Donor T cells lacking Fas ligand and perforin retain the capacity to induce severe GvHD in minor histocompatibility antigen mismatched bone-marrow transplantation recipients

Transplantation. 2004 Mar 27;77(6):804-12. doi: 10.1097/01.tp.0000110416.96307.d5.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Bone Marrow Transplantation / immunology*
  • Bone Marrow Transplantation / pathology
  • Cross-Linking Reagents
  • DNA Primers
  • Fas Ligand Protein
  • Graft Survival
  • Graft vs Host Disease / immunology
  • Histocompatibility Testing
  • Immunophenotyping
  • Lymphocyte Transfusion
  • Membrane Glycoproteins / deficiency*
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Minor Histocompatibility Antigens / immunology
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • T-Lymphocytes / immunology*
  • T-Lymphocytes, Cytotoxic / immunology
  • Transplantation, Homologous

Substances

  • Cross-Linking Reagents
  • DNA Primers
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Membrane Glycoproteins
  • Minor Histocompatibility Antigens
  • Pore Forming Cytotoxic Proteins
  • Perforin