Co-transplantation of human fetal thymus, bone and CD34(+) cells into young adult immunodeficient NOD/SCID IL2Rγ(null) mice optimizes humanized mice that mount adaptive antibody responses

• Published in: Clinical immunology (Orlando, Fla.) Vol. 157; no. 2; pp. 156 - 165
• Main Authors: Chung, Yun Shin, Son, Jin Kyung, Choi, Bongkum, Joo, Sung-Yeon, Lee, Yong-Soo, Park, Jae Berm, Moon, Hana, Kim, Tae Jin, Kim, Se Ho, Hong, Seokmann, Chang, Jun, Kang, Myung-Soo, Kim, Sung Joo
• Format: Journal Article
• Language: English
• Published: United States 01.04.2015
• Subjects: Adaptive Immunity - immunology; Animals; Antibodies - immunology; Antibody Formation; Antigens, CD34 - metabolism; Bone Transplantation; Fetal Tissue Transplantation; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - metabolism; Heterografts; Humans; Immunoglobulin G - immunology; Immunoglobulin M - immunology; Interleukin Receptor Common gamma Subunit - genetics; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Spleen - immunology; Spleen - pathology; Thymus Gland - transplantation; CD34(+) cells; Bone; Humanized mice; Young adult NOD/SCID IL2Rγ(null); Hematopoiesis; Thymus
• ISSN: 1521-7035
• DOI: 10.1016/j.clim.2015.02.005

Both the thymus (T) and bone (B) are necessary hematopoietic niches in adult humans. We previously showed that co-transplantation of human fetal T and B tissues into neonatal immunodeficient NOD/SCID IL2Rγ(null) (NSG, N) mice facilitated hematopoiesis. However, transplantation into neonatal mice resulted in high frequency of early death, making it unrealistic for repetitive experiments. In this study, young adult N mice were pre-engrafted with T and B, T alone, B alone or no tissues. The animals were irradiated and injected with autologous fetal liver (FL)-derived CD34(+) cells (34). The resultant mice were TB34N, T34N, B34N and 34N, respectively, and challenged with T cell dependent antigens (Ags). The humanized TB34N mice showed best performance of these mouse models in many aspects resembling the adult human Ag-experienced spleen. The TB34N mice exhibited better hematopoietic reconstitution; balanced development of T- and B-cell, and common progenitor cells; follicular lymphoid structures with a functional germinal center (GC) enriched with follicular dendritic cells (FDCs) and plasma cells (PCs); secretion of hIgG in the sera in response to Ags at comparable levels to those of human; derivations of hIgG mAb-secreting hybridoma clones. Collectively, the humanized TB34N mice could develop an adaptive immunity that was capable of producing Ag-specific hIgG at a significant level via class switching. This unprecedented TB34N platform in humanized mice would be useful in dissecting human immunity, for generating human Abs and clinical applications.