title: Donor T cells lacking Fas ligand and perforin retain the capacity to induce severe GvHD in minor histocompatibility antigen mismatched bone-marrow transplantation recipients.
abstract: Graft-versus-host disease (GvHD) is a frequent impediment to therapeutically successful allogeneic bone-marrow transplantation (BMT). This investigation further examines the roles of two potential donor cytotoxic effector mechanisms previously implicated in tissue pathogenesis. Cytotoxically double deficient (B6-cdd) T cells (lacking functional fas ligand and perforin) and wild-type (B6-wt) donor T-cell transplantation in a minor antigen-mismatched BMT model (C57BL/6 --> C3H.SW) resulted in similar mortality and weight loss. Histopathologic findings revealed mononuclear infiltrates and cellular atrophy in GvHD target tissues (liver, stomach) in recipients of B6-wt and B6-cdd donor T cells. Both recipients also exhibited GvH-associated lymphohematopoietic compartment (LHC) alterations as evidenced by inverted CD4:CD8 ratios and B-cell hypoplasia. Notably, transplants using recombinant inbred mHAg disparate recipients demonstrated that B6-cdd T cells induced lethal GvHD in CXBE but not CXBG recipients: the same pattern induced by B6-wt T cells. This observation is consistent with previous findings that cytotoxic T lymphocyte (CTL) responses against CXBG and CXBE antigens did not correlate with GvH responses in these strains. In contrast with the typical pattern of donor T-cell expansion and contraction, T cells lacking perforin and FasL function exhibited extensive expansion postBMT. In summary, these findings support the notion that donor anti-host cytotoxicity by way of the two major pathways is not a prerequisite for induction of GvHD. In addition, the results suggest that this model will be useful to investigate the regulation of allogeneic donor T-cell expansion after major histocompatibility complex-matched allogeneic BMT.
authors.affiliation: Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33101, USA.
authors.forename: Lianne
authors.initials: L
authors.lastname: Marks
authors.forename: Norman H
authors.initials: NH
authors.lastname: Altman
authors.forename: Eckhard R
authors.initials: ER
authors.lastname: Podack
authors.forename: Robert B
authors.initials: RB
authors.lastname: Levy
mesh_terms: D000818:Animals; D001483:Base Sequence; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000473:pathology; D003432:Cross-Linking Reagents; D017931:DNA Primers; D053222:Fas Ligand Protein; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000276:immunology; D006650:Histocompatibility Testing; D016130:Immunophenotyping; D017710:Lymphocyte Transfusion; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D003432:Cross-Linking Reagents; D017931:DNA Primers; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D015778:Minor Histocompatibility Antigens; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin