Down-regulation of human alloimmune responses by genetically engineered expression of CD95 ligand on stimulatory and target cells.
Transgenic expression of apoptosis-inducing molecules could be a strategy to protect cells and tissues from destruction by apoptosis-susceptible effector T cells. Some evidence for the potency of this approach has been obtained in mouse and rat transplantation models. However, limited data are available on the capacity of apoptosis-inducing molecules to modulate human alloimmune responses. In this study we analyzed the in vitro consequences of an interaction of human T cells with allogeneic 293 cells and 293 transfectants stably expressing high levels of the apoptosis-inducing CD95 ligand (CD95L). Both, CD95L(-) and CD95L(+) 293 cells were able to activate allogeneic T cells as demonstrated by comparable CD25 expression at day 2 of culture. The analysis of viable T cells at day 7, however, revealed anti-293 cytotoxic activity only in cultures that had been stimulated with CD95L(-) 293 cells. Alloactivated effector T cells lysed CD95L(-) and CD95L(+) 293 targets with similar efficiency when tested in a 4-h 51Cr-release assay. Prolongation of the effector phase to 20 h resulted in a further increase in the destruction of CD95L(-) target cells, whereas lysis of CD95L(+) targets remained low. These data suggest that genetically engineered expression of CD95L on cells or tissues could be an approach to control human T cell reactivity towards allografts. During the induction of an alloimmune response depletion of cytotoxic precursor cells may be obtained by overexpressing CD95L on stimulatory cells; CD95L expression on graft tissue might limit T cell-mediated destruction of the transplant during the effector phase of the response.
Dulat
H J
HJ
Transplantationslabor, Klinik für Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Germany.
von Grumbkow
C
C
Baars
W
W
Schröder
N
N
Wonigeit
K
K
Schwinzer
R
R
D017209:Apoptosis; D002460:Cell Line; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D015536:Down-Regulation; D053222:Fas Ligand Protein; D005818:Genetic Engineering; D006801:Humans; D007108:Immune Tolerance; D007519:Isoantigens / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D007519:Isoantigens; D008562:Membrane Glycoproteins