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  • Keynote presentation.ppt256.wav I would like to thank the organisers for the invitation to speak on my topic which is the route to tolerance induction and the role of MHC in future advances for organ transplantation. You will note this is a PowerPoint pre-narrated presentation, which is chosen because I have Parkinson's disease and would find it difficult to speak if I were to present this topic live. The target audience will be scientists and clinicians who are not immunologists and the presentation will be made as jargon-free as possible.
  • Keynote.ppt256-2.wav The use of powerful immunosuppressive drugs with relatively minor short term side effects produces results which appear to be almost perfect at 1 year, if you take one-year graft survival as your criteria for success, as shown here using graphs taken from the CTS study.
  • In t his review the position regarding HLA matching in renal transplantation is discussed. It ha s been more or less abandoned in many c entres p articularly in the USA because the t rade-Off between m atching and n egative i nfluences s uch a s c old i schaemia showed no benefit with “modern” immunosuppression. This reference is often quoted to support that change when in fact the paper argues strongly for regular review.
  • But if we look at the results of kidney transplantation over ten years we find a profound effect of HLA matching. In this graph from the CTS, HLA identical siblings are compared at 10 years with one haplotype matched relatives and cadaveric donor kidneys.
  • The physicians who look after the long-term care of transplant recipients know we are a long way from perfection. There is a definite and continuing risk of malignancy.
  • Keynote presentation.ppt263.WAV The clinical importance and financial penalty of not matching MHC molecules is emphasised by observing the 20 year graft survival and comparing the half life of HLA identical siblings, which is more double that of recipients of cadaveric kidneys. Over a 20 year period the number of years of graft function lost is huge and the costs major
  • Eureka moments are rare in modern science and most advances are gained in small increments repeating the work to ensure the findings are true. In a complex topic such as immunology the incremental approach has intellectual rigour but is very slow. At some point it may be worthwhile taking an educated guess at how it all links up. To take such a leap requires a different mindset and is not an approach likely to be enthusiastically supported by those who have hewn hard-won facts from the incremental rock face. Furthermore it is likely that a person who takes on such a project will be outside of mainstream thinking and inevitably place different interpretations on the work of others. My specific topic concerns the role of MHC in transplantation with the underlying hypothesis being that the MHC has a key role in tolerance induction.
  • There is a progressive loss of graft function which is likely to be due to the immune recognition of allogeneic molecules now known to be MHC or HLA in man.
  • In man the MHC system is known as HLA, and molecules appear to be designed to bind a short peptide in a specialised groove. The combined MHC/peptide complex can be recognised by T cells only if both HLA and peptide are bound together. The combined MHC molecule is bound to the cell membrane by transmembrane segments.
  • MBS theory and its interaction with T cells. T cells are educated in the thymus and undergo positive and negative selection. However an important question is which peptide is in the groove of the MHC molecule during positive selection. This represents the maximum inhibitory setting of the thresholds in MHC based suppression, MHC derived peptides are used to set the inhibitory signal to maximum.
  • 2. Natlet V2.ppt256-2.wav [56 s] The theory known as MBS stands for the major histo compatibility based suppression theory. The MBS theory is proposed by the author as a way of controlling T cells and is dependant upon T cell contact with MHC. There are many aspects of this theory that for reasons of limited time, will not be discussed here. The purpose of this presentation is to point out a particularly inclusive potential mechanism that is MHC based. This mechanism uses MHC-derived peptides to "read out" a unique identity code for every T cell clone. By identifying when all T cells are derived from a single clone versus multiple clones, this allows T cells to make the correct decision between self (a single clone) and invader derived proteins (multiple clones). The reader may like to view the references at the end of this presentation.
  • I will be talking about evidence for and against observed phenomena, which have been investigated and found to be repeatable. Current dogma is either unable to explain or find a reason for these phenomena. I have been placed these in conceptual evidence text boxes and will explain how my theory fits.
  • After release of T cells into the peripheral circulation they continuously receive MBS signals every time a T cell receptor locks onto a MHC molecule. The detection of cognate ligand peptide produces internal signalling and activates cellular transfer of the MHC/peptide complex. A process of identifying the clonality of the surrounding T cells takes place. It is likely this process is relatively slow, taking possibly several weeks or even months. At the end of the process if all the T Cells are from 1 clone this will result in the T cell decision being made and the T cell will take the suppressor route. Thereafter further T cells arriving at the peripheral site will be contacted by suppressor T cells of the same clone. The process continues until there are no further uncommitted T cells of the single clone origin.
  • This keynote presentation summarised the key points in the MBS theory. We will look at the role of MHC in transplantation in my presentation tomorrow. Thank you for listening.

Transcript

  • 1. The route to tolerance induction and the role ofMHC in future advances for organ transplantation Presented by Derek W R Gray
  • 2. 1 yr
  • 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. 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. Over a 20 year period numberof years graft function wastedby uncontrolled immune attack = 3.25 million
  • 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. 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. 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. 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. 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. 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. MBS theory and interaction with T cellsMultiple cells and a variety of MHCmolecules contribute to the MBS signal
  • 13. The route to tolerance induction andthe role of MHC in future advances for organ transplantation Tuesday 21 August 10:35