Modulation of CSF-1-regulated post-natal development with anti-CSF-1 antibody

Immunobiology. 2005;210(2-4):109-19. doi: 10.1016/j.imbio.2005.05.005.

Abstract

Colony-stimulating factor-1 (CSF-1) regulates the survival, proliferation and differentiation of macrophages. CSF-1-deficient mice are osteopetrotic due to a lack of osteoclasts, while their tissue macrophage deficiencies and an absence of CSF-1 regulation of CSF-1 receptor-expressing cells in the female reproductive tract contribute to their pleiotropic phenotype. To further understand CSF-1 regulation of macrophages in vivo, we developed a neutralizing anti-mouse CSF-1 antibody which was expressed as a recombinant Fab' fragment and coupled to 40 kDa polyethylene glycol. As developmental regulation by CSF-1 is highest during the early post-natal period, the ability of this anti-CSF-1 reagent to inhibit development was tested by regular subcutaneous injection of mice from post-natal days 0.5-57.5. Antibody treatment decreased growth rate, decreased osteoclast number, induced osteopetrosis, decreased macrophage density in bone marrow, liver, dermis, synovium and kidney and decreased adipocyte size in adipose tissue, thereby inducing phenotypes shared by CSF-1- and CSF-1 receptor-deficient mice. While the antibody blocked macrophage development in some tissues, macrophage densities in other tissues were initially high and were reduced by treatment, proving that the antibody also blocked macrophage maintenance. Since cell surface CSF-1 is sufficient for the maintenance of normal synovial macrophage densities, these studies suggest that anti-CSF-1 Fab'-PEG efficiently neutralizes all three CSF-1 isoforms in vivo, namely the secreted proteoglycan, secreted glycoprotein and cell surface glycoprotein. Since CSF-1 has been shown to enhance chronic disease development in a number of mouse model systems, these studies demonstrate the feasibility of neutralizing CSF-1 effects in these models with an anti-CSF-1 antibody.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipocytes / pathology
  • Animals
  • Bone and Bones / drug effects
  • Bone and Bones / pathology
  • Immune System / drug effects
  • Immune System / growth & development*
  • Immunoglobulin Fab Fragments / immunology
  • Immunoglobulin Fab Fragments / pharmacology*
  • Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
  • Macrophage Colony-Stimulating Factor / drug effects
  • Macrophage Colony-Stimulating Factor / metabolism*
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • Osteopetrosis / etiology
  • Osteopetrosis / pathology

Substances

  • Immunoglobulin Fab Fragments
  • Macrophage Colony-Stimulating Factor