Recombinant glycosylated human interleukin-6 accelerates peripheral blood platelet count recovery in radiation-induced bone marrow depression in baboons

Abstract

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.

IL-6-induced anaemia in rats: possible pathogenetic implications for anaemia observed in chronic inflammations

“…The results of present study are in accordance with previous observations, which showed the ability of IL-6 to induce anaemia in different animal models and in humans [12,15]. Thus, a relationship between IL-6 and anaemia seems to be established.…”

“…Finally, sequestration of erythrocytes was mentioned as a possible explanation for IL-6 induced anaemia [12,15], whereas previously a shortened life span of erythrocytes was postulated to be involved in ACD [29]. No evidence for enhanced elimination of erythrocytes, from the circulation to the liver, was found after i.p.…”

“…Administration of IL-6 induced anaemia in experimental animals [12][13][14] and in humans [15,16]. The pathogenesis of this IL-6-induced anaemia has not been fully elucidated.…”

Structure, Stability and Biological Properties of a N‐terminally Truncated form of Recombinant Human Interleukin‐6 Containing a Single Disulfide Bond

“…To summarize, in this study we have described a useful procedure for the large-scale production and the detailed chemical, physicochemical and functional characterization of a recombinant mutant IL-6. Sufficient amounts of a clinical-grade cytokine are now available for future structure/function studies and for investigating its therapeutic use, specifically in platelet recovery after radiotherapy, chemotherapy (Kimura et al, 1990 ;Carrington et al, 1992), and bone marrow transplantation (Herodin et al, 1992).…”

Recombinant Human Ligand for MPL, Megakaryocyte Growth and Development Factor (MGDF), Stimulates Thrombopoiesis in Vivo in Normal and Myelosuppressed Baboons

“…It was possible to detect activity in the serum and urine of thrombocytopenic animals that stimulated the growth of megakaryocytic progenitors in vitro, yet purification of thrombopoietin remained elusive. Factors that can promote the in vitro proliferation of megakaryocytic progenitor cells, and to a lesser extent, indirectly stimulate in vivo thrombocytopoiesis, have been identified, including IL-3 [35], IL-6 [36][37][38], IL-1 [35], IL-11 [39,40] and GM-CSF [41]. However, stimulation of the terminal differentiative events in steady-state thrombocytopoiesis does not appear to be a primary role for most of these factors, as experiments with knock-out mice have demonstrated [42][43][44][45].…”