Transplant Immunobiology Douglas Stahura DO Grandview Hospital November 6, 2002.
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Transcript of Transplant Immunobiology Douglas Stahura DO Grandview Hospital November 6, 2002.
Transplant ImmunobiologyTransplant Immunobiology
Douglas Stahura DO
Grandview Hospital
November 6, 2002
GoalsGoals
Review definitionsReview basic mechanisms of
immunologic systemUnderstand T-cell immunityReview transplant medications and
mechanisms
DefinitionsDefinitions
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
DefinitionsDefinitions
Alloantigens – antigens recognized as foreign on allografts
Alloreactive – lymphocytes that recognize and respond to alloantigens
DefinitionsDefinitions
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
MHCMHC
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
MHCMHC
Located on short arm of chromosome 6Six 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
MHCMHC
HLA Class IFound on all nucleated cellsFunction as immunorecognition site for
endogenously synthesized foreign protein antigens
Recognized by CD8+ T cells
MHCMHC
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
T cell activationT cell activation
T cell activationT cell activation
Allorecognition – recognition of TRANSPLANT antigens by T cells
TCR – T cell receptor “recognizes” MHC/antigen complex
CD3 complex initiates intracellular signalling
T cell activationT 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
T cell activationT 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
T cell CostimulationT cell Costimulation
Immunosuppressive Immunosuppressive MedicationsMedications
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
Immunosuppressive Immunosuppressive MedicationsMedications
Signal Two – no currently approvedSignal 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
Immunosuppressive Immunosuppressive MedicationsMedications
Corticosteroids– Blocks T-cell and APC cytokine and
cytokine receptor expression (inhibits transcription)
– Blocks migration of lymphocytes to tissues (anti-inflammatory)