Tissue graft rejection Flashcards
Autograft
From self to self
Does not trigger an immune response
eg. skin graft, segment of vein to bypass blocked arteries
Isograft
Different individuals, genetically
laboratory mice
Does not trigger an immune response
Allograft
Different individuals- not genetically identical
The most frequent type of graft
does not equal MHC and blood group -> strong immune response
graft rejection in 1-2 weeks
Xenograft
Different species
Not equal biochemically and immunologically
Rapid, intense rejection- Hours
Allograft rejection
Several antigens
- blood group glycoproteins
- MHC molecules (main ones)
- Endogenous antigens presented in the MHC I (can have cumulative effects)
Same mechanisms irrespective of the organ grafted
Both cellular and humoral immunity
Genetics of graft rejections
Grafts between genetically identical individuals are never rejected (MHC identical)
Grafts between genetically non-identical individuals are always rejected
Offspring of genetically different individuals will not reject grafts from either parent
A graft from the offspring of two different individuals will be rejected by either parent
-This rule is violated by bone marrow transplantation, when NK cells in an [AxB] F1 recipient do reject bone marrow cells from either parent
Allograft rejection (pt 2)
Blood groups are easier to match so wont be as big of an issue
polymorphism-> individuals differ in their MHC haplotype- number of mismatched alleles influences allograft survival (more differences= more mismatches =more intense/more likely the rejection is)
Rejection of MHC and blood group- compatible grafts. due to cumulative effects of many minor antigenic differences (like antigen coded by genes on the Y chromosomes- in females can be enough to cause rejection)
Rejection pathogenesis: innate mechanisms
- surgical trauma and ischemia (cutting into tissue and suturing etc- leads to tissue damage)
- increase MHC expression
- -DAMPs
- cytokines and inflammatory mediators
- TLRs (induce innate response)
- MICA molecules can activate NK cells
Allograft rejection: adaptive mechanisms
will involves lymphocytes (T cells), T cells will create cytokines and stimulate cell mediated immunity etc.
Direct pathway
- Donor APCs presenting to recipient T cells
- acute rejection
Indirect pathway
- recipient APC presenting to Recipient T calls
- Chronic rejection
If skin graft: there arent only epithelial cells in it. Any other cell in the graft portion will go with it- like APCs
Recipient will respond with own T cells, T cells proliferate and cause response
Allograft rejection: graft destruction
CD8+ T cells destroy vascular endothelium and other accessible cells through caspase-mediated apoptosis
-hemorrhage, platelet aggregation, thrombosis, and stoppage of blood flow to the graft
CD4+ T cells release cytotoxic cytokines (TNF-a)
-apoptosis in endothelial cells
Activated macrophages
-pro-inflammatory cytokines impair graft function and intensify T cell-mediated rejection
Hyperacute rejection
up to 48 hours after grafting (usually blood group)
Thrombotic occlusion of the graft vasculature- blocking blood flow to graft
Minutes to hours after host-graft blood vessels are anastomosed
Mediated by preexisting antibodies in the host circulation that binds to donor endothelial antigens
Accelerated/acute rejection
up to 7 days after grafting
after 7 days
Injury to the graft parenchyma and blood vessels mediated by alloreactive T cells and antibodies
Inflammation caused by cytokines produced by helper T cells and CTL-mediated killing of graft parencymal cells and endothelial cells
Alloantibodies bind to donor endothelial antigens and cause damage
Chronic rejection
Several months after grafting
Arterial occlusion due to proliferation of intimal smooth muscle cells
Graft eventually fails due to ischemic damage
Prevention of allograft rejection
Immunosuppression to prevent rejection while not making the recipient more susceptible tan necessary to infection
General strategies
- inhibitors of T cell signaling pathways (prevent excessive cytokine production -IL2)
- Antimetabolites-metabolic toxins that kill proliferating T cells
- Function-blocking or depleting anti-lymphocyte antibodies (anti-CD3)
- costimulatory blockade-drugs that block T cell costimulatory pathways (CTLA4-Ig which binds to B7 molecules)
- Targeting alloantibodies and alloreactive B cells
- Anti-inflammatory drugs (corticosteroids)
Prevention of allograft rejection: dogs
Very strong responses
Rejection in 6-14 days if untreated
Unrelated dogs with renal allografts
-50% 1 year survival when treated with azathioprine, prenisolone, and cyclosporine
-simultaneous bone marrow allograft from the donor animal
-rabbit antidog thymocyte serum
Median survival times of 8 months
Prevention of allograft rejection: cats
without immunosuppression die in 8-34 days
prednisolone and cyclosporine possibly supplemented with ketoconazole (suppresses cyclosporine metabolism in the liver and prolongs its half-life)
6 month survival 59-70%
3 year survival ranges from 40-50%
the longest survuval time reported: 8 years
