Lecture 12

Organized Notes: Transplantation & MHC

1. Discovery of Immune Tolerance

• Sir Peter Medawar (Nobel Prize, 1960 with Macfarlane Burnet)

  • Foreign cells/tissues injected into another animal → recognized & destroyed by the immune system

  • Second exposure → faster immune response

  • Newborn exposure to foreign grafts → lifelong tolerance to the donor

  • Grafts between identical twins are always tolerated

2. Organ Transplantation

• Joseph E. Murray (1954) - First Successful Kidney Transplant

  • Performed on identical twins, leading to long-term survival

  • Discovery of immunological tolerance in genetically identical individuals

  • Nobel Prize in Physiology/Medicine (1990, shared with E. Donnall Thomas)

3. MHC and Tissue Rejection

• What makes individuals of the same species immunologically different?

  • Human Leukocyte Antigens (HLA) in humans

  • Histocompatibility Antigens (H2) in mice

• Major Histocompatibility Complex (MHC)

  • Location: Chromosome 6 (humans), Chromosome 17 (mice)

  • Size: 4 million base pairs, encodes over 200 genes

  • Function: Encodes proteins responsible for tissue rejection in transplantation

4. MHC Genetic Diversity

• MHC Locus is Polygenic & Polymorphic

  • Polygenic: 6 different Class I genes, 13 different Class II genes

  • Polymorphic: Many alleles exist in the population → high genetic variability

  • Why so many alleles?

    • Provides greater immune diversity

    • Enhances survival against infectious diseases → evolutionary advantage

5. Function of MHC Molecules

• Antigen Presentation to T Cells (Figure 2-8)

  • MHC molecules bind peptide fragments and display them on cell surfaces

  • T cells only recognize antigens bound to MHC → MHC restriction

  • Different MHC molecules present different peptides → diversity is essential for immune defense

• Peptide Binding & Variability

  • Class I MHC: Binds short peptides (8-10 amino acids) → closed binding groove

  • Class II MHC: Binds longer peptides (13+ amino acids) → open binding groove

  • Allelic variability clusters around peptide-binding pockets

6. MHC & Antigen Sources

• MHC Class I: Displays intracellular peptides (self-proteins, viral proteins)

• MHC Class II: Displays extracellular peptides (bacterial & parasitic infections)

7. MHC in Organ Transplants & T Cell Recognition

• Allorecognition: Recognition of "non-self" MHC (Briscoe & Sayegh, Nature Medicine 2002)

  • Direct Allorecognition: T cells recognize donor (non-self) MHC presenting donor/self peptides

  • Indirect Allorecognition: T cells recognize recipient (self) MHC presenting donor (non-self) peptides (allopeptides)