Swindle - Chapter 14 Flashcards
(20 cards)
Why are NHPs not used as organ donors?
Ethical resistance, potential for lethal diseases, extended time required for breeding to appropriate size, and overall smaller organ size.
Why are swine ideal for xenotransplantation?
Grow quickly to reach similar organ size as humans, comparable physiology, less public scrutiny, and short gestation length with well-developed production practices.
What are the two major complications of xenotransplantation?
Rejection of graft or infection
Describe immunological tolerance.
Immune system is re-educated with the intention of organ acceptance without immunosuppression.
What is hyperacute rejection mediated by?
Natural antibodies directed toward the Gal-a-1,3 Gal-B-1-4GlcNac. Alpha 1,3-galactosyltransferase is enzyme responsible for synthesizing.
Even if Gal-KO swine are used, why does rejection still occur?
Antibodies nonspecific for Gal develop. Targets for non-Gal antibodies, which develop in the first year of life, remain to be fully described. May be directed toward swine leukocyte antigen.
What must immunosuppressive drug cocktails target?
B cells, T cells, macrophages, and NK cells.
What is the goal of immunological tolerance?
Induction of a state of mixed chimerism leading to tolerance of B and T cells. Use of swine thymus or bone marrow.
What do NK cells excrete?
Lytic proteins, such as perforin and granyzme, and inflammatory cytokines, including TNFa and IFNy
How is the activity of NK cells regulated?
Cell surface receptors that either provide inhibitory or stimulatory signals. Inhibitory signals recognize MHC I antigen-presenting molecules expressed in nearly all cells. Deficiency in MHC I as a result of viral infection or inability to recognize in swine cells induces NK cells to degranulate. Can also kill via antibody-dependent cell-mediated toxicity.
Which cells result in rapid rejection of xenogeneic bone marrow?
Macrophages
What is the inhibitory signal present on macrophages and self cells? How does this impact xenotransplantation?
Macrophages: CD172
Self: CD47
Species incompatibility between CD47 and CD172 may contribute to phagocytosis of xenogeneic cells.
What are the mechanisms by which the complement system can be activated? What is the outcome?
Classical (antibody-mediated), alternative, or lectin pathway. Final outcome is membrane attack complex which creates pores in cell membranes and leads to lysis.
How does activation of the complement pathway lead to rejection? How can this risk be reduced?
Xenoreactive antibodies attach to endothelium of discordant organ, activate complement, and graft develops edema, hemorrhage, clotting, and decreased blood supply.
Reduce circulating antibodies by plasmapheresis or immunoabsorption delays time for hyperacute rejection. Clusters of differentiation are needed to inhibit activation of complement, so pigs expressing human CD46, CD55, and CD59 have been developed - less susceptible to hyperacute rejection.
What is the most inbred of the three homozygous swine leucocyte antigen lines of mini swine? What was created in this line, and how?
DD line (>97% cosanguinity).
GalT-KO pig was created in this line via somatic cell nuclear transfer. Removed the GGTA1 gene.
What are the primary disease agents of concern?
Influenza and retroviruses.
Why are swine retroviruses so concerning?
Porcine endogenous retroviruses can infect human cell lines in vitro, but no in vivo infection in humans or NHPs. Comparison to HIV, which is a retrovirus of NHPs, especially considering the immunosuppression needed following a transplant. Concern regarding PERVs can mutate or combine with human retroviruses creating a novel and virulent virus. Even if genetically engineered out of pigs, concern regarding as-of-yet unidentified viruses.
What porcine retroviruses exist?
PERV A, B, and C.
What is the primary protozoal agent of concern?
Balantidium coli
What congenital defects exist in the Gal-KO pigs?
Angular limb deformities, cryptorchidism, heart defects (valvular anomalies and teratology of Fallot), and myeloid leukemias.
