Cancer: The Amazing World of Cytokines
In my last article, I introduced you to the world of cytokines. For some, the article may have been a little technospeak heavy, but its the basic concepts that need to be remembered. Simply, there are these proteinaceous regulators that control practically everything in our body, cancer included. Over the past thirty years, the study of cytokines has become a science all on its own. Understanding how these various protein-chemicals regulate and modify cell reactions is still in its infancy. It is not merely a case of adding the cytokine to the cells, but knowing exactly how much to add and when to add it. The major concern of pharmacology regarding cytokines is the result of there now being plentiful data showing an association between gross changes in their production and pathophysiological or disease processes. Despite the enigmatic role of cytokines in diseases, we now use them routinely even though in the themselves they can cause disease. We still need to learn more regarding the secretion of cytokines and their expression.
Choosing the Correct Cytokine
Basically, cytokines can be divided into two specific groups. The first group consists of growth factors, such as IL2, IL7 and IL15. The second group consists of immune modulators such as IL12 and IFNγ. Growth factors when expressed will improve cell numbers (quantity) by prolonging T cell survival and expansion. But to date, none of these cytokines has been associated with T cell immortalization (cells reproducing forever). For infusion protocols of immunotherapy, the impact on quantity is incremental and manageable as long as the cytokines are added in the correct quantity and at the right time. In contrast, immune modulators like IL12 make T cells more potent (quality) without affecting cell numbers. Where these cytokines take on special significance, however, is in engraftment protocols. With 1011or more cells post-recovery secreting cytokine, high systemic exposures may create a risk that is off-target and potentially life-long. Therefore ensuring that only the correct cytokines are being released and in the correct quantity is essential lest the potential treatment actually becomes the cause of potentiated disease and even death. Basically, finding the on/off switch is key to our controlling and managing the use of cytokines.
Varieties of Cytokines
Currently, there are more than 200 cytokines recognized. In contrast to hormones, cytokines are small polypeptides and glycoproteins usually produced by a variety of cell types. The biological effects of several cytokines often overlap and individual cytokines can possess multiple regulatory functions. A further way of categorizing cytokines is by whether they are produced by T-helper cells Type 1 or Type 2. Th1 cells will produce IFN-γ, interleukin IL-2, IL-15 and lymphotoxin TNF-β. The Th2 cells produce IL-4, IL-5, IL-6, IL-9 and IL-13. Both Th1 and Th2 cells produce IL-10. The Th1 cytokines inhibit growth of intracellular pathogens (viruses, bacteria, fungi) and tumour cells. They enhance the delayed type hypersensitivity, phagocytosis, oxidative burst, inflammatory reactions and expression of class I and II MHC molecules. Simply put, in cancer, it is the Th1 cytokines that we are most interested in.
The Th2 cytokines inhibit growth of extracellular parasites and suppress phagocytosis. They augment B cell proliferation, drive antibody production and switch IgG to IgE class of antibodies. They are associated with the development of allergic and related IgE-mediated diseases. So when we think infection, then we think Th2 cells.
The function of cytokines in not always to enhance the immune response. But depressing the response has advantages as well. Both TGF-β and IL-10 negatively regulate production of Th1 and Th2 cytokines. Their overexpression may impair the immune mechanisms directed against pathogens and tumour antigens. IL-10 possesses antifibrotic activities and may be valuable as a therapeutic cytokine for patients with liver cirrhosis. The anti-inflammatory effects of IL-10 have led to its use in hyper-inflammatory states such as psoriasis, organ transplantation and Crohn’s disease (Spellberg and Edwards, 2001). TGF-b is a multifunctional polypeptide that stimulates synthesis of many components of extracellular matrix, such as collagens, fibronectin and proteoglycans. Increased production of TGF-β1 is associated with normal reparative as well as pathological fibrotic processes in many organs.
It remains unlikely that the therapeutic usage of any individual cytokine can provide complete resolution of the disease or cancer. The major limitation is the pleiotropic nature of cytokines and integrated alterations that occur within the cytokine network in a diseased host that we don’t understand as yet. The enhancement of efficacy of immunotherapeutic treatments using cytokine stimulation will require more research into their exact function and nature as well as designing more complex and novel strategies for the treatment of cancer in the future. It is no longer acceptable for immunotherapy companies/labs/hospitals just to add cytokines and hope for the best without having some preconceived knowledge of the outcome.
Drugs with more specific effects on secretion of cytokines are required. Studies of prospective drug candidates of both natural and synthetic origin need more complex analysis of the effects within the cytokine network. At present we work with very limited knowledge of cytokines in our immunotherapeutic treatments, barely scraping the potential surface of these protein-chemical agents. It is not only their immune-modulating effect that must be understood but also their ability to act independently as therapeutic treatments.
Essentially, you now have an insight into the work that I'm involved with. I'll explain it in more detail in further articles, but the overall message I want to pass on is that every day we are beginning to understand the mechanisms of cancer more. It is only a matter of time until it is no longer a 'black box', a mystery of medical science. Once that day comes, cancer will be beaten.
As I explain in my other articles on philosophy, history and religion, we all have a purpose in life. This is my purpose; this is my world and I hope I can give you some insights into it along with hope for all those that have faced the scourge of cancer in their families and in their own lives.
Dr. Allen Goldenthal
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