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Major Histocompatibility Complex and Autoimmune Disease
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Ursula Holzer, Gerald T. Nepom
The HLA class III region located between class I and II regions contain at least 59 genes and is the highest gene density region among the three HLA regions, including—among others—genes for complement proteins and the cytokines TNF α and β. HLA alleles are codominantly expressed; in other words, both inherited maternal and paternal HLA molecules are present in an individual. Because the class II molecules are heterodimers, heterologous molecules containing one maternal-derived chain and one paternal-derived chain are produced. Thus, combinatorial diversity can increase the number of expressed class II molecules.
Ethical Aspects of Translating Research with Human Pluripotent Stem Cell Products into Clinical Practice: A Stakeholder Approach
Published in The New Bioethics, 2020
Clemens Heyder, Solveig Lena Hansen, Claudia Wiesemann
The field of translational hESCs and hiPSCs research is rapidly evolving. In a systematic review, Zhao, et al. (2017) listed 10 phase I/II trials that involve the use of stem or progenitor cells for treating glaucoma, Retinitis pigmentosa and AMD. First studies with hiPSCs are currently underway (Cyranoski 2017a, Cyranoski 2017b, Cyranoski 2018). As the allogenic derivation of stem cell products is increasingly considered to be the only reasonable approach, both hESC and hiPSC research rely on either stem cells from surplus embryos in vitro or the biobanking of somatic cells from adult donors stored to create suitable stem cell lines. Although the obvious advantage of autologous over allogeneic cells is avoiding immunological reactions, a defence mechanism that only immunosuppressive drugs can override, the reprogramming of autologous cells for use in medical treatments is considered to be too expensive, since the differentiation and quality control of cell derivatives is a lengthy process usually taking several months. Because of considerable differences in quality, the hiPSC researcher Masayo Takahashi had to generate 30 cell lines in order to be able to choose the best ones for treating age-related macular degeneration in the first patient in the RIKEN trial (Chakradhar 2016). For safety reasons each stem cell line had to be genetically sequenced. The lengthy manufacturing period renders the use of autologous hiPSC therapies inefficient for many indications; the limited life expectancy of, for example, a patient in the final stage of hepatic cirrhosis may not allow enough time for the cultivation of autologously derived liver tissue. Moreover, in the case of a genetic disease, the defect would still have to be removed from the reprogrammed stem cells since the cells derived from them will carry the same genome. Allogenic derivation involves none of these difficulties, and it allows one to keep derived cells in stock, which cuts costs and time in manufacturing products. Once generated and controlled for quality, cells can be stored in so-called haplo banks from where they can be provided to researchers and manufacturers. As with organ transplants, they can be matched according to the HLA types of donor and recipient, thus reducing immunological responses. It is estimated that 50 lines are sufficient for 90% of the population of Japan (Taylor et al.2005). About 150 lines are needed to cover 93% of the population of the UK (Gourraud, et al.2012).