Murine acute graft-versus-host disease can be prevented by depletion of alloreactive T lymphocytes using activation-induced cell death.
Depletion of T lymphocytes from allogeneic bone marrow transplants successfully prevents the development of graft-versus-host disease (GvHD) but is associated with impaired engraftment, immunosuppression, and abrogation of the graft-versus-leukemia effect. We therefore explored the possibility of selectively eliminating alloreactive T cells by CD95/CD95L-mediated activation-induced cell death (AICD) in a major histocompatibility complex allogeneic murine model system. Activation of resting or preactivated T lymphocytes from C3H/HeJ (H-2(k)) mice was induced with irradiated BALB/cJ (H-2(d)) mouse-derived stimulators. Substantial decrease (> or = 80%) of proliferative and lytic responses by activated alloreactive T cells was subsequently achieved by incubating the mixed lymphocyte culture with an agonistic monoclonal antibody to CD95, and residual T cells recovered did not elicit alloreactivity upon challenge to H-2(d). Depletion of alloreactive T lymphocytes by AICD was specific because reactivity to an I-A(d)-restricted ovalbumin (OVA) peptide by OVA-specific CD4(+) T cells mixed into the allogeneic T-cell pool and subjected to induction of AICD in the absence of OVA peptide could be preserved. Adoptive transfer of donor-derived allogeneic T lymphocytes, depleted from alloreactive T cells by AICD in vitro, in the parent (C3H/He) to F(1) (C3H/He x BALB/c) GvHD model prevented lethal GvHD. The results presented suggest that alloreactive T cells can effectively be depleted from allogeneic T cells by induction of AICD to prevent GvHD and might introduce a new strategy for the separation of GvH-reactive T cells and T cells mediating antiviral and possibly graft-versus-leukemia effects.
Hartwig
Udo F
UF
Division of Hematology, III Department of Medicine, University Medical School Mainz, Germany. uhartwig@mail.uni-mainz.de
Robbers
Michael
M
Wickenhauser
Claudia
C
Huber
Christoph
C
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008212:Lymphocyte Depletion / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D014184:Transplantation, Homologous / Q000379:methods; D019014:fas Receptor / Q000276:immunology
D000911:Antibodies, Monoclonal; D007519:Isoantigens; D019014:fas Receptor