Ma. Coccia et al., Prolonged neutropenia in a novel mouse granulocyte colony-stimulating factor neutralizing auto-immunoglobulin G mouse model, EXP HEMATOL, 29(1), 2001, pp. 59-67
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.