1: Development of an immunodeficient pig model allowing long-term accommodation of artificial human vascular tubes
Science of the Month - July 2019
NATURE COMMUNICATIONS,
10 10.1038/s41467-019-10107-1 MAY 21 2019
Itoh M, Mukae Y, Kitsuka T, Arai K, Nakamura A, Uchihashi K, Toda S, Matsubayashi K,Oyama J, Node K, Kami D,Gojo S,Morita S,Nishida T, Nakayama K, Kobayashi E
Preclinical studies using pig-sized laboratory animals have been desired to verify the efficacy and safety of regenerative medicine products derived from human cells. However, controlling the xenogeneic immune response that occurs when transplanting human cell-derived products into pigs has been difficult. Although SCID pigs have been created through genetic manipulation, similar to mice, they could not be raised in a general animal testing environment. We have now succeeded in creating a pig model in which the immunodeficient state can be adjusted using a surgical technique. This technique can be used to create these models in many experimental pig facilities, using mature pigs of any breed. In the paper, we first transplanted blood vessels made from human-derived fibroblasts as shunts into the cervical artery and vein, using a standard three-drug immunosuppressant regimen for transplanting human-derived cells into pigs. However, although the grafts remained, the rejection response could not be controlled, and thrombosis occurred in the lumen within two weeks (Figures A, B). In contrast, when transplanted using a newly developed protocol, the human-derived artificial blood vessels remained patent for up to nearly six months and matured into vessels with an intima and media (Figures C, D). This validation study was conducted by a third-party organization in compliance with reliability standards. We hope to apply this to future research aimed at creating human organs within pigs.
(Eiji Kobayashi, Project Professor, Bridgestone Endowed Department of Organ Regeneration Medical Sciences, Class of '00 equivalent)
2: Molecular dynamics simulation-guided drug sensitivity prediction for lung cancer with rare EGFR mutations
PNAS,
116 (20):10025-10030; 10.1073/pnas.1819430116 MAY 14 2019
Ikemura S,Yasuda H,Matsumoto S,Kamada M, Hamamoto J, Masuzawa K, Kobayashi K, Manabe T, Arai D, Nakachi I, Kawada I, Ishioka K, Nakamura M, Namkoong H, Naoki K, Ono F, Araki M, Kanada R, Ma B, Hayashi Y, Mimaki S, Yoh K, Kobayashi SS, Kohno T, Okuno Y, Goto K, Tsuchihara K ,Soejima K
In recent years, cancer genomic medicine, which selects optimal anticancer drugs based on cancer's genetic abnormalities, has been gaining attention. With the spread of cancer genomic medicine, many "rare genetic mutations" of unknown biological significance are being identified, in addition to the major, frequently reported genetic mutations. The lack of a method for selecting effective therapeutic drugs for these rare genetic mutations poses a major challenge in cancer genomic medicine. In collaboration with LC-SCRUM-Japan, the largest lung cancer gene screening network in the country, our research group clarified the distribution of rare EGFR gene mutations in 2,164 lung cancer patients registered in Japan's largest clinical genome database. We also evaluated the drug sensitivity of rare EGFR gene mutations through cell-based experiments. As a result, we revealed the diverse drug sensitivities of these rare EGFR gene mutations. Furthermore, to predict the diverse sensitivities for each genetic mutation without conducting cell-based experiments, we performed molecular dynamics simulations using the K supercomputer. The results showed that the drug sensitivity predicted in silico has a high correlation with the data obtained from cell-based experiments. It is expected that the practical application of this system will enable the in silico selection of optimal drugs for cancer patients with rare genetic mutations.
(Hiroyuki Yasuda, Lecturer, Department of Respiratory Medicine, 80th Graduating Class)
Other Publications
1: Mining the microbiota for microbial and metabolite-based immunotherapies
NATURE REVIEWS IMMUNOLOGY,
19 (5):305-323; 10.1038/s41577-019-0144-5 MAY 2019
Skelly AN, Sato Y, Kearney S, Honda K
2: Ras homolog gene family H (RhoH) deficiency induces psoriasis-like chronic dermatitis by promoting T(H)17 cell polarization
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY,
143(5):1878-1891;10.1016/j.jaci.2018.09.032 MAY 2019
Tamehiro N, Nishida K, Sugita Y, Hayakawa K, Oda H ,Nitta T, Nakano M, Nishioka A, Yanobu-Takanashi R, Goto M, Okamura T, Adachi R, Kondo K, Morita A, Suzuki H