Recombinant glycosylated human interleukin-6 accelerates peripheral blood platelet count recovery in radiation-induced bone marrow depression in baboons.
This report was aimed at confirming the potential clinical use for a genetically engineered glycosylated human interleukin-6 (rhIL-6) in hematopoiesis. Its tolerance and efficacy were assessed on hematopoietic restoration after neutron radiation-induced bone marrow injury on baboons, which represent an adequate model of parallelism for studying hematology in the human. The particular neutron radiation absorption pattern in the body allows the preservation of underexposed bone marrow areas that mimics an autotransplantation-like situation. An initial dose finding study (1 microgram up to 20 micrograms/kg/d for 8 consecutive days) in normal baboons established a dose-dependent response regarding the peripheral platelet count (range of increase, 1.5- to 4-fold). A significant elevation in white blood cell (WBC) count, as well as a substantial reversible normochromic normocytic anemia, were observed for the highest doses only (10 and 20 micrograms/kg/d). All rhIL-6 administered doses were clinically well tolerated. In myelosuppressed baboons, a selected dose of 10 micrograms/kg/d of rhIL-6 for 13 consecutive days significantly lessened the degree of induced thrombocytopenia as compared with the control group (P = .01) and shortened the time to occurrence of the nadir, showing that the onset of recovery occurs much earlier, ie, an average of 5 days (P = .003), in the treated group. Moreover, this accelerated platelet recovery is evidenced by an 8-day shorter mean time back to baseline values (P = .03) in the rhIL-6--treated animals. At this dose no effect was observed on the WBC recovery pattern. Importantly rhIL-6 did not accentuate the radiation-induced anemia and was clinically well tolerated. All tested monkeys recovered from their induced pancytopenia and no animal loss was recorded. IL-6, tumor necrosis factor, and IL-1 blood measurements are reported. In conclusion, rhIL-6 is a potent thrombopoietic factor for the treatment of induced thrombocytopenia in nonhuman primates at a clinically well-tolerated dose.
Herodin
F
F
Department of Radiobiology, Centre de Recherches du Service de Santé des Armées, La Tronche, France.
Mestries
J C
JC
Janodet
D
D
Martin
S
S
Mathieu
J
J
Gascon
M P
MP
Pernin
M O
MO
Ythier
A
A
D000818:Animals; D001853:Bone Marrow / Q000528:radiation effects*; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D006031:Glycosylation; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000494:pharmacology*; D007958:Leukocyte Count / Q000187:drug effects* / Q000528:radiation effects; D010215:Papio; D010976:Platelet Count / Q000187:drug effects* / Q000528:radiation effects; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors
D006454:Hemoglobins; D015850:Interleukin-6; D011994:Recombinant Proteins