Transplantation Flashcards
Define Autologous graft
A graft transplanted from an individual to the same individual.
Ex; bone marrow or blood harvested and saved for future use
define Syngeneic grafts
or syngraft is a transplant between two genetically identical individuals (i.e identical twins)
Define allogeneic graft
transplanted between two genetically dissimilar individuals of the same species
Most common form of transplant
Define Xenogeneic graft
Aka xenograft is a transplant between members of two different species. (pigs etc.)
Define Orthotopic transplant
graft placed in its normal anatomic location
Define Heterotopic transplant
Placed in an anatomically different sites.
Describe the mechanisms of privileged sites
- -> extracellular fluid bathes these tissues and doesn’t leave through conventional lymphatics
- -> TGF-beta is produced at these sites (inhibitory cytokine)
- -> Fas ligand –> reacts with Fas on lymphocytes to induce apoptosis
Describe incidences when privileged sites are disrupted
antigens at these sites can be targeted:
- Sympathetic ophthalmia –> one eye is damaged by trauma and autoimmune response to eye proteins threatens the undamaged eye
- —– Immunosuppressive therapy required to prevent destruction of undamaged eye. removal of damaged eye may be required
What are the three laws that govern transplantation
1) Transplants between identical twins are never rejected
2) transplants between genetically dissimilar individuals are almost always rejected (without immunosuppression)
3) grafts derived from children will be rejected by either parent. Children would express antigens that either parent sees as foreign.
What are antigens perceived as foreign
Class I and class II MHC proteins are perceived as foreign because:
- Expression = polymorphic –> all express particular set of “self” MHC
- Education of thymocytes –> other MHC proteins perceived as foreign
- Probability that two random individuals express same MHC proteins is extremely small
Describe Hyperacute Rejection*
Takes place within minutes of attaching the graft to the recipient’s blood supply
- -> mediated by pre-existing antibodies
- -> E.G Anti-ABO blood group antibodies (give you the wrong blood)
- -> Essentially untreatable, but uncommon
Describe Acute Rejection
Takes place within 1 month of transplantation
Two basic types:
- Acute humoral rejection: Antibody and complement-medaited lysis of graft tissue –> Necrosis of the blood vessel walls
- Acute cellular rejection: cell-mediated lysis of grafts tissue by CTL’s NK cells and or macrophages
**Treated with increased immunosuppression, e.g. high does of steroid therapy or anti-T cell antibodies
Describe Chronic Rejection
May occurs months or years after transplantation
- -> mechanism unknown: May involved antibody-mediated injury (DTH rxn)
- -> fibrosis and deposition of collagen are characteristic with accelerated arteriosclerosis resulting in vascular occlusion
- -> unresponsive to increased immunosuppression.
Define Alloreactivity (direct alloantigen recognition)
Recognition of foreign MHC proteins by the TCR due to polymorphic amino acids of foreign MHC proteins mimicking conformation of BOTH self MHC and foreign peptide
- -> same TCR can recognize self MHC + foreign peptide conformations as well as foreign MHC proteins
- -> 20% of T cells can be alloreactive toward a set of foreign MHC proteins, therefore alloreactivity is felt to be the most important mechanism for T-helper cell activation
Define Indirect alloantigen presentation
Recipient APC's could present foreign MHC peptides in conjunction with self class II MHC proteins to activate T-helper cells: --> Does occur, but cannot be primary mechanism for T-helper cell activation, since CTL's could not lyse the foreign MHC class I-bearing graft cells (since they could NOT recognize non-self class I MHC)
Define the mechanism of Allorecognition
1) The self MHC - restricted T cell recognizes a structure formed by both the allgogeneic MHC molecule and the bound peptide
2) The self MHC - restricted T cell recognizes the allogeneic MHC molecule whose structure resembles a self MHC –> foreign peptide complex
Define the steps of activation of alloreactivity
Step 1: Direct (using donor dendritic cells) and indirect (using recipient dendritic cells) presentation of alloantigens stimulate CD4+ alloreactive T cells (from the recipient to become activated
Step 2: Alloreactive CD4+ T helper cells provide IL-2 and IFN-gamma to alloreactive CD8+ T cells to produce CTL’s that can lyse graft cells, alloreactive B cells to produce anti-graft antibodies
Describe strategies of preventing Rejection
1) Reduce graft immunogenicity by selecting most compatible graft:
2) Immunosupression is used to ward of graft rejection
- -> corticosteroids - lyse immature thymocytes, block release of cytokine and inhibit leukocyte migration
- -> cyclosporine = drug of choice for immunosuppression (more effective against primary immune response)
3) depletion of passenger leukocytes from graft can eliminate or delay graft rejection
Describe Graft Vs Host disease
Differentiates bone marrow transplantation from all other types:
- -> Acute GVHD - quickly following bone marrow transplantation and involved epithelial cell necrosis of the skin liver and GI tract (fatal in severe cases)
- -> Chronic GVHD - Fibrosis in organs causing dysfunction. Fatal if severely affects critical organs
How do you prevent Graft vs Host disease
Anti-CD3 monoclonal antibodies (with complement) –> leads to a decrease incidence of GVHD, but reduces chance of engraftment
–> Graft-versus-leukemia effect = helps prevent recurrence of cancer because the GVHD reaction removes minimal residual disease
Describe Fetal Immunology
Maternal-fetal interaction mimics alloreactivity and graft rejection, i.e. fetus is a naturally occuring allografts
Describe the mechanism of fetal immunology
1) Trophoblast cells don’t express paternal MHC proteins. in addition, HLA-G (MHC class I-like protein) keeps NK cells from becoming activated by the trophoblast cells that express no MHC proteins
2) Trophoblast cells may secrete INHIBITORY cytokines such as TGF-Beta
3) Tryptophan is broken down at the fetal-maternal interface by the enzyme indolamine 2,3-dioxygenase. Tryptophan-starved T lymphocytes react poorly to antigen
