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Tumor Immunology, Tumors express tumor rej Ags -specific for indiv. tumors -irrad. tumor cells can confer elimination of same, viable tumor -T cell-mediated -not expressed on normal cells -presented to T cells Formation of TRAs Or no mutation -NL self peptides 1.Reactivate germ cell genes ->novel peptides to immune system 2.Overexpress NL self protein ->inc. peptide presentation density ->T cell recognition -eg. Her2/neu, Tumor Immunology To augment tumor immunity 1. Tumor vaccine-tumor Ag w/ bacterial adjuvant (BCG) -some help in melanomas, otherwise disappointing 2. Recombinant IFN-renal cell carcinoma Tx 3. IL-2-adoptive cellular immunotherapy-may be toxic -generate LAK, TIL 4. Heat shock proteins-from tumor; already bound to Ag -non-specific phagocytosis->present Ag to T cell 5. Genetic modification of tumor cell-transfect w/ co-stim genes (B7) or GM-CSF->recruit DCs 6. DC-based vaccines-fuse DC w/ tumor cell (hybridoma) 7. Immunization w/ DCs-pulse DCs w/ protein or mRNA extract ->present to T cells, Tumors express tumor rej Ags -specific for indiv. tumors -irrad. tumor cells can confer elimination of same, viable tumor -T cell-mediated -not expressed on normal cells -presented to T cells Formation of TRAs Point Mutations in Self Ags 1-binding of new peptide to MHC 2-new epitope for T cell to recognize, Transplantation Immunology Types of Rejection Opposite=GVHD -from allogeneic bone marrow xplant -mature graft, immunodeficient recipient ->severe inflamm rxn-rashes, diarrhea, liver dmg -must use immunosupps even if HLA matched (minor H) -if donor T cells eliminated->inc. leukemia incidence, Rejection even w/ syngeneic HLA loci ->minor histocompatibility Ags (but rejection is slower) -if multiple minor loci diff->rejection as fast as if MHC are unmatched Minor H Ags Minor Histocompatibility Ags -self protein digested by proteasome -displayed on MHC-I -could differ b/w graft, recipient ->immune rxn, Transplantation Immunology Graft Rejection ALWAYS -MUST use immunosuppressives CRITICAL PERIOD-2-4 wks post T cell-mediated immune response -accelerated 2nd-set rejection -can xfer sensitized T cells to naive mouse-ɮnd set rejection -won't even vascularize the 2nd time -just dies, Tumor Immunology Immunodiagnoses Use mABs to detect biomarkers -figure out cells of origin -AB against cytokeratin-find carcinoma -anti-CD45 to see if lymphoma -immunoscintigraphy to see where radioactivity localizes -monitor CEA levels after removing colon CA -predict metastasis, Transplantation Immunology Types of Rejection Improve Survivability via: -HLA matching HLA-D mismatches->more rejection than HLA-A,B -immunosuppressive drugs a.anti-inflamm corticosteroids-prednisone -binds steroid receptor, displacing Hsp90 b.cytotoxic drugs-azathioprine, cyclophosphamide aza-purine analog->prevents prolif (affects gut epith) cyclophos-alkylating agent, enters into DNA c.fungal, bacterial derivs inhibiting T signalling -cyclosporin, tacrolimus -interfere w/ calcineurin->can't activate NFATc family, Transplantation Immunology Types of Rejection 2. Acute-7-14 days - primary allograft response T cell-mediated a.lymphocytic/monocytic infiltration like DTH b.athymic mice, DiGeorge pts accept grafts c.allograft-primed T cells induces 2nd set rejection d.deplete CD4 or CD8 cells->inhibit rejection, 1. Tumor heterogeneity 2. Low density of tumor Ag, or loss of Ag 3. Human anti-mouse AB (HAMA) response ->human ABs clear responding mouse mABs 4. Immunotoxins must bind to every cell to kill To Decrease HAMA Diminish mu IgG immunogenicity 1. Humanize ABs 2. Make ABs smaller (MRU<Fv<Fab<F(ab')2<IgG) 3. Make bifunctional ABs -2 specificities: tumor, Tx agent