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)