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Demonstration of a blood-bone marrow barrier to macrophage colony-stimulating factor
R K Shadduck1, A Waheed, E J Wing
1Department of Medicine, Montefiore Hospital, Pittsburgh, PA 15213.
Abstract:
Several previous studies suggested that murine macrophage colony-stimulating factor (CSF-1) might have impaired access to hematopoietic cells in the marrow. The apparent lack of hematopoietic responses to exogenous CSF and the finding of available or unoccupied CSF receptors despite saturating CSF levels in the serum led to studies of a potential blood-bone marrow barrier for this factor. Groups of mice were injected with pure unlabeled CSF-1 by either intravenous (IV) or intraperitoneal (IP) routes. Marrow and spleen cells were obtained at intervals after injection, held at 0 degree C, and assessed for changes in binding of 125I-CSF. Saturation of all available CSF receptors is achieved in vitro with 100 to 150 U CSF/mL. Despite achieving serum levels of 5,000 to 7,000 U/mL after IV injection of 25,000 units of CSF, less than 50% of the marrow receptors and less than 85% of the splenic receptors were saturated or downregulated. The decline in receptor availability was transient, with return of receptor sites in two to four hours. Increasing the IV dose to 125,000 units increased serum CSF values to approximately 20,000 U/mL and led to a virtual disappearance of available receptors for two to three hours. When administered IP, only approximately 40% of marrow and 80% of splenic receptors were affected for two hours. It was necessary to increase the dose of CSF to 250,000 units IP to saturate or downregulate receptors for three to four hours after injection. These observations indicate a marked blood-bone marrow barrier and lesser blood-spleen barrier for the transfer of serum CSF to responsive hematopoietic cells in vivo.
Insights
A blood-bone marrow barrier limits access for macrophage colony-stimulating factor (CSF-1) to hematopoietic cells. Even high serum CSF-1 levels only partially saturate marrow receptors, indicating restricted transfer in vivo.
Area of Science:
- Hematology
- Immunology
- Cell Biology
Background:
- Previous studies suggested impaired access of macrophage colony-stimulating factor (CSF-1) to hematopoietic cells in bone marrow.
- Observed lack of hematopoietic responses to exogenous CSF and unoccupied CSF receptors indicated a potential blood-bone marrow barrier.
Purpose of the Study:
- To investigate the existence and extent of a blood-bone marrow barrier for CSF-1 transfer.
- To assess the impact of different administration routes (intravenous vs. intraperitoneal) and doses of CSF-1 on receptor saturation in marrow and spleen.
Main Methods:
- Mice were injected with CSF-1 via IV or IP routes.
- Marrow and spleen cells were collected at intervals post-injection.
- Binding of 125I-CSF to cell receptors was measured to assess receptor saturation or downregulation.
Main Results:
- High serum CSF-1 levels (5,000-7,000 U/mL) after IV injection only saturated <50% of marrow receptors and <85% of spleen receptors.
- A higher IV dose (125,000 units) achieved near-complete receptor saturation for 2-3 hours.
- IP administration showed less receptor saturation, requiring higher doses for comparable effects.
Conclusions:
- A significant blood-bone marrow barrier restricts CSF-1 transfer to hematopoietic cells in vivo.
- A less pronounced blood-spleen barrier also exists for CSF-1.
- These findings highlight the challenges in achieving therapeutic levels of CSF-1 in the bone marrow via systemic administration.