Prevention of graft-versus-host disease (GVHD) by elimination of recipient-reactive donor T cells with recombinant toxins that target the interleukin 2 (IL-2) receptor

D. T. Harris, D. Sakiestewa, C. Lyons, R. J. Kreitman, I. Pastan

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Graft-versus-host disease (GVHD), due to the presence of recipient-reactive T cells, limits the usefulness of bone marrow transplantation (BMT) and is a major contributor to patient mortality. To prevent GVHD, murine and human T cells were activated by antigen or mitogens and treated with a genetically engineered form of Pseudomonas exotoxin A (PE) directed against the IL-2 receptor. Treatment with the chimeric toxin eliminated alloreactive cytotoxic T lymphocytes (CTL) as determined by cytotoxicity and mixed lymphocyte culture assays. Precursor frequencies of alloreactive cytotoxic T cells and proliferative T cells were reduced up to 100-fold as shown by limiting dilution assays. Flow cytometric analyses revealed that treatment with the chimeric toxin completely eliminated CD25+ cells from the cultures. Toxin treatment had no significant effect on hematopoietic stem and progenitor cells as determined in vitro by colony-forming assays and in vivo by long-term hematopoietic recovery after 950 rad irradiation. Toxin treatment decreased GVHD in transplanted mice to less than 10% (as compared to 88% in untreated controls). Thus, it is possible to prevent life-threatening GVHD after BMT by using a CD25 receptor-directed toxin to eliminate host-reactive T cells from bone marrow grafts.

Original languageEnglish (US)
Pages (from-to)137-144
Number of pages8
JournalBone Marrow Transplantation
Volume23
Issue number2
DOIs
StatePublished - Jan 1 1999

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Keywords

  • GVHD
  • Graft-versus-host disease
  • Immunotoxin
  • T cells

ASJC Scopus subject areas

  • Hematology
  • Transplantation

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