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

Lianne Marks, Norman H. Altman, Eckhard R. Podack, Robert B. Levy

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)804-812
Number of pages9
JournalTransplantation
Volume77
Issue number6
DOIs
StatePublished - Mar 27 2004

ASJC Scopus subject areas

  • Transplantation

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