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

Objective. Therapeutic use of recombinant human cytokines in humans can res ult in the generation of drug-specific antibodies, To predetermine the maxi mum potential effects of a granulocyte colony-stimulating factor (G-CSF) ne utralizing auto-immunoglobulin G (auto-IgG) response during recombinant hum an G-CSF therapy, we developed a mouse model of mouse C-CSF (mG-CSF) neutra lizing auto-IgG response. Materials and Methods. Mice were immunized and boosted with mG-CSF chemical ly conjugated to either keyhole limpet hemocyanin or ovalbumin on an altern ating schedule. Sera were analyzed for mG-CSF-specific titers and full bloo d counts were performed on a Technicon H-1E, On day 252, tissues were colle cted for histology, IgG was protein ii. affinity purified from pooled mG-CS F autoimmune sera, Results. Mice immunized with mG-CSF conjugates produced mG-CSF-specific aut o-IgG responses that lasted for the length of the study. Significant neutro penia (p(max) < 0.004) was concurrent with the rise in mG-CSF-specific IgG titers, However, neutrophil counts remained at <similar to>20% of preimmuni zation levels through day 252, Endogenous mG-CSF neutralizing auto-IgG had no significant effect on hemoglobin, erythrocyte, lymphocyte, eosinophil, b asophil, and platelet counts, and had minor, transient, or no effects on mo nocyte counts. Bone marrow colony assays from mG-CSF autoimmune mice demons trated no significant effect of G-CSP neutralization on the numbers or prol iferative capacity of preneutrophil lineage progenitors. purified Ige from mG-CSF autoimmune mice neutralized mG-CSF in vitro. Conclusion. 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, (C)2001 International Society f or Experimental Hematology, Published by Elsevier Science Inc.