scholarly journals In vivo effects of recombinant human interleukin-6 in primates: stimulated production of platelets

Blood ◽  
1990 ◽  
Vol 75 (8) ◽  
pp. 1602-1605 ◽  
Author(s):  
S Asano ◽  
A Okano ◽  
K Ozawa ◽  
T Nakahata ◽  
T Ishibashi ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
C Reactive Protein ◽  
Subcutaneous Injections ◽  
Acid Glycoprotein ◽  
Reactive Protein ◽  
Morphologic Analysis ◽  
In Vivo Effects ◽  
Dose Dependent ◽  
Second Peak

Abstract In cynomolgus monkeys, twice daily subcutaneous injections of recombinant human interleukin-6 (rhIL-6) at doses of 5 to 80 micrograms/kg/d for 14 consecutive days caused dose-dependent increases in platelet count, usually continuing for more than 1 week after cessation of the injections. The count reached a level approximately twofold or more above the preinjection level even at 5 micrograms/kg/d, and at doses of more than 20 micrograms/kg/d, the increase became biphasic with a higher second peak 3 days after cessation of the injections. Morphologic analysis of the bone marrow after the 7 day- injections with 80 micrograms/kg/d revealed a marked increment in size of megakaryocytes compared with control, indicating the promotion of megakaryocyte maturation. Other changes attributable to the rhIL-6 treatment include dose-dependent loss of body weight, anemia, neutrophilia and monocytosis, elevation of serum C-reactive protein and alpha-1 acid glycoprotein levels, and decrease of serum albumin; all of which returned to normal within 1 week after cessation of the injections and were tolerable at doses of less than 10 micrograms/kg/d. These findings suggest that rhIL-6 may be an effective strategy for the treatment of thrombocytopenia.

scholarly journals In vivo effects of recombinant human interleukin-6 in primates: stimulated production of platelets

Blood ◽  
1990 ◽  
Vol 75 (8) ◽  
pp. 1602-1605 ◽  
Author(s):  
S Asano ◽  
A Okano ◽  
K Ozawa ◽  
T Nakahata ◽  
T Ishibashi ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
C Reactive Protein ◽  
Subcutaneous Injections ◽  
Acid Glycoprotein ◽  
Reactive Protein ◽  
Morphologic Analysis ◽  
In Vivo Effects ◽  
Dose Dependent ◽  
Second Peak

In cynomolgus monkeys, twice daily subcutaneous injections of recombinant human interleukin-6 (rhIL-6) at doses of 5 to 80 micrograms/kg/d for 14 consecutive days caused dose-dependent increases in platelet count, usually continuing for more than 1 week after cessation of the injections. The count reached a level approximately twofold or more above the preinjection level even at 5 micrograms/kg/d, and at doses of more than 20 micrograms/kg/d, the increase became biphasic with a higher second peak 3 days after cessation of the injections. Morphologic analysis of the bone marrow after the 7 day- injections with 80 micrograms/kg/d revealed a marked increment in size of megakaryocytes compared with control, indicating the promotion of megakaryocyte maturation. Other changes attributable to the rhIL-6 treatment include dose-dependent loss of body weight, anemia, neutrophilia and monocytosis, elevation of serum C-reactive protein and alpha-1 acid glycoprotein levels, and decrease of serum albumin; all of which returned to normal within 1 week after cessation of the injections and were tolerable at doses of less than 10 micrograms/kg/d. These findings suggest that rhIL-6 may be an effective strategy for the treatment of thrombocytopenia.

Menstrual cycle-associated changes in blood levels of interleukin-6, α1 acid glycoprotein, and C-reactive protein

1997 ◽  
Vol 130 (1) ◽  
pp. 69-75 ◽  
Author(s):  
Bernd Jilma ◽  
EVA Dirnberger ◽  
Isabella Löscher ◽  
Anna Rumplmayr ◽  
Jörg Hildebrandt ◽  
...  
Keyword(s):  
Menstrual Cycle ◽  
Interleukin 6 ◽  
Blood Levels ◽  
C Reactive Protein ◽  
Acid Glycoprotein ◽  
Reactive Protein

The Effect of Factor Xa/Phospholipid Infusion on the Acute Phase Response in Baboons

1997 ◽  
Vol 77 (02) ◽  
pp. 308-311 ◽  
Author(s):  
Egbert K O Kruithof ◽  
Diane Agay ◽  
Jean Claude Mestries ◽  
Marie-Paule Gascon ◽  
Arnaud Ythier
Keyword(s):  
Acute Phase ◽  
Interleukin 6 ◽  
Acute Phase Response ◽  
Tissue Injury ◽  
Peak Plasma ◽  
Factor Xa ◽  
Phase Response ◽  
C Reactive Protein ◽  
Reactive Protein

SummaryDisseminated intravascular coagulation (DIC) is a frequent complication of septicemia or tissue injury and may be accompanied by elevations of interleukin-6, a mediator of the acute phase response. It is not known whether thrombin or fibrin deposition may directly induce an acute phase response. To study this, we employed a baboon model of in vivo thrombin generation, induced by the administration of purified bovine Factor Xa and phospholipid vesicles. Two Xa/phospholipid dosages were used, a low dosage (2 animals) leading to a rapid 49% decrease in fibrinogen and a high dosage (two injections at 5h interval; 3 animals) leading to complete fibrinogen depletion. Thereafter, fibrinogen levels increased in both treatment groups, reached a maximum of 2.52 ± 0.23 g/1 (mean ± SE, n = 5; p <0.01 with respect to basal levels) at day 2, and returned to normal by day seven. In five control (injection of 0.15% NaCl) baboons no significant changes of fibrinogen were observed (maximal values: 1.88 ± 0.12 g/1). Serum concentrations of C-reactive protein, an acute phase protein, increased from 3.7 ± 0.4 mg/1 to a maximum of 33.0 ± 7.3 at day one, which was five-fold higher (p <0.01) than in control animals at day one (6.2 ± 0.5 mg/1). Transient increases were observed within 6 h for interleukin-6 from basal values of 6.2 ± 1.7 ng/1 to peak plasma levels of 42.9 ±21.4 ng/1, a value threefold higher (p = 0.07) than in control animals (14.8 ± 4.0 ng/1).The preliminary results of this observational study suggest that factor Xa/phospholipid infusion is followed by an acute phase response, leading after one day to significant increases of fibrinogen and of C-reactive protein.

scholarly journals Thrombopoietic effects and toxicity of interleukin-6 in patients with ovarian cancer before and after chemotherapy: a multicentric placebo- controlled, randomized phase Ib study

Blood ◽  
1995 ◽  
Vol 85 (9) ◽  
pp. 2347-2353 ◽  
Author(s):  
V D'Hondt ◽  
Y Humblet ◽  
T Guillaume ◽  
S Baatout ◽  
C Chatelain ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
C Reactive Protein ◽  
Platelet Recovery ◽  
Phase Ib ◽  
Reactive Protein ◽  
Before And After ◽  
Systemic Symptoms ◽  
Dose Levels ◽  
Dose Dependent Increase ◽  
Dose Dependent

Recombinant human interleukin-6 (IL-6) has previously been shown to increase platelet counts in normal and sublethally irradiated mice, dogs, and primates. To assess its tolerance and efficacy in clinical use, we performed a randomized phase Ib study in patients with ovarian carcinoma. IL-6 was administered during an initial 7-day cycle before any chemotherapy. Beginning 7 days later, six cycles of chemotherapy containing carboplatin were administered every 3 weeks. During chemotherapy cycles 2 to 6, IL-6 was administered from day 4 through day 17 at escalating dose levels from 0.5 to 10 micrograms/kg/d. At each level, three patients received IL-6 and one patient received a placebo. During the prechemotherapy cycle of IL-6, a dose-dependent increase in platelet count was observed from day 12 to 15 and was maximal on day 15 (r = .77; P < .01). The median ploidy of bone marrow megakaryocytes shifted from 16 N to 32 N after 7 days of the initial prechemotherapy IL-6 administration. Dose-dependent increases in C-reactive protein (CRP) and fibrinogen levels were observed on day 8 (P < .0001 for both). A significant decrease in hemoglobin level occured rapidly after initiation of IL-6 therapy and was maximal on day 8 (P < .001). When given after chemotherapy, IL-6 accelerated platelet recovery after chemotherapy cycles 2 to 6. Postponements of scheduled chemotherapy due to thrombocytopenia were less frequent in patients treated with IL-6. No difference in either neutrophils or peripheral blood progenitor assays was observed during or after IL-6 treatment. Toxicity of IL-6 appeared mild and was not dose-limiting up to 10 micrograms/kg/d. Systemic symptoms such as fever, headache, and myalgia were the main side effects and were easily relieved by acetaminophen administration. No biologic toxicity was observed. The data indicate that IL-6 is a well-tolerated cytokine and capable of accelerating platelet recovery in patients receiving chemotherapy.

scholarly journals Measurement of whole body interleukin-6 (IL-6) production: prediction of the efficacy of anti-IL-6 treatments

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3123-3131 ◽  
Author(s):  
ZY Lu ◽  
H Brailly ◽  
J Wijdenes ◽  
R Bataille ◽  
JF Rossi ◽  
...  
Keyword(s):  
Immune Complexes ◽  
Interleukin 6 ◽  
Acute Phase Protein ◽  
Whole Body ◽  
Tumor Proliferation ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Phase Protein ◽  
New Strategies

A major limitation on the therapeutic use of cytokine antagonists is that the amount of cytokine to be neutralized in vivo is not presently known. We previously reported that anti-interleukin-6 (IL-6) monoclonal antibody (MoAb) administered to a patient with multiple myeloma (MM) induced high amounts of IL-6 to circulate in the form of monomeric immune complexes. Based on this observation, the present study developed a new methodology to estimate daily IL-6 production in 13 patients with MM or renal cancer who received anti-IL-6 MoAb. Treatment was considered effective when the production of C-reactive protein (CRP) was inhibited. The production of this acute-phase protein by hepatocytes is dependent on the activation of IL-6 gp130 transducer. Inhibition of tumor proliferation was also evaluated in patients with MM. In 7 of 13 patients whose CRP production was completely inhibited (> 96%) and who showed some antitumoral effects, whole-body IL-6 production in vivo was less than 18 micrograms/d (median, 5.7 micrograms/d; range, 0.5 to 17.5 micrograms/d). In the other 6 patients, subtotal inhibition of CRP production and a lack of antitumoral response were associated with high IL-6 production (median, 180 micrograms/d; range, 18 to 358 micrograms/d). These in vivo observations were consistent with mathematical modeling that predicted that anti-IL-6 MoAb treatment would be efficient only in low IL-6 producers. These data indicate the difficulty of neutralizing IL-6 with a single anti-IL-6 MoAb in vivo and call for new strategies to avoid accumulation of IL-6 in the form of stable immune complexes.

scholarly journals Measurement of whole body interleukin-6 (IL-6) production: prediction of the efficacy of anti-IL-6 treatments

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3123-3131 ◽  
Author(s):  
ZY Lu ◽  
H Brailly ◽  
J Wijdenes ◽  
R Bataille ◽  
JF Rossi ◽  
...  
Keyword(s):  
Immune Complexes ◽  
Interleukin 6 ◽  
Acute Phase Protein ◽  
Whole Body ◽  
Tumor Proliferation ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Phase Protein ◽  
New Strategies

Abstract A major limitation on the therapeutic use of cytokine antagonists is that the amount of cytokine to be neutralized in vivo is not presently known. We previously reported that anti-interleukin-6 (IL-6) monoclonal antibody (MoAb) administered to a patient with multiple myeloma (MM) induced high amounts of IL-6 to circulate in the form of monomeric immune complexes. Based on this observation, the present study developed a new methodology to estimate daily IL-6 production in 13 patients with MM or renal cancer who received anti-IL-6 MoAb. Treatment was considered effective when the production of C-reactive protein (CRP) was inhibited. The production of this acute-phase protein by hepatocytes is dependent on the activation of IL-6 gp130 transducer. Inhibition of tumor proliferation was also evaluated in patients with MM. In 7 of 13 patients whose CRP production was completely inhibited (> 96%) and who showed some antitumoral effects, whole-body IL-6 production in vivo was less than 18 micrograms/d (median, 5.7 micrograms/d; range, 0.5 to 17.5 micrograms/d). In the other 6 patients, subtotal inhibition of CRP production and a lack of antitumoral response were associated with high IL-6 production (median, 180 micrograms/d; range, 18 to 358 micrograms/d). These in vivo observations were consistent with mathematical modeling that predicted that anti-IL-6 MoAb treatment would be efficient only in low IL-6 producers. These data indicate the difficulty of neutralizing IL-6 with a single anti-IL-6 MoAb in vivo and call for new strategies to avoid accumulation of IL-6 in the form of stable immune complexes.

scholarly journals Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia

Blood ◽  
1991 ◽  
Vol 78 (5) ◽  
pp. 1198-1204 ◽  
Author(s):  
B Klein ◽  
J Wijdenes ◽  
XG Zhang ◽  
M Jourdan ◽  
JM Boiron ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Side Effects ◽  
Interleukin 6 ◽  
Myeloma Cell ◽  
S Phase ◽  
Cell Leukemia ◽  
C Reactive Protein ◽  
Myeloma Cells ◽  
Reactive Protein

Abstract A patient with primary plasma cell leukemia resistant to chemotherapy was treated for 2 months with daily intravenous injections of anti- interleukin-6 (IL-6) monoclonal antibodies (MoAbs). The patient's clinical status improved throughout the treatment and no major side effects were observed. Serial monitoring showed blockage of the myeloma cell proliferation in the bone marrow (from 4.5% to 0% myeloma cells in the S-phase in vivo) as well as reduction in the serum calcium, serum monoclonal IgG, and the serum C-reactive protein levels. The serum calcium and serum monoclonal IgG corrected by approximately 30%, whereas the C-reactive protein corrected to undetectable levels during treatment. No major side effects developed, although both platelet and circulating neutrophil counts decreased during anti-IL-6 therapy. A transient immunization was detected 15 days after the initiation of the treatment, which could explain the recovery of myeloma cell proliferation after 2 months of treatment (2% myeloma cells in the S phase). In conclusion, this first anti-IL-6 clinical trial demonstrated the feasibility of injecting anti-IL-6 MoAbs, and also a transient tumor cytostasis and a reduction in IL-6-related toxicities. It gave insight into the major biologic activities of IL-6 in vivo and may serve as a basis for further development of anti-IL-6 therapy in myeloma and other IL-6-related diseases.

scholarly journals Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia

Blood ◽  
1991 ◽  
Vol 78 (5) ◽  
pp. 1198-1204 ◽  
Author(s):  
B Klein ◽  
J Wijdenes ◽  
XG Zhang ◽  
M Jourdan ◽  
JM Boiron ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Side Effects ◽  
Interleukin 6 ◽  
Myeloma Cell ◽  
S Phase ◽  
Cell Leukemia ◽  
C Reactive Protein ◽  
Myeloma Cells ◽  
Reactive Protein

A patient with primary plasma cell leukemia resistant to chemotherapy was treated for 2 months with daily intravenous injections of anti- interleukin-6 (IL-6) monoclonal antibodies (MoAbs). The patient's clinical status improved throughout the treatment and no major side effects were observed. Serial monitoring showed blockage of the myeloma cell proliferation in the bone marrow (from 4.5% to 0% myeloma cells in the S-phase in vivo) as well as reduction in the serum calcium, serum monoclonal IgG, and the serum C-reactive protein levels. The serum calcium and serum monoclonal IgG corrected by approximately 30%, whereas the C-reactive protein corrected to undetectable levels during treatment. No major side effects developed, although both platelet and circulating neutrophil counts decreased during anti-IL-6 therapy. A transient immunization was detected 15 days after the initiation of the treatment, which could explain the recovery of myeloma cell proliferation after 2 months of treatment (2% myeloma cells in the S phase). In conclusion, this first anti-IL-6 clinical trial demonstrated the feasibility of injecting anti-IL-6 MoAbs, and also a transient tumor cytostasis and a reduction in IL-6-related toxicities. It gave insight into the major biologic activities of IL-6 in vivo and may serve as a basis for further development of anti-IL-6 therapy in myeloma and other IL-6-related diseases.

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