Graft-versus-host-disease-associated lymphoid hypoplasia and B cell dysfunction is dependent upon donor T cell-mediated Fas-ligand function, but not perform function

Matthew B. Baker, Richard L. Riley, Eckhard R. Podack, Robert B. Levy

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

Allogeneic bone marrow transplant recipients often exhibit a graft- versus-host-disease (GVHD)associated immune deficiency that can be prolonged and lead to life-threatening infections. We have examined the role of donor T cell-mediated cytotoxic function in the development of GVHD-associated immune deficiency. A major histocompatibility complex-matched model of allogeneic bone marrow transplantation was employed in which lethally irradiated C3H.SW mice received a nonlethal dose of T cells from either perforin-deficient (B6- perforin 0/0), Fas-ligand (FasL)defective (B6-gld), or normal (B6) allogeneic donor mice. T cell-depleted marrow from B6-Ly-5.1 congenic donor mice was transplanted along with the donor T cell populations to determine the effects of donor T cell-mediated cytotoxicity on engraftment. Our results demonstrate that recipients of perforin-deficient or normal allogeneic T cells exhibit profound lymphoid hypoplasia and severely reduced splenic proliferative responses to lipopolysaccharide in vitro. In contrast, GVHD-associated lymphoid hypoplasia is dramatically reduced and in vitro B cell function is intact in recipients of FasL-defective allogeneic T cells. Engraftment of myeloid and erythroid lineage cells occurs irrespective of donor T cell cytotoxic function. Although recipients of perforin-deficient or normal allogeneic T cells exhibited hematopoietic engraftment exclusively of donor origin, recipients of FasL-defective donor T cells exhibited significant mixed chimerism (Ly-5.1/Ly-5.2). Because only marrow of donor origin was transplanted, this finding suggests that Fas-mediated antirecipient cytotoxicity is required for clearance of residual hematopoietic stem cells of host origin that persist following lethal irradiation.

Original languageEnglish (US)
Pages (from-to)1366-1371
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number4
DOIs
StatePublished - Feb 18 1997

Keywords

  • bone marrow transplanlation
  • chimerism
  • cytotoxicity
  • engraftment
  • immune dysfunction

ASJC Scopus subject areas

  • Genetics
  • General

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