New Research Suggests Lymphatic Tissue Self-Regeneration May Hold Promise for Treating Secondary Lymphedema

The chronic swelling condition known as Secondary Lymphedema arises due to damage of the lymphatic system (typically as a side-effect of cancer treatment) which decreases the ability of the system to drain excess tissue fluid back into the blood stream.  There is currently no cure for lymphedema, which must instead be managed using manual lymphatic drainage and other combined decongestive therapy (CDT) techniques.  In addition to surgical strategies that are currently being investigated to help alleviate the condition, researchers are exploring the possibility of inducing the body to regenerate its own healthy vessels and nodes by supplementing with proteins and other factors normally involved in the healing process.

Naturally produced proteins in the body known as cytokines are involved in all aspects of tissue regeneration and healing, including the development of new blood and lymphatic vessels.  This makes them intriguing therapeutic drug candidates for a wide range of conditions including lymphedema.  However, the therapeutic utility of these proteins has been severely hamstrung by their near-universal involvement in numerous other cellular processes outside of tissue regeneration, including most notably, tumor growth and inflammation.  This has made it difficult to isolate the actions of individual cytokines, and to identify those that can accomplish a specific therapeutic goal – without unwanted side-effects.

An impressive research paper published this past week (Choi, I., Lee, Y.S., et al. Interleukin-8 reduces post-surgical lymphedema formation by promoting lymphatic vessel regeneration. Angiogenesis. 2012 Sep 4) explores a potential therapeutic role for the cytokine known as “Interleukin-8” (IL-8) in lymphangiogenesis – the growth of new lymph vessels and nodes.   IL-8 has well known roles in inducing inflammation, a complex process that can indirectly promote new blood vessel or lymph vessel growth (among other things) due to the secretion of a complex milieu of related cytokines.   But can IL-8 promote therapeutic levels of lymphangiogenesis, and directly, rather than through the potentially life-threatening process of inflammation?  This paper for the first time defines a direct role for IL-8 in lymphangiogenesis, and validates it as a promising therapeutic target for treating Secondary Lymphedema.

Of the numerous experiments reported in the paper, the keystone of their conclusion comes from studies involving mice that were genetically modified to produce human IL-8.  The researchers induced lymphedema in the tail of these mice and their normal siblings by surgically obstructing the lymphatic networks of the tail (which is the most widely studied animal model of secondary lymphedema).  Mice that were genetically modified to produce IL-8 exhibited the same onset of lymphedema as the normal mice, but their flare up began to subside after only 1 week, as opposed to 3 weeks in the normal mice.  What’s especially interesting is that this correlated with an increase in new lymphatic vessel growth, without an increase in inflammation.

Lymphedema was surgically induced in the tails of both normal and genetically modified IL-8 mice. Unlike normal mice, IL-8 mice show a dramatic reduction in lymphedema by Day 19.

While showing therapeutic efficacy in an animal model of secondary lymphedema is both exciting and promising, the road to human studies and commercialization is a long one.  Should IL-8 be shown to have similar therapeutic efficacy and specificity in humans, commercialization is by no means assured.  The multifaceted roles of cytokines such as IL-8 increases the risk of unintended side-effects, and consequently, increases the burden of evidence necessary to receive regulatory approval.   Sadly, the fact that lymphedema can be adequately managed through CDT, combined with marginal public awareness, and the incredible cost of bringing a drug to market, make commercialization of IL-8 or other therapeutic drugs for lymphedema a formidable task.