Research Round-up

From the Summer 2016 edition of Vanderbilt Medicine Magazine

Immune defenses in asthma

Patients with asthma are at increased risk for invasive bacterial infections and bacterial pneumonia, but the mechanisms that impair their immune system defenses against pathogens are unknown.

Melissa Bloodworth, R. Stokes Peebles, Jr., M.D., and colleagues explored whether STAT6—a transcription factor that is expressed at high levels in the T cells of people with asthma—impacts the function of gamma-delta-17 cells, critical first-line responders against bacterial pathogens.

The investigators found that increased STAT6 activation and signaling through STAT6 inhibited gamma-delta-17 cell production of the cytokine IL-17A, an immune system signaling protein. Using a mouse model, the researchers demonstrated that STAT6 signaling reduces the numbers of gamma-delta-17 cells during acute Klebsiella pneumoniae infection.

These findings, reported in Infection and Immunity, show that STAT6 negatively regulates first-line responder immune cells and provide one explanation for why patients with asthma are at greater risk for invasive bacterial disease.

 

New treatment for Crohn’s disease  

Crohn’s disease—a chronic inflammatory disease of the digestive tract—causes abdominal pain, diarrhea and weight loss. Immunosuppressive and anti-inflammatory treatments fail in up to 40 percent of patients. In clinical trials, ustekinumab, a new biological therapy that is approved for treatment of psoriasis, is inducing and maintaining remission in Crohn’s disease.

Kimberly Harris, M.D., and colleagues conducted a retrospective chart review to evaluate the effectiveness of ustekinumab in the treatment of Crohn’s disease.

Patients received a novel subcutaneous dosing schedule that was designed to match the intravenous dose being used in clinical trials. The investigators found that out of 45 patients who were resistant to other therapies, including anti-TNFs, 46 percent achieved a clinical response, and 35 percent achieved clinical remission. Laboratory and endoscopic markers of Crohn’s disease were also reduced.

The findings, reported in the February issue of Inflammatory Bowel Diseases, demonstrate that a subcutaneous dosing schedule of ustekinumab was successful in improving markers of disease activity in patients with severe, refractory Crohn’s disease.

 

Improving natural killer cancer therapy

Natural Killer (NK) cells are a type of white blood cell that specifically recognizes and destroys tumor cells.

For this reason, NK cell transfer therapy is a promising cancer treatment. Expansion and persistence of donor NK cells correlate with tumor clearance, suggesting that therapeutic efficacy can be enhanced by augmenting NK cell survival.

Now, Whitney Rabacal, Eric Sebzda, Ph.D., and colleagues show in a study published in the Proceedings of the National Academy of Sciences that a transcription factor called KLF2 is critical for NK cell expansion and survival.

They discovered that KLF2 both limits immature NK cell proliferation and instructs mature NK cells to home to niches rich in interleukin 15 (IL-15), which is necessary for their continued survival.

Importantly, this report suggests that tumors avoid immune clearance by promoting KLF2 destruction within the NK cell population, thereby starving these cells of

IL-15. Therefore, recruiting IL-15 transpresenting cells to tumor microenvironments may improve NK cell-mediated cancer therapy by preventing NK cell exhaustion and restoring antitumor immunity. This research was supported in part by the National Institutes of Health (grant HL069765).