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Transplant Rejection

Transplant Rejection. Major Histocompatibility complex (MHC). Also known as Human Leukocyte Antigen (HLA) They are encoded cell surface molecules that are specialized to present antigenic peptide to T-cells. Controlled by Genes Located on Chromosome 6. Role of MHC.

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Transplant Rejection

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  1. Transplant Rejection

  2. Major Histocompatibility complex (MHC) • Also known as Human Leukocyte Antigen (HLA) • They are encoded cell surface molecules that are specialized to present antigenic peptide to T-cells. • Controlled by Genes Located on Chromosome 6.

  3. Role of MHC • T-lymphocytes recognize antigens that are presented by MHC. • Two types of MHC (class I and class II) are recognized by different T cells. • CTL recognizes Ag peptide in MHC class I • T-helper recognizes Ag peptide in MHC class II

  4. Antigens • Are proteins that have been clipped into smaller subunits. • Made from: • Viral • Bacterial • Tissues • Used to make antibodies.

  5. Structure of MHC class I • Two polypeptide chains • Long α chain and short β • Made up of 350 a.a • 57 kDa [purple, turquoise, green] = α region [pink] = β region

  6. Antigen Binding Cleft (MHC I) • Cleft is composed of: • walls made up of both α helical sections • floor made up of β sheets • Residues lining floor are most polymorphic • They are the most different from person to person • Contains Tyrosine, used for anchoring the antigen • Groove binds peptides ~10 AA long Non-Covalent Interactions occur

  7. Structure of MHC class II • Two polypeptide chains • α and β • approx equal length • α = 230 a.a • Β = 240 a.a • Each segment ~ 30 kDa

  8. Antigen Binding Cleft (MHC II) • Groove composed of • α helix walls • β pleated floor • Floor residues are polymorphic • In place of Tyrosine, there are more Valine and glycine. • Groove binds peptides ~15 - 20 AA long

  9. Each MHC has ONEantigen binding site • Each MHC can bind several different antigens but only “ONE” at a time. • Peptide must bind with individual’s MHC to induce immune response • No “Conformational” change is induced

  10. T-cell Antigen MHC Complex

  11. Allograft Rejection Overview

  12. Rejection through MHC I

  13. Rejection through MHC II

  14. Rejection Effects • Hyperacute – within minutes • Acute – within hours to days • Chronic – episode occur overtime

  15. Corticosteroids • Used first in the drug treatment. • Exerts negative regulatory effect on the cytokine gene expression on the T-cell. • Causes Lyphocytopenia, causing the lysis of immature T-cells • Impedes inflammatory response by eliminating vasoactive and chemo-attractant substances.

  16. Calcineurin Inhibitors

  17. Anitmetabolites • Causes metabolic dysfunction in the T-cell. • Inhibits: • Purine Metabolism • Nucleotide Synthesis • Inhibition of DNA synthesis • Works by acting like a purine or pyrimidine analog and incorporating itself into the DNA sequence causing faulty base pairing • Works by competitive inhibition to prevent AMP production.

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