Prolonged neutropenia in a novel mouse granulocyte colony-stimulating factor neutralizing auto-immunoglobulin G mouse model.
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.
Coccia
M A
MA
Pharmacology-Pathology Department, Amgen, Inc., One Amgen Center Drive, M/S 99-1-A, Thousand Oaks, CA 91320, USA. mcoccia@amgen.com
Hartley
C
C
Sutherland
W
W
Del Castillo
J
J
McElroy
P
P
Pistillo
J
J
Tarpley
J E
JE
Molineux
G
G
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology*; D001327:Autoimmune Diseases / Q000209:etiology* / Q000276:immunology; D003114:Colony-Forming Units Assay; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000502:physiology; D006410:Hematopoiesis / Q000276:immunology; D019650:Hematopoietic Stem Cell Mobilization / Q000009:adverse effects; D006433:Hemocyanins / Q000276:immunology; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology*; D051379:Mice; D023421:Models, Animal; D009503:Neutropenia / Q000209:etiology* / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D015203:Reproducibility of Results; D013047:Specific Pathogen-Free Organisms
D001323:Autoantibodies; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D010047:Ovalbumin; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin