and recipient are genetically unrelated but within the same species
Xenograft: donor and recipient are from different species
**dont have to worry about rejection
what are triggers of allograft rejection mediated by
- Blood group antigen mismatches (e.g., blood inside the organ/tissue)
- Mismatched histocompatibility antigens (major [MHC] class I and II and minor histocompatibility antigens)
- Foreign antigens presented by MHC
MHC matching promotes graft survival; type of match and when rejection happens
order of fastest/highest chance of rejection –> slowest/lowest chance
-none -> class I -> class II -> both
survival time of organ allografts between SLA-incompatible minipigs clearly depends on the degree of MHC compatability between donor and host
four clinical transplant rejection syndromes
- Hyperacute rejection: within minutes – hours; mediated by pre‐
existing antibodies that recognize antigens expressed by endothelial cells lining the blood vessels of the graft (e.g., xenografts get hyperacutely rejected) - Accelerated rejection: within days; requires previous exposure to a graft that was acutely rejected; due to memory cells, the rejection is faster the 2nd time
- Acute rejection: within weeks; primary antibody and T cell responses play a big role in naïve host; T cells are the dominant problem in this phase
- Chronic rejection: months later; Abs are the primary problem in this phase (remember, B cells are more difficult to tolerize)
the role of the innate immune response in graft rejection
Danger‐associated molecular patterns (DAMPs) and inflammatory cytokines get upregulated in grafts due to:
* Surgical trauma
* Ischemia (oxygen deprivation)
As a consequence:
* Neutrophils and macrophages get recruited into the graft
* NK cells get activated
* Antigen‐presenting cells get recruited and matured and start presenting graft‐derived antigens
graft destruction; activation details, what does it cause
- Activated cytotoxic T cells reach the graft through the bloodstream
- They bind and destroy vascular endothelium and other accessible cells
- CD4+ T cells that enter the graft release cytotoxic cytokines such as TNF‐α, which triggers apoptosis in
endothelial cells - This damage causes hemorrhage, platelet aggregation, thrombosis, and stoppage of blood flow
- Grafted tissue dies because of a lack of blood supply
preventing allograft rejection
- A fine balance between suppressing the immune system enough to prevent graft rejection without making the patient overly susceptible to life‐threatening infections
- Highly immunosuppressive drugs like cyclosporin are used with a lot of dose adjustments
- Simultaneous bone marrow engraftment often reduces the need for immunosuppression because the immune system is repopulated by cells originating from the same donor (i.e., they recognize the graft as self)
- Antibodies to transiently deplete host T cells can help
- If a graft survives long enough, the host may become tolerant, and it might be possible to gradually wean the patient off immunosuppressive drugs
skin allografts
- It takes longer for skin allografts to be rejected because the blood supply is not directly connected to the tissue at the time of surgery
- Instead, it takes days for blood and lymphatic vessel connections to be made between the graft and host tissues
liver allografts
- Rejection of liver grafts in dogs tends to occur slowly
- This is because canine hepatocytes tend to produce a lot of IDO (indoleanime 2,3 dioxygenase)
- IDO catabolizes tryptophan
- Th1 cells need to metabolize large amounts of tryptophan
- So Th1 function is impeded in canine liver allografts
corneal allografts
- The eye is an immunoprivileged site
(i.e., inflammation is tightly controlled to prevent damage to sensitive tissues) - As a consequence, corneas can often be engrafted without tissue typing or the use of immunosuppressive drugs
bone allografts
- Used in dogs to repair severe fractures and sometimes to reconstruct bones that are affected by resection of tumours
- Engraftment is often successful due to the lack of soft tissues and cells in cortical bone
- A long‐term problem is mechanical failure of the graft because the engrafted bone is resorbed faster than new bone can replace it
joint transplants in horses
- Joints can sometimes be successfully transplanted between horses
- Requires freezing of the joint prior to transplantation, presumably to kill cells that could serve as targets of the immune system
bone marrow allografts in dogs
Often used to treat leukemias
* High‐dose whole‐body irradiation kills the host’s bone marrow
* Donor bone marrow is infused intravenously and repopulates the host’s bones
* The recipient must be on prophylactic antibiotics to protect against infections until a new immune system is reconstituted (30 days for granulocytes; 200 days for
lymphocytes)
graft vs host disease; cause, recognition
- Caused by engraftment of bone marrow with significant MHC mismatches with the host tissues
- The donor leukocytes recognize cells of the new host as dangerous
Very severe cutaneous erythematous
lesions on the face of a dog suffering from graft‐versus‐host disease because of a bone marrow allograft.
xenografts
- The demand for organs and tissues greatly outweighs the supply
- Therefore, alternative donor sources are sought
- Concordant xenografts: grafting between different but related species (e.g., chimpanzee to human)
- Rejection mechanisms are more vigorous than with an allograft; acute cell‐mediated rejection is the key problem
- But, not practical due to limited potential donor supply and serious ethical issues
- Alternative = discordant xenografts (grafting between unrelated species; e.g., pig to human)
- Rejection is vigorous (a lot of work needs to be done to control this); natural, pre‐existing antibodies recognizing carbohydrate residues on porcine epithelium cause hyperacute rejection within minutes of the blood supply being connected
