Development of an immunodeficient pig model allowing long-term accommodation of artificial human vascular tubes

Manabu Itoh,Yosuke Mukae,Kazuyoshi Uchihashi,Daisuke Kami,Koichi Node,Kenichi Arai,Takahiro Nishida,Shigeki Morita,Koichi Nakayama,Jun-Ichi Oyama,Satoshi Gojo,Kumika Matsubayashi,Anna Nakamura,Shuji Toda,Takahiro Kitsuka,Eiji Kobayashi

doi:10.1038/s41467-019-10107-1

Abstract

Before they are used in the clinical setting, the effectiveness of artificially produced human-derived tissue-engineered medical products should be verified in an immunodeficient animal model, such as severe combined immunodeficient mice. However, small animal models are not sufficient to evaluate large-sized products for human use. Thus, an immunodeficient large animal model is necessary in order to properly evaluate the clinical efficacy of human-derived tissue-engineered products, such as artificial grafts. Here we report the development of an immunodeficient pig model, the operational immunodeficient pig (OIDP), by surgically removing the thymus and spleen, and creating a controlled immunosuppressive protocol using a combination of drugs commonly used in the clinical setting. We find that this model allows the long-term accommodation of artificial human vascular grafts. The development of the OIDP is an essential step towards a comprehensive and clinically relevant evaluation of human cell regeneration strategies at the preclinical stage.

Highlights

As various powerful immunosuppressive agents were developed in the 1980s, the results of organ transplantation in humans have dramatically improved, resulting in an increased need for organs for transplantation
The respective serum IgG and IgM concentrations were 4970 ± 2810 μg/ml, 1637 ± 123 μg/ml in the conventional immunosuppressive pig (CISP) group and 3467 ± 958 μg/ml, 1053 ± 70 μg/ml in the OISP group at 2 weeks after implantation (Supplementary Fig. 4b). Both the number of inflammatory cells and the serum levels of immunoglobulin were suppressed in the operational immunodeficient pig (OIDP) group compared with the CISP group. In this present study, we clearly showed that we could successfully induce an immunodeficient state in mature mini-pigs in which long-term feeding was enabled by the surgical removal of the major immune organs, including the thymus and spleen, and by adjusting the immunosuppressive agents based on the physical condition of the pigs (OIDP group; Fig. 1, Supplementary Fig. 1)
Using our OIDP model, we confirmed that all human original 3D bioprinted tube (HOBPT) were patent in the OIDP group

Summary

Introduction

As various powerful immunosuppressive agents were developed in the 1980s, the results of organ transplantation in humans have dramatically improved, resulting in an increased need for organs for transplantation. Three-dimensional (3D) bioprinting technology has been developed, which allows for the construction of any 3D structure using cells alone, without scaffold materials[4,5], and we successfully developed the human original 3D bioprinted tube (HOBPT)[6] using our original 3D bioprinting system This system has enabled the production of organs that can be implanted into small animals, such as vascular grafts[6], substitute nerves[7], liver[8], and myocardium[9] using humanderived cells, the development of large animal models to be used for preclinical studies to evaluate the efficacy and safety of the implantation of human organs produced using this technology is currently underway. The development of OIDPs without the rejection of human cell-derived organs symbolizes an essential step toward the comprehensive evaluation of preclinical cell regeneration strategies and contributes to the development of regenerative medicine using human organs

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