IL-2 for GvHD: How can IL-2 both promote and suppress immune responses??

Recently, a friend of mine alerted me to an article that appeared in the New England Journal of Medicine entitled “Interleukin-2 and regulatory T cells in graft-versus-host disease” (vol. 365:2055, 2012). This report details the experience of the use of daily subcutaneous low dose IL-2 (0.3-3 x 10⁶ IU/m²),compared with high dose IL-2 therapy used for cancer therapy (4.9 x 10⁹ IU daily x 7), which itself causes severe toxicity via cytokine storm. A total of 29 subjects with chronic GvHD refractory to glucocorticoid therapy received IL-2 daily for eight weeks. Then, after a four-week hiatus, subjects who responded could receive IL-2 for an extended period. Of 23 evaluable subjects, 12 had major clinical responses involving multiple sites. The numbers of circulating CD4+IL-2Rα+FOXP3+ cells (T-Regs) were selectively increased in all subjects, with a peak median value at 4-weeks > 8-fold above baseline values (p < 0.001), without changes in other immunological parameters. Immunological and clinical responses were sustained in patients who received IL-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60%.

 

The senior investigators of this study were Jerome Ritz and Robert Soiffer, old friends who were responsible for me becoming involved in their low dose IL-2 therapy trials more than 20 years ago (J. Clin. Onc. 9:2110, 1991). Therefore, I wrote to them, inquiring whether they thought that their results were compatible with the recent notion that one of the major molecular mechanisms of T-reg immunosuppression might be the degradation of IL-2 and other cytokines, as discussed by several groups of investigators in a Research Topic that I hosted and which was recently published in an eBook :

http://flashbook.frontiersin.org//clients/Frontiers/The%20Molecular%20Mechanisms%20of%20Regulatory/EBook.html

 

They wrote back that the ideas set forth in this Frontiers in Immunology Research Topic, that IL-2 initiates feed-forward promotion of immune/inflammatory responses, while simultaneously it initiates feedback inhibition of immune/inflammatory responses, is entirely consistent with the effects of low dose IL-2 in their subjects. Thus, I recommend all of these references to those interested in therapeutically altering immunity, either suppressing it or enhancing it.