Hematologic and bone marrow changes after short- and long-term administration of two recombinant bovine granulocyte colony-stimulating factors.

Colony-stimulating factors are a category of glycoproteins that are instrumental in the regulation of hematopoiesis and inflammation. This investigation documented the clinical bone marrow and peripheral blood responses to short-term and long-term administration of a recombinant bovine granulocyte colony­ stimulating factor (rb-GCSF) and an analog, where the cysteine at position 17 was substituted with a serine (rb­ GCSF ser!'). The colony-stimulating factors produced the expected changes in the hematologic findings of the bovine subjects in the study, and there was a cell-specific response to the compounds. The sustained neutrophilia in the long-term study indicates that the bovine species can tolerate the administration of recombinant forms of bovine GCSF for extended periods of time without detectable adverse side effects. The neutrophils from the short-term study revealed no apparent fluctuation, either as enhanced or reduced capability to reduce nitro blue tetrazolium as compared to pretreatment neutrophils. The administration of both recombinant forms ofGCSF produced large increases in the bone marrow myeloid: erythroid (M: E) ratio concomitantly with the neutro­ philias. This is the first preliminary report documenting the bone marrow response of cattle to the native and recombinant (rb-GCSF ser'") forms of bovine GCSF. As nonantibiotic therapeutic modalities become a press.5.6.9.17 Subcutaneous administration of rh-GCSF more sought after goal, colony-stimulating factors that to adult lactating dairy cows results in a dose-depen­ are capable of modulating the hematologic parameters dent increase in the number ofcirculating neutrophils.' within hours of administration will become of great At a "screening dose" of 1 j.Lg/kg, rh-GCSF adminis­ interest. 22 Many infectious disease processes in farm tered to three study subjects produced a three- to four­ animal adults> and neonates-" require an adequate fold increase in peripheral blood mature neutrophil neutrophil response in order to avert serious clinical counts by day 12 of the trial. The "priming dose" consequences. The compounds examined in this series treatment group of four lactating dairy cows (3 j.Lg/kg of experiments may present an unusual opportunity of rh-GCSF) produced a three- to fivefold increase in for the clinician to intervene and aid the patient in peripheral blood mature neutrophil counts and two­ nonspecific host defense. to threefold increases in white blood cell counts by day Granulocyte colony-stimulating factor (GCSF) is 5 of the trial. In these studies, the milk somatic cell produced by fibroblasts and keratinocytes-t-a-" and is count was not statistically greater than the baseline required for the growth, survival, and differentiation values in any of the control or rh-GCSF treatment ofgranulocytic cells in vitro and is presumed to possess groups.' At the highest doses reported (10 j.Lg/kg once a similar role in vivo." Recombinant human (rh)-GCSF daily), this neutrophilia was characterized as possess­ is a glycoprotein with an apparent molecular weight of ing an initial left shift with the appearance ofimmature 20 kd. Target cells in hematopoietic tissues are undif- forms of neutrophils (band neutrophils, metamyelo­ ferentiated granulocytic precursor cells that express the cytes, and myelocytes) in circulation within 2 days of GCSF receptor gene.' GCSF manifests a short half-life the initial treatrnent.s This investigation sought to doc­ in circulation and it is rapidly cleared from the blood ument the clinical bone marrow and peripheral blood