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Lecture 31- Transplantation.docx

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McGill University
PHGY 313
Russell Jones

Lecture 31- 04/08/2013- Transplantation From last lecture... Examples of Autoimmune Disease:  APECED = Autoimmune Polyendocrinopathy Cadidiasis-Ectodermal Dystrophy o There's a deficiency in the AIRE gene o Endocrine organs are destroyed since specialized proteins are not being made in the thymic epithelium for T cell negative selection. o Result: Self reactive T cells against distant proteins  Type 1 diabetes o Specific destruction of the β-cell producing insulin in the Islets of Langerhans  Mediated by CD8+ T cells. They recognize insulin as the auto antigen.  The β-cells present insulin on their cell surface but the T cells recognize it as foreign.  Injection of insulin **  Multiple Sclerosis: o Most common disorder of the CNS. o Mediated by T cells where there's an immune response against your neurons via several brain antigens:  myelin basic protein,  proteolipid protein  myelin oligodendrocyte glycoprotein o The pathological trigger is still largely unknown. Once triggered however, leukocytes and blood proteins become permeable through the blood brain barrier. o One treatment is a stent in the brain, which will remove inflammation. Doesn't treat the cause but relieves symptoms. Transplantation  The act of transferring cells, tissues, or whole organs from a different individual 1. Also includes moving your own skin to a different location.  A transplanted organ/tissue is called a graft  The key issue is rejection. Your T cells are sensitive to foreign antigen (either foreign MHC or foreign peptides).  In general, 3 advances have been made that makes transplantation a routine and effective treatment. 5 year survival rates for kidney, liver, and heart transplants are all around 70% 1. Technical skills of surgeons increased 2. Better network centers matching HLA with the organ and patient. To avoid rejection, the donated organ's MHC must be very similar to the patient's/ 3. Immunosuppressive drugs have become available. However, immunosuppressive drugs put the patient at risk for other infections and they must be taken for the rest of their life. In fact, the person who got the world's first heart transplant died from pneumonia 18 days later because we weren't sure how to use these drugs yet. Some common immunosuppressive drugs include:  Cyclosporin-A  FRK-506: inhibits T cell activation, shutting down the host response to the organ  Rapamycin: blocks the IL2 receptor signal. IL2 is an important growth factor for T cells.  Transplantation has some problems. 1. Availability of healthy donor organs is low. 2. The original disease that destroyed the patient's own organ may persist to destroy the graft. This happens in autoimmune type 1 diabetes, so it's important not to transplant a pancreas in these people or the organ is wasted. 3. The immunosuppressive drugs increase the risk of cancer and infection Commonly transplanted organs. RED: from living donor GREEN: from cadaver  The MHC molecules in the donor's graft and the recipient need to be as similar as possible because T cells always respond to the MHC on the graft.  MHC not only presents peptide fragments, but also refers to a genetic complex. The MHC itself (as well as any foreign peptides it's presenting) is an alloantigen and can trigger a reaction  There are hundreds of different MHC alleles, and the particular combination of alleles found on a single chromosome is your haplotype. We are essentially always heterozygous because of excessive polymorphisms (a slight variation in a gene). o The MHC gene is on chromosome 6  The expression of MHC alleles is codominant; both alleles at a locus are expressed.  Even siblings don't have to have the same MHC alleles. Take the situation on the right: The boy on the left has the "blue" and "green" alleles, while the right has red and yellow.  If the boy were to receive a liver from the girl, his body would reject it because he would recognize her MHC as foreign antigens.  His TCRs have never been trained to see those MHCs.  Main matching is for 5 different genes, 2 alleles each.  Even if you have perfect matching of MHC, rejection can occur. Why? o Due to minor histocompatibility antigens. Some proteins can have polymorphisms changing one amino acid for another in the sequence. Functionally the proteins may look the same, but immunologically they are different. o These slightl
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