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

• Published in: Experimental hematology Vol. 29; no. 1; pp. 59 - 67
• Main Authors: Coccia, Marco A., Hartley, Cynthia, Sutherland, Weston, Del Castillo, Juan, McElroy, Patricia, Pistillo, Jeanne, Tarpley, John E., Molineux, Graham
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 2001
• Subjects: Animals; Antibody; Autoantibodies - biosynthesis; Autoantibodies - immunology; Autoimmune Diseases - etiology; Autoimmune Diseases - immunology; Colony-Forming Units Assay; Cytokine; Female; Granulocyte colony-stimulating factor; Granulocyte Colony-Stimulating Factor - antagonists & inhibitors; Granulocyte Colony-Stimulating Factor - immunology; Granulocyte Colony-Stimulating Factor - physiology; Granulopoiesis; 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; Granulocyte colony-stimulating factor; Antibody; Cytokine; Granulopoiesis
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/S0301-472X(00)00614-7

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 ∼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.