Myelosuppressive effects in vivo with very low dosages of monomeric recombinant murine macrophage inflammatory protein-1α

S. Cooper, C. Mantel, H. E. Broxmeyer

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Abstract

Macrophage inflammatory protein (MIP)-1α has myelosuppressive/myeloprotective effects in vivo in mice. We recently reported that >99.7% of recombinant murine (rm) MIP-1α polymerizes rapidly at relatively high concentrations in physiological salt solution, and it is the monomeric form of MIP-1α that is active in vitro as a myelosuppressive factor. Polymerized MIP-1α is inactive in this effect and does not block the myelosuppressive action of monomeric MIP-1α. MIP-1α could be maintained in monomeric form in physiological saline if diluted to low concentrations. This led us to reevaluate the actual amounts of MIP-1α necessary for myelosuppression in vivo. G3H/He1 mice were injected intravenously (IV) with monomeric rmMIP-1α or control diluent and effects were evaluated on progenitor cells-multipotent colony-forming units (CFU-GEMM), burst-forming units-erythroid (BFU-E), and colony-forming units-granulocyte/macrophage (CFU-GM)-as described in previous studies in which MIP-1α concentrations were used that we now know to have been mainly in polymerized form. Monomeric MIP-1α rapidly decreased cycling rates and absolute numbers of myeloid progenitor cells in marrow and spleen. These effects, which occurred with about 1000-fold less MIP-1α than we previously reported, were dose- dependent, time-related, and reversible. Suppressive effects were noted within 3 hours for cell cycling and within 24 hours for absolute numbers of progenitor cells in marrow and spleen and were lost by 48 hours. Decreased circulating neutrophils were noted at 48 hours. Column-separated polymerized rmMIP-1α was inactive in vivo. These results demonstrate the potency of low doses of monomeric MIP-1α in vivo. Since clinical administration of large amounts of an agent that is mainly in an inactive form may result in severe pharmacological side effects, the information presented here is of relevance for potential clinical trials using MIP-1α as a myelosuppressive/myeloprotective agent.

Original languageEnglish (US)
Pages (from-to)186-193
Number of pages8
JournalExperimental Hematology
Volume22
Issue number2
StatePublished - Jan 1 1994

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Keywords

  • In vivo
  • MIP-1α
  • Myelosuppression
  • Progenitor cells

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

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