Constitutive systemic expression of IL-1Ra or soluble TNF receptor by genetically modified hematopoietic cells suppresses LPS induction of IL-6 and IL-10

L. A. Doughty, K. D. Patrene, C. H. Evans, S. S. Boggs, P. D. Robbins

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

We have been developing both local and systemic gene therapy approaches to treat inflammatory and autoimmune diseases. To determine if systemic, constitutive expression of biologically active anti-inflammatory agents is therapeutic and/or has associated toxicity, mouse hematopoietic stem cells were infected with retroviral vectors carrying the genes for human IL-1 receptor antagonist (IL-1Ra), human soluble TNF receptor p75 (sTNFR), or the β-galactosidase (lacZ) gene and transplanted into lethally irradiated recipients. The serum levels of human IL-1Ra and human sTNFR in the long-term reconstituted mice, 2-7 months after transplantation, were 596 and 158 ng/ml respectively. The long-term expression of human IL-1Ra had minimal effects on the PBMC profile whereas human sTNFR expression increased the percentage of B220 and Mac.1 stained cells and decreased slightly the specific T cell subsets. The ability of these proteins to protect the transplanted mice from endotoxin treatment was determined by measuring serum interleukin-6 (IL-6) and interleukin-10 (IL-10) responses after LPS injection at 1.5, 3, 4.5 and 24 h after treatment. The IL-1Ra group showed diminished IL-10 levels and less mortality after injection of LPS compared to the lacZ controls. Mice expressing sTNFR had lower IL-10 and IL-6 levels following injection of LPS. These results demonstrate that constitutive, systemic expression of IL-1Ra and sTNFR is able to confer partial protective effects following treatment with endotoxin. These results further demonstrate that gene transfer methods which result in systemic, long-term expression of immunodulatory proteins could be applied to the treatment of inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)252-257
Number of pages6
JournalGene Therapy
Volume4
Issue number3
DOIs
StatePublished - Jan 1 1997

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Keywords

  • Gene-therapy
  • IL-1Ra
  • Interleukin-10
  • Interleukin-6
  • sTNF receptor

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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