Keynote presentation

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Keynote presentation

  1. 1. The route to tolerance induction and the role ofMHC in future advances for organ transplantation Presented by Derek W R Gray
  2. 2. 1 yr
  3. 3. Transplantation. 2004 Feb 27;77(4):623-6.The case to abandon human leukocyte antigen matching forkidney allocation: would it be wise to throw out the baby withthe bathwater?.Hiesse C, Pessione F, Houssin DAbstractSince major histocompatibility (MHC) antigen matching wasintroduced in the early 1970s as the key factor determining kidneytransplant allocation, several studies, mainly arising from organ-sharing organizations in the United States and Europe, havedebated this complex issue. The first fundamental concern is the interaction of human leukocyte antigen matching with other transplant outcome risk factors, for example, prolongation of ischemia and matching for age. ....... (contd)
  4. 4. Physicians involved in the long term managementof transplant recipients know that the problemscome later:• Lymphoma > 2%• Skin cancer: - BCC - SCC - Melanoma - Generalised field change• Graft deterioration
  5. 5. Over a 20 year period numberof years graft function wastedby uncontrolled immune attack = 3.25 million
  6. 6. Facts that are difficult for conventional immunology to explain• MHC exchange between cells• The effect of altered peptides and single amino acid mutation on T cell activation• The effects of self peptides especially MHC derived.
  7. 7. 2 sets of MHC (HLA) genes co-expressed HLA-A HLA-B HLA-DR HLA-DP HLA-DQ Z HLA-A HLA-B HLA-DR HLA-DP HLA-DQ Z
  8. 8. Major Histocompatibility Complex (MHC) in man = Human Leukocyte Antigens (HLA) (terms used interchangeably in this presentation) Invader Proteins taken in by phagocytic cells Broken down to peptides Peptide binding grooveMembrane binding domain MHC Class I MHC Class II = HLA A,B[+] = HLA DP,DQ, DR
  9. 9. MBS theory and interaction with T cells CD4 or T-cell receptor (varied by somatic CD8 mutation, positive selection for binding to MHC, negative selection for self-peptide)Peptide binding in groove MHC Class I MHC Class II = HLA A & B = HLA DP,DQ, DR
  10. 10. MHC-based suppression theory• Proposed as a way of controlling T cells• Dependant upon T cell contact with MHC• uses MHC-derived peptides to "read out" a unique clonal identity code.• When responding T cells derive from a single clone = self derived peptide• When responding T cells derive from multiple clones = invader derived peptide
  11. 11. Evidence text boxes •Purpose of MCC polymorphism •T cells have a internal inhibitory pathway separate from activation •Antigen presenting cells transfer MHC/peptide onto T cells •MHC-derived peptides have special properties •The proteasome converts proteins including MHC to peptides •Changing single amino acids into the TCR/MHC/peptide has strong but unpredictable effects
  12. 12. MBS theory and interaction with T cellsMultiple cells and a variety of MHCmolecules contribute to the MBS signal
  13. 13. The route to tolerance induction andthe role of MHC in future advances for organ transplantation Tuesday 21 August 10:35

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