CTLA-4. FasL induces alloantigen-specific hyporesponsiveness.
The APC:T cell interface can be effectively targeted with immunotherapeutic proteins. We previously described a unique trans signal converter protein, CTLA-4. Fas ligand (FasL), that has the inherent capacities to tether the T cell inhibitor FasL (CD95 ligand) to the surfaces of B7 (CD80 and CD86)-positive APC (via CTLA-4:B7 interaction), and in so doing, to simultaneously interfere with B7-to-CD28 T cell activation signals. Given the continuing need for agents capable of inducing allograft tolerance without generalized immunosuppression, we have explored in depth the functional activity of CTLA-4. FasL in human allogeneic MLR. CTLA-4. FasL inhibits 1 degrees MLR and induces specific hyporesponsiveness in 2 degrees MLR, with both effects only partially reversible with exogenous IL-2. Moreover, the presence of exogenous IL-2 during the 1 degrees MLR does not affect the induction of hyporesponsiveness upon restimulation. Furthermore, CTLA-4. FasL enables partial activation of allostimulated T cells, reduces the fraction of actively dividing cells, and increases the percentage of dead cells among dividing T cells. Taken together, these findings suggest that CTLA-4. FasL-mediated inhibition of secondary alloantigenic responses involves both anergy induction and clonal deletion. Thus, CTLA-4. FasL, a paradigmatic trans signal converter protein, manifests unique functional properties and emerges as a potentially useful immunotherapeutic for modulating alloresponsiveness.
Elhalel
Michal Dranitzki
MD
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Huang
Jui-Han
JH
Schmidt
William
W
Rachmilewitz
Jacob
J
Tykocinski
Mark L
ML
D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology; D060908:CTLA-4 Antigen; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D006131:Growth Inhibitors / Q000502:physiology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D007519:Isoantigens / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D006131:Growth Inhibitors; D007376:Interleukin-2; D007519:Isoantigens; D008024:Ligands; D008562:Membrane Glycoproteins; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; D016753:Interleukin-10