In the classic tale of Dr. Jekyll and Mr. Hyde, two opposing characters — one a respected gentleman, the other a violent brute — are revealed to be in fact the same person, blurring the lines between good and evil.
For patients with leukemia or lymphoma who have undergone bone marrow transplantation, the same could be said for the immune system: it is at once a source of “good,” fending off cancer and infection, and a potential source of “evil,” attacking the body in the form of a debilitating condition called chronic graft-versus-host-disease (GVHD).
The natural question: is there a way to maintain the “good” while minimizing the “evil” when the two are so intimately connected?
In this week’s issue of NEJM, Koreth et al. propose a novel answer. It has to do with interleukin-2 (IL-2), a signaling molecule that activates many components of the immune system. Most notably, IL-2 activates both conventional T (Tcon) cells, which promote immune activity – including autoimmune responses – and regulatory T (Treg) cells, which keep Tcon cells in check. Koreth et al. report that when given at low doses, IL-2 tips the balance of Treg:Tcon cells in favor of Treg cells –enough to reverse GVHD, but not so much as to lose the benefits of fighting cancer and infection.
The authors conducted a 12-week observational cohort study of 29 patients with chronic GVHD who had not responded to treatment with steroids. They measured the levels of Treg and Tcon cells before initiating treatment, and again after 4 weeks of treatment with daily low-dose IL-2. They found that in this time, the median Treg cell count increased eightfold (P<0.001), while the Tcon cell count did not change significantly. This translated to a five-fold increase in the Treg:Tcon ratio (0.39, from a baseline of 0.07; P<0.001).
Clinically, about half of the patients demonstrated a partial response to IL-2 therapy. Responses included softened skin, improved joint mobility, improved liver function, and resolution of neuropathy. The other patients who did not respond showed stable disease. No patients developed a flare of GVHD or recurrence of cancer, and no increase in opportunistic infections was observed.
Interestingly, there did not seem to be a significant difference in T cell counts between patients who responded clinically to IL-2 therapy versus those who did not. Dr. Jeffrey Bluestone of the University of California, San Francisco, explains in an accompanying editorial that multiple factors may have contributed to this phenomenon, including variation among patients in adjunct immunosuppressive drug regimens and the incompletely elucidated role of natural killer cells.
Despite the gaps in knowledge that remain to be filled, these findings mark an exciting step forward in the ongoing search for treatments of immune-mediated disease. IL-2 may be the key that unlocks both the Jekyll and Hyde of the immune system – a key that, if used properly, can boost the benefits of the former while keeping the damage from the latter at bay.
In your clinical practice, how have you approached treating GVHD? Based on the results of this study, will you consider using low-dose IL-2?