Homeostasis of human NK cells is not IL-15 dependent
Herve Lebrec,Michelle Horner,Kevin S. Gorski,Wayne Tsuji,Dong Xia,Wei Jian Pan,Gary Means,Greg Pietz,Nianyu Li,Marc W. Retter,Kathy Shaffer,Neha Patel,Padma K. Narayanan,Eric A. Butz +13 more
TLDR
It is demonstrated that NK cell homeostasis is obligatorily dependent upon IL-15 in both mice and NHPs, but that IL- 15 is dispensable for maintenance of circulating human NK cells.Abstract:
IL-15 is a proinflammatory cytokine that plays an important role in the development and activation of NK cells and is a potential target for inflammatory disease therapy. Studies conducted in IL-15- and IL-15R knockout mice identified IL-15 as an important cytokine for NK cell homeostasis. Consistent with this information derived from genetically modified mice, we demonstrated that neutralizing IL-15 with a mouse anti-mouse IL-15 mAb (M96) depletes C57BL/6 mouse NK cells. An mAb directed against macaque IL-15 (Hu714MuXHu) was manufactured and demonstrated to block IL-15-induced activation of nonhuman primate (NHP) NK cells in vitro. Neutralization of macaque IL-15 by parenteral administration of Hu714MuXHu reduces (>95%) circulating NK cell counts in NHPs. A blocking mAb directed against human IL-15 (huIL-15; AMG 714) was manufactured. Unexpectedly, when human subjects were treated with the blocking anti-IL-15 Ab AMG 714 in clinical trials, no reductions in circulating NK cell counts were observed despite achieving significantly higher exposures than the levels of Hu714MuXHu needed to cause NK cell count reductions in NHPs in vivo. Both AMG 714 and Hu714MuXHu are able to block huIL-15 activity in a human T cell blast proliferation and IFN-γ production assay. Both Abs block huIL-15-mediated Stat5 activation and CD69 expression in human NK cells. Collectively, these results demonstrate that NK cell homeostasis is obligatorily dependent upon IL-15 in both mice and NHPs, but that IL-15 is dispensable for maintenance of circulating human NK cells.read more
Citations
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IL-15 is a component of the inflammatory milieu in the tumor microenvironment promoting antitumor responses.
Rosa M. Santana Carrero,Figen Beceren-Braun,Sarai C. Rivas,Shweta M. Hegde,Achintyan Gangadharan,Devin Plote,Gabriel Pham,Scott M. Anthony,Kimberly S. Schluns +8 more
TL;DR: In analyses of mice implanted with various tumor cell lines, soluble IL-15/IL-15Rα complexes are abundant in the interstitial fluid of tumors with expression preceding the infiltration of tumor-infiltrating lymphocytes, providing insight into an unappreciated attribute of the tumor landscape that contributes to antitumor immunity.
Journal ArticleDOI
Interleukin-15 in the treatment of cancer.
TL;DR: In rhesus macaques, continuous infusion of recombinant human IL-15 at 20 μg/kg/day was associated with approximately a 10-fold increase in the numbers of circulating NK, γ/δ cells and monocytes, and an 80- to 100-fold increased in the number of effector memory CD8 T cells.
Journal ArticleDOI
Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: a phase 2a, randomised, double-blind, placebo-controlled study.
Marja-Leena Lähdeaho,Mika Scheinin,Pekka Vuotikka,Juha Taavela,Alina Popp,Johanna Laukkarinen,Jukka Koffert,Olli-Pekka Koivurova,Marko Pesu,Laura Kivelä,Zsófia Lovró,Joni Keisala,Jorma Isola,Jane R. Parnes,Francisco Leon,Markku Mäki +15 more
TL;DR: AMG 714 did not prevent mucosal injury due to gluten challenge and Serum antibody titres for anti-tTG and anti-DGP antibodies increased in all three treatment groups, with no significant difference between AMG 7 14 and placebo.
Journal ArticleDOI
Safety and efficacy of AMG 714 in patients with type 2 refractory coeliac disease: a phase 2a, randomised, double-blind, placebo-controlled, parallel-group study
Christophe Cellier,Gerd Bouma,Tom van Gils,Sherine Khater,Georgia Malamut,Laura Crespo,Pekka Collin,Peter H.R. Green,Sheila E. Crowe,Wayne Tsuji,Eric Butz,Nadine Cerf-Bensussan,Elizabeth Macintyre,Jane R. Parnes,Francisco Leon,Olivier Hermine,Chris J. J. Mulder,Bana Jabri,Joseph A. Murray,Anthony J. DiMarino,Ciaran P. Kelly,Valerie Byrnes,David S Sanders,Knut E.A. Lundin,Michael Schumann,Hetty J. Bontkes,Bertrand Meresse,Garbiñe Roy Ariño,Govind Bhagat,Keijo Viiri,Samuli Rounioja,Jack D. Bui,Raquel Perez Maseda,Carlota García-Hoz,Amélie Trinquand,George Vlad,Marios Hadjivassiliou,Michel Azizi,Anne Blanchard,Beth Llewellyn,Ashleigh Palmer,Ralph Raymond +41 more
TL;DR: The effects of AMG 714, an anti-IL-15 monoclonal antibody, on the activity and symptoms of refractory coeliac disease type 2 and atypical intraepithelial lymphocytes were investigated.
Journal ArticleDOI
Therapeutic approaches for celiac disease.
TL;DR: The status of both emerging and potential therapeutic strategies in the context of disease pathophysiology are reviewed and a discussion of how genes identified during GWAS and follow-up studies that enhance susceptibility may offer insight into developing novel therapies is discussed.
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