A team of Japanese researchers uncovered the mechanism for side effects such as fever and bone tissue pain caused by G-CSF, which is widely used for peripheral bloodstream hematopoietic stem cell harvesting (PBSCH). This is an important way of hematopoietic stem cell transplantation (HSCT) used to treat hematological malignancies such as leukemia.

G-CSF is essential for treatment of hematological malignancies and other types of malignancies, but the mechanism for its unfavorable side effects has not been elucidated so far. The findings from this research revealed not only the system of the unfavorable effects of G-CSF, but also a new function associated with neutrophils, a type of blood cell which was previously recognized just like a consumer of invading substances. This research can lead to much better understanding of the homeostasis of blood-forming (hematopoietic) cells along with improving the methods of PBSCH. The findings, by a study group led by Junior Associate Professor KATAYAMA Yoshio and graduate student KAWANO Yuko from the Kobe University or college Graduate School of Medicine, Hematology, were published within the online version of Blood on November 9 (Japan time).

In recent years, there has been a growing need for HSCT to treat hematological malignancies. HSCT is done to rescue an ordinary generation of blood cells (hematopoiesis) after the treatment of malignancies. Hematopoietic stem cells are usually found in the bone marrow, but under certain conditions they are released into the peripheral blood (regular blood vessels) where they can be harvested within blood samples.

G-CSF stimulates the bone marrow to mobilize stem cells into the peripheral blood. G-CSF has been widely used for PBSCH because it is a safe technique. However , the mechanism for the mobilization of hematopoietic tissues by G-CSF largely remained unclear, and there is no persuading reason to explain the existence of “poor mobilizers” (people who shown poor mobilization of hematopoietic cells to peripheral bloodstream by G-CSF which results in the insufficiency of hematopoietic cells for HSCT) and the mechanism of unfavorable results such as fever and bone pain caused by G-CSF. Knowledge of those mechanisms could largely contribute to the improvement associated with transplantation therapy.

Professor Katayama’s research team focused on the effectiveness of standard anti-inflammatory drugs in treating fever plus bone pain caused by G-CSF. These anti-inflammatory drugs reduce the production of PGE2, which is involved in inflammation and discomfort, so the group expected that PGE2 might be the cause of undesirable effects by G-CSF.

Using mouse versions to test this hypothesis, they discovered that PGE2 inhibited the particular mobilization of hematopoietic stem cells to peripheral bloodstream, and that blood cells produced PGE2 by the treatment of G-CSF. Furthermore, they revealed that, among blood cells, neutrophils produced PGE2 by G-CSF-induced stress stimulation (sympathetic neural stimulation). The researchers investigated the fever response within denervated mice by neurotoxin and neutrophil-depleted mice simply by antibodies, and displayed that in these mice fever brought on by G-CSF was diminished. PGE2 also affected osteoblastic cellular material in the bone marrow to increase osteopontin (OPN), an identified inhibiting factor of stem cell mobilization to peripheral blood which resulted in decreases in the numbers of mobilized originate cells.

These findings displayed that the manufacturing of PGE2 by neutrophils governed by the sympathetic anxious system is behind the unpleasant symptoms caused by G-CSF, which is one of the causes of suppression of stem cell mobilization. Depending on this discovery, researchers now have information to treat unfavorable associated with G-CSF as well as to predict the currently unpredictable poor mobilizers and treat them using OPN antibodies.

Because sympathetic nerve stimulation occurs under stress conditions, the truth that sympathetic signals stimulate neutrophils to produce the inflammatory PGE2 means that highly-motile neutrophils may be involved in stress-related inflammation within the whole body. These facts indicate the possibility that neutrophils are also associated with carcinogenesis, the progression of cancer, autoimmune disorders plus hardened arteries.

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