Generation of regulatory gut-homing human T lymphocytes using ex vivo interleukin 10 gene transfer

Gastroenterology. 2002 Dec;123(6):1877-88. doi: 10.1053/gast.2002.37066.

Abstract

Background & aims: Systemic treatment of Crohn's disease patients using recombinant interleukin (rIL)-10 has not resulted in significant therapeutic benefit presumably because of limited bioavailability and unexpected proinflammatory effects of high-dose rIL-10. Ex vivo gene transfer of the interleukin (IL)-10 gene to gut-homing CD4(+) cells may lead to improved long-term management.

Methods: Peripheral blood mononuclear cells (PBMCs) were transduced with a retroviral vector containing the IL-10 and green fluorescent protein (GFP) gene or a control vector containing GFP only. Transduced CD4(+) cells were sorted and maintained in culture for phenotypic and functional analysis.

Results: Stimulated IL-10-GFP CD4(+) cells produced significantly higher levels of IL-10 than control cells for at least 4 months. The IL-10 transgene was biologically active and decreased proliferation of IL-10-GFP CD4(+) cells as well as expression of major histocompatibility class (MHC) class II, proliferation of autologous responder cells, and IL-12 production by dendritic cells (DCs). The majority of transduced CD4(+) cells had a gut-homing potential because they expressed the mucosal integrin alpha4beta7, and displayed efficient binding to MAdCAM-1-expressing cells in vitro.

Conclusions: Transduction of peripheral blood CD4(+) lymphocytes with IL-10 results in a regulatory phenotype. The use of regulatory gut-homing human CD4(+) cells may provide a novel approach to local delivery of immunomodulatory signals to the intestine in Crohn's disease.

MeSH terms

  • Cell Adhesion / physiology
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cytokines / biosynthesis
  • Dendritic Cells / metabolism
  • Gene Transfer Techniques*
  • Green Fluorescent Proteins
  • Humans
  • Immunoglobulins / physiology
  • Interleukin-10 / genetics*
  • Interleukin-12 / biosynthesis
  • Intestines / physiology*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Mucoproteins / physiology
  • Paracrine Communication / physiology
  • Receptors, Lymphocyte Homing / physiology*
  • T-Lymphocytes / physiology*
  • Transduction, Genetic

Substances

  • Cytokines
  • Immunoglobulins
  • Luminescent Proteins
  • MADCAM1 protein, human
  • Mucoproteins
  • Receptors, Lymphocyte Homing
  • Interleukin-10
  • Green Fluorescent Proteins
  • Interleukin-12