Immunology Exam 4

• Origins of Tissue Grafts


  • Living Donors
  • Cadavers
  • Tissue Culture
  • Xenotransplantation

  
• Transplantation solves lack of organ problems
• Organs / Tissues Types that Can Be Transplanted


  • Bone Marrow
  • Blood
  • Appendages – hands
  • Face

  
• Autograft


  Transplant of tissue to the same person – skin, blood, vein, stem cells

  
• Allograft


  Transplant of tissue between two genetically non-identical members of the same species – most tissue transplants

  
• Isograft (Syngeneic)


  Transplant tissue between identical twins, genetically identical
• Xenograft


  Transplant of tissue from one species to another (recent porcine heart transplant)

  
• Split Transplant


  Donor organ divided between two recipients – liver divided between an adult and child
• Domino Transplant


  Transplantation of a complete set of organs – lungs and heart from a donor to a cystic fibrosis patient, CF patient's heart to another recipient
• Rejection timeline is the same as the timeline observed for a primary and secondary immune response
• Tissue rejection / acceptance is a function of the immune response
• What is the Evidence for tissue rejection / acceptance being a function of the immune response?

  • Memory from 1st transplant
  • New Donor strain, No Memory
• Tolerance


  what is demonstrated In this experiment where establishment of self tolerance is demonstrated by injecting rabbit cells into a developing rat fetus. As the immune system develops it recognizes the rabbit cells as self. After birth, the rabbit cells are accepted as self.
• Transfer of Immunity


  What is demonstrated in this experiment where immunity against a graft can be transferred from one mouse to another by transferring immune cells.
• MHC I


  Cell marker on all nucleated cells

  
• MHC II


  Cell marker on Antigen Presenting Cells
• MHC genes are co-dominantly expressed, meaning both maternal and paternal genes are expressed

  
• MHC genes are polymorphic, so there is variation in expression within a population

  
• A person can have as many as 12 different MHC molecules or as few as 6, if mom and dad possessed identical genetic information

  
• There is extensive polymorphism of MHC genes, it is unlikely to find two individuals to be identical

  
• Maintaining many MHC genes in a population ensures binding sites for all pathogens at least in some people to prevent the species from being wiped out
• MHC Inheritance

  Expressed as a haplotype or passed as a unit

  
• Chances of a sibling match for a transplant

  • 25% are 100% MHC match
  • 25% are 0% MHC match
  • 50% are 50% MHC match
• Chances of a parent match for a transplant

  • 100% are 50% MHC match

  
• Each human expresses six MHC class I alleles and six MHC class II alleles

  
• The MHC variation in the human population is high:

  
  

  ~ 350 alleles for HLA-A genes

  
  

  ~ 620 alleles for HLA-B genes

  
  

  ~ 400 alleles for DR genes

  
  

  ~ 90 alleles for DQ genes

  
  

  HLA-C and HLA-DP show low polymorphism

  
• Differences in any MHC marker can mediate transplantation rejection

  
• Serological Based Tissue Typing:

  
  

  Need:

  
  

  • Patient Lymphocytes
  • Ab to MHC markers, in this case B1 through B620
  • Complement
  • 96-Well Plate
• Antibodies to MHC markers are collected from patients undergoing pregnancy, blood transfusion, or previous transplant
• Mixed Lymphocyte Reaction Assay


  To see if recipient lymphocytes respond to donor MHC markers, especially MHC II markers

  
• Tissue matching and wait times for kidney transplant are also affected by whether the recipient has pre-existing antibodies to donor HLA / MHC antigens

  
• Only grafts between identical twins and syngeneic animals are not rejected, perfect MHC I and II matches are eventually rejected unless the recipient is immunosuppressed

  
• Rejection is mediated by minor MHC genes that code for 9 to 12 amino acid long markers on cells
• Hyperacute rejection


  Due to pre-existing antibodies, not an immune response to the graft, very quick rejection in minutes to hours
• Hyperacute rejection


  Pre-existing antibodies enter grafted tissue, bind to membrane-bound MHC markers, activate complement cascade, call in neutrophils, leading to tissue damage and vascular blockage
• Acute rejection


  Weeks to months, due to recognition of foreign MHC markers, improper immunosuppression, inflammation, humoral and cellular mediated, predominantly Type II, Type III and Type IV reactions and T cytotoxic reactions
• Chronic rejection


  Months to years, directed against major and minor MHC, resulting in inflammation, fibrosis, inflammation of small arteries, occlusion of lumens - vanishing bile duct syndrome
• Immunosuppression Therapy Phases


  • Induction Therapy - Strong suppression of the immune system, especially T-cells, prior to transplantation
  • Maintenance Therapy - Lower doses of immunosuppressive drugs, suboptimal immune function to limit recognition of graft, but minimize infection
  • Specific Treatments - For acute rejection episodes, resembles induction therapy

  
• Graft versus Host Disease


  Donor cells react against recipient tissue, requires recipient to be immunosuppressed and donor tissue to be immunocompetent, most common in allogeneic stem cell transplants
• Autologous stem cell transplant prevents Graft versus Host Disease