Colony-stimulating factors (CSF) are intriguing molecules, which are glycoproteins that control the production and even some functions of granulocytes and macrophages, the immune cells that are primarily responsible for protecting the body against infections. While their presence was suspected in the early part of the 20th century, it was only in 1965 that researchers observed the growth of white blood cells in colonies derived from one single cell each, called the precursor or progenitor cells.
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The colonies consisted of growing granulocytes. Their growth was in direct proportion to the presence of some factor called, for the time, colony-stimulating factor, or CSF. Today these factors are known to be of immense significance in the treatment of low white blood cell levels following chemotherapy in cancer patients.
Types of CSFs
There are four separate CSFs which have separate modes of actions, and are found in small amounts in tissue. They are called:
- GM-CSF or CSF2, which stimulates the proliferation of granulocytes, macrophages, and also eosinophils, as well as megakaryocytes, the progenitor cells of platelets, at high doses
- M-CSF or CSF1 which stimulates macrophage colony formation
- G-CSF or CSF3 which causes granulocyte colony formation but also granulocyte-macrophage colonies to a lesser extent
- Multi-CSF or IL-3 which stimulates colony formation for a broad spectrum of blood cells
History of CSF extraction
The first ones to be purified were GM-CSF and M-CSF in 1977, followed by IL-3 and G-CSF, from rats. Soon after, human CSFs were purified using human tumor cell lines. Still later, molecular biology techniques were successful in producing cloned cDNAs for all the four molecules in the couple of years from 1984 to 1986. They are produced in very minute amounts, except in the presence of infections or endotoxins, or other foreign antigens, when the level shoots up a thousand times within the span of a few hours.
The exception is M-CSF which is more stable. Overall, the CSFs are very responsive to external stimuli and able to regulate the rate of proliferation of blood cells. They act on specific receptors present on granulocytes and monocyte-macrophage cells, stimulating them to mature from progenitor cells to mature cells. This causes them to leave the blood stream and enter the cells via binding to the receptors, following which they are broken down.
The CSFs are essential to allow all blood cells in the granulocyte and monocyte series to divide, both the progenitor cells and their progeny. An S-shaped curve reflects the way in which these cells respond to CSF, with shorter cell cycles leading to faster cell division.
Again, they cause increased proliferation at each new turn of the reproduction wheel, and prevent apoptosis (programmed cell death). Thus, they are also necessary to the survival of hemopoietic cells. Each CSF acts on specific cell populations predominantly, such as G-CSF acting to produce 75% of granulocytes in normal conditions.
On the other hand, GM-CSF acts to promote the functions of mature cells rather than their formation per se.
M-CSF is required both to form and to mature macrophages, but also for tooth eruption and for successful gestations.
IL-3 is involved in responses to parasites involving mast cells and basophils, in the form of type IV hypersensitivity reactions.
All of them also act in harmony to regulate blood formation both in health and in disease, promoting or inhibiting the actions of each other to produce the right mix of cells and functions.
CSFs also promote faster maturation and improved survival as well as higher grades of function of mature cells. Along with stem cell factor, CSFs can promote the division of the earliest blood-forming cells. They also are capable of producing maturation in leukemic cell lines and may decide which way blood cell precursors mature, in the granulocyte or macrophage series, based upon events observed in the laboratory. They can also promote cell function in mature cells, including chemotaxis, oxidative events involved in cell metabolism, antibody-dependent phagocytosis and microbial killing.
Early research showed that the prior administration of CSF could enhance immunity in patients on chemotherapy if given before exposure to infections. However, excessively high levels of these molecules caused serious and life-threatening inflammation of many organs including the lung, muscles and bowel, itching of the skin refractory to treatment, and paralysis with rapid mortality, in mouse experiments using different CSFs.
The finding that GM-CSF and IL-3 are necessary for the division and survival of leukemic cells, and may even act as oncogenes to transform blood cells into leukemic cells, may mean that cell division must be imbalanced to favor the excessive and autonomous formation of one series of blood-forming cells, along with its gaining the power to stimulate its own growth through the secretion of these CSFs.
- G-CSF and GM-CSF have been used to increase the granulocyte levels in peripheral blood in cancer patients on chemotherapy, with a clear dose-dependent response, and so prevent falling neutrophil counts with fever following chemotherapy. This is associated with a higher risk of infection up to 60%, which not only requires intensive treatment but may delay chemotherapy or make lower doses necessary. This improves patient survival, in turn.
- G-CSF is used in non-Hodgkin’s lymphoma and breast carcinoma (early stage). Their use is associated with an almost 50% reduction in neutropenia with fever and death due to infection, while survival improves by 40%.
- A newly approved drug is polyethylene glycol (PEG)-conjugated G-CSF, also called pegylated G-CSF or pegfilgrastim. It is retained for a longer period in the body and can thus drastically reduce the number of injections required to allow normal chemotherapeutic schedules to go on, especially in older and more frail patients. Many major professional oncologic bodies now recommend that these factors be used to prevent infective complications due to neutropenia if a chemotherapy recipient has a 20% or more risk of febrile neutropenia, or other risk factors for such complications.
- CSFs may prevent the need for bone marrow transplantation in chemotherapy-induced aplastic anemia. The use of GM-CSF or G-CSF can push up peripheral blood stem cell (PBSC) counts, which can then be used to repopulate the blood with neutrophils and platelets, much faster than by bone marrow transplants using bone marrow cells, and comparable to the use of bone marrow grafts with CSF. CSF-stimulated PBSC grafting is now the preferred technology especially since the safety of the CSFs in the normal donors has been proved, because of its relative simplicity, high effectiveness, and range of application.
- CSFs can be used to prevent infection for years in conditions such as chronic neutropenia.
- GM-CSF can also help improve immunity by regulating dendritic cell development. These cells are an essential part of innate immunity as they present captured and processed antigens for antibody and cellular immune responses.
- The use of these CSFs to stimulate local immunity within a tumor and so shrink or remove it is presently being studied.
- A recent area of interest is CSF use to help restore normal bone marrow function in victims of accidental radiation exposure.