Prolonged neutropenia in a novel mouse granulocyte colony-stimulating factor neutralizing auto-immunoglobulin G mouse model

Exp Hematol. 2001 Jan;29(1):59-67. doi: 10.1016/s0301-472x(00)00614-7.

Abstract

Therapeutic use of recombinant human cytokines in humans can result in the generation of drug-specific antibodies. To predetermine the maximum potential effects of a granulocyte colony-stimulating factor (G-CSF) neutralizing auto-immunoglobulin G (auto-IgG) response during recombinant human G-CSF therapy, we developed a mouse model of mouse G-CSF (mG-CSF) neutralizing auto-IgG response. Mice were immunized and boosted with mG-CSF chemically conjugated to either keyhole limpet hemocyanin or ovalbumin on an alternating schedule. Sera were analyzed for mG-CSF-specific titers and full blood counts were performed on a Technicon H-1E. On day 252, tissues were collected for histology. IgG was protein A affinity purified from pooled mG-CSF autoimmune sera. Mice immunized with mG-CSF conjugates produced mG-CSF-specific auto-IgG responses that lasted for the length of the study. Significant neutropenia (p(max) < 0.004) was concurrent with the rise in mG-CSF-specific IgG titers. However, neutrophil counts remained at approximately 20% of preimmunization levels through day 252. Endogenous mG-CSF neutralizing auto-IgG had no significant effect on hemoglobin, erythrocyte, lymphocyte, eosinophil, basophil, and platelet counts, and had minor, transient, or no effects on monocyte counts. Bone marrow colony assays from mG-CSF autoimmune mice demonstrated no significant effect of G-CSF neutralization on the numbers or proliferative capacity of preneutrophil lineage progenitors. Purified IgG from mG-CSF autoimmune mice neutralized mG-CSF in vitro. High-titer G-CSF neutralizing auto-IgG in adult mice partially inhibited steady-state granulopoiesis and had little or no effect on steady-state levels of other hematopoietic cells.

MeSH terms

  • Animals
  • Autoantibodies / biosynthesis
  • Autoantibodies / immunology*
  • Autoimmune Diseases / etiology*
  • Autoimmune Diseases / immunology
  • Colony-Forming Units Assay
  • Female
  • Granulocyte Colony-Stimulating Factor / antagonists & inhibitors
  • Granulocyte Colony-Stimulating Factor / immunology*
  • Granulocyte Colony-Stimulating Factor / physiology
  • Hematopoiesis / immunology
  • Hematopoietic Stem Cell Mobilization / adverse effects
  • Hemocyanins / immunology
  • Immunization
  • Immunoglobulin G / immunology*
  • Mice
  • Models, Animal
  • Neutropenia / etiology*
  • Neutropenia / immunology
  • Ovalbumin / immunology
  • Recombinant Proteins / pharmacology
  • Reproducibility of Results
  • Specific Pathogen-Free Organisms

Substances

  • Autoantibodies
  • Immunoglobulin G
  • Recombinant Proteins
  • Granulocyte Colony-Stimulating Factor
  • Ovalbumin
  • Hemocyanins
  • keyhole-limpet hemocyanin