1. Transplant Immunobiology
Douglas Stahura DO
Grandview Hospital
November 6, 2002

2. Goals Review definitions Review basic mechanisms of immunologic system
Understand T-cell immunity
Review transplant medications and mechanisms

3. Definitions
Autograft – transplantation of one’s own tissue to another site
Syngraft – transplantation of graft between two genetically identical individuals
Allograft – transplantation of graft between individuals of the same species
Xenograft – transplantation of graft between individuals of different species

4. Definitions
Alloantigens – antigens recognized as foreign on allografts
Alloreactive – lymphocytes that recognize and respond to alloantigens

5. Definitions Major Histocompatibility Complex (MHC)
In humans, known as HLA system
Central role in antigen recognition
Principal immunologic function of MHC gene product is to present antigens as fragments of foreign proteins, forming complexes that can be recognized by T lymphocytes

6. MHC MHC molecules are membrane associated
Antigen-specific T lymphocytes recognize fragments of antigens only when bound to the surface of other cells that bear MHC molecules
Mature T lymphocytes recognize and react to foreign antigens and not to self
Clonal deletion
Self tolerance

7. MHC Located on short arm of chromosome 6 Six separate genes;
Class I = HLA-A,B,C
Class II = DR,DQ,DP
Each gene is represented by one of two codominant alleles (paternal +maternal)
Haplotype – alleles of HLA system passed to offspring via meiosis

8. MHC HLA Class I Found on all nucleated cells
Function as immunorecognition site for endogenously synthesized foreign protein antigens
Recognized by CD8+ T cells

9. Figure 3 (facing page).
Antigen Processing.
Panel A shows the principal pathways of generating petides for loading onto HLA class I molecules. Worn-out or defective proteins
in the cytosol are degraded into e tides in proteasomes. Selected petides are then transported into the endoplasmic reticulum,
where they are loaded onto newly synthesized class I molecules. The HLA– petide complexes are exported by way of the Golgi
aparatus to the surface of the cell. In tissues infected with a virus, viral particles are taken up by cells and uncoated. The viral DNA
or RNA enters the nucleus and replicates within it. The viral messenger RNA (mRNA) then enters the cytosol and is transcribed
into proteins. Some of the proteins are subsequently degraded in proteasomes, and the petides are delivered into the endoplasmic
reticulum, where they are loaded onto class I molecules for export to the surface of the cell. Panel B shows the processing of extracellular
proteins. Self or foreign proteins are taken up by endocytosis (or phagocytosis) and sequestered into endosomes. Class
II molecules synthesized in the endoplasmic reticulum are delivered by way of the Golgi aparatus into primary lysosomes, which
fuse with the early endosomes to form the major-histocompatibility-com lex (MHC) class II com artment. Enzymes brought into
this compartment by the lysosomes degrade the engulfed roteins into e tides. HLA- M molecules synthesized in the endoplasmic
reticulum and delivered into the MHC class II compartment by trans ort vesicles hel load the petides onto the class II molecules.
The HLA– petide com lexes are then exported to the surface of the cell.

10. MHC HLA Class II Found on APC (antigen presenting cells)
B monocytes, macrophages, dendritic cells, mesangial cells, Kupffer’s cells, alveolar type 2 cells
central role in the initiation of the immune response to transplantation antigens

14. T cell activation

16. T cell activation
Allorecognition – recognition of TRANSPLANT antigens by T cells
TCR – T cell receptor “recognizes” MHC/antigen complex
CD3 complex initiates intracellular signalling

17. T cell activation
CD3 complex – five peptide chain closely arrayed in cell membrane alongside TCR
TCR binding induces conformational change in CD3 which initiates intracellular signal pathways

19. T cell activation Accessory molecules
Stabilize the interaction between cytotoxic T cells and their target cell
Provide a non-antigen “second” signal for T cell activation
Adhesion molecules enhance antigen recognition by increasing affinity between T cell and MHC cell
TCR recognition without accessory molecule co-stimulation results in clonal anergy or apoptosis

20. T cell Costimulation

22. Immunosuppressive Medications
Drugs target the cellular mechanisms that are known
Signal ONE
Calcineurin inhibitors
Cylosporine (Sandimmune, Neoral)
Tacrolimus (FK506, Prograf)
Monoclonal Antibodies
OKT3 – targets CD3 molecule
Polyclonal Antibodies (ALG)
Thymoglobulin

23. Immunosuppressive Medications
Signal Two – no currently approved
Signal Three
Sirolimus (Rapamycin)
Monoclonal Ab that target IL-2 receptors
Anti-metabolite
Azathioprine (Imuran) nonspecific inhibitor of purine synthesis
Mycophenolate mofetil (Cellcept) lymphocyte selective inhibitor of de novo purine synthesis

24. Immunosuppressive Medications
Corticosteroids
Blocks T-cell and APC cytokine and cytokine receptor expression (inhibits transcription)
Blocks migration of lymphocytes to tissues (anti-inflammatory)