**4. Stem cell mobilization from patients with autoimmune diseases**

Originally, HSCs were collected directly from the bone marrow donors by repeated aspirations performed under epidural or general anesthesia. Subsequently, to facilitate hematopoietic reconstitution and avoid the discomfort associated with multiple bone punctures, as well as the need for operating room and general anesthesia, the most common method of collecting HSCs has become mobilization from the peripheral blood. Since negligible HSCs are detectable in the peripheral blood during steady state, either a hematopoietic growth factor such as granulocyte colony-stimulating factor (G-CSF) or chemotherapy (usually cyclophosphamide) with or without G-CSF is necessary in order to mobilize HSCs from the marrow to the vasculature where it can be easily collected [60].

Hematopoietic growth factors used to mobilize stem cells also have cytokine immunemodulating effects [61] and, depending on growth factor and autoimmune disease, may

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either exacerbate or ameliorate disease severity. For example, in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), growth factors such as Flt-3 ligand, stem cell factor (SCF), and G-CSF exacerbate disease, while thrombopoietin (TPO) mobilizes stem cells without affecting disease severity. G-CSF may also cause an exacerbation of MS, sometimes with significant neurological deterioration [60, 62]. In both EAE and MS, simultaneous use of daily corticosteroids or infusion of cyclophosphamide prior to starting G-CSF prevents disease flares [62]. The same may be for RA where G-CSF may cause an increase in joint swelling, tenderness and pain that responds to corticosteroids. On the other hand, G-CSF has not been reported to exacerbate scleroderma. Based on the above, growth factors selected for mobilizing HSCs from patients with autoimmune diseases need to be considered on a disease-specific basis. Hematopoietic growth factors that stimulate production of proinflammatory cytokines or alter trafficking of neutrophils, lymphocytes or dendritic cells may exacerbate some autoimmune diseases. This effect may be prevented by either administration of corticosteroids or mobilization with combined cyclophosphamide and G-CSF. Mobilization with chemotherapy alone or in combination with G-CSF may cause neutropenic fevers and infection-related mortality if prophylactic antibacterial and antifungal antibiotics are not utilized. This can be prevented if only G-CSF will be used. Nevertheless, combined cyclophosphamide with G-CSF for mobilization will sum in higher stem cell yields, an in vivo purge effect by selectively killing lymphocytes in cell cycle, and a disease-ameliorating effect.
