Dendritic Cell–Mediated Immune Humanization of Mice: Implications for Allogeneic and Xenogeneic Stem Cell Transplantation

Abstract

De novo regeneration of immunity is a major problem after allogeneic hematopoietic stem cell transplantation (HCT). HCT modeling in severely compromised immune-deficient animals transplanted with human stem cells is currently limited because of incomplete maturation of lymphocytes and scarce adaptive responses. Dendritic cells (DC) are pivotal for the organization of lymph nodes and activation of naive T and B cells. Human DC function after HCT could be augmented with adoptively transferred donor-derived DC. In this study, we demonstrate that adoptive transfer of long-lived human DC coexpressing high levels of human IFN-α, human GM-CSF, and a clinically relevant Ag (CMV pp65 protein) promoted human lymphatic remodeling in immune-deficient NOD.Rag1−/−.IL-2rγ−/− mice transplanted with human CD34+ cells. After immunization, draining lymph nodes became replenished with terminally differentiated human follicular Th cells, plasma B cells, and memory helper and cytotoxic T cells. Human Igs against pp65 were detectable in plasma, demonstrating IgG class-switch recombination. Human T cells recovered from mice showed functional reactivity against pp65. Adoptive immunotherapy with engineered DC provides a novel strategy for de novo immune reconstitution after human HCT and a practical and effective tool for studying human lymphatic regeneration in vivo in immune deficient xenograft hosts.

Viral infections in mice with reconstituted human immune system components

“…This was reported for huNSG, huBRG and BLT mice after HIV, HSV-2, adeno-, EBV, dengue and JC virus infection [16,40,43,62,66,77,78]. Consistent with these findings, the B cell areas of secondary lymphoid tissues of HIS mice do not show germinal center development [79], but can develop these structures after prolonged or repeated immunization [75,80]. In these structures, B cell differentiation beyond transitional and naïve B cells can be found and significant numbers of follicular helper T cells are present [75].…”

“…Consistent with these findings, the B cell areas of secondary lymphoid tissues of HIS mice do not show germinal center development [79], but can develop these structures after prolonged or repeated immunization [75,80]. In these structures, B cell differentiation beyond transitional and naïve B cells can be found and significant numbers of follicular helper T cells are present [75]. Also in line with a young immune system, NK cells efficiently restrict primary viral infections, like EBV, which are better handled in children than adults, while further differentiation by IL-15 injection compromises this innate immune control in HIS mice [27].…”

Lentivirus-Induced Dendritic Cells (iDC) for Immune-Regenerative Therapies in Cancer and Stem Cell Transplantation

“…We demonstrated the adaptive pp65-specific IgG recombination switch and functional human T cell responses against pp65. Despite of the immune responses, some mice showed only minor signs of GVHD [44]. Our results demonstrated in the HIS-NRG model reconstituted with adult CD34 + stem cells the significant role of potent and long-lasting SmyleDCpp65 functions after HSCT as a switch for remodeling of peripheral lymph node and lymphatic flow regeneration resulting into activation, mobilization, and finally maturation of lymphocytes towards full immune function.…”

Analysis of the skin of mice humanized for the immune system

“…T-cell responses, we speculated that hAPC density of at the site of administration (ie the skin) is potentially too low to optimally trigger T cells. We thus tested the capacity of human DC complementation in the skin of the NSG-HLA-A2-HIS mice, [9] deriving autologous human cDC from human CD14 + cells isolated from the same cord blood than the hHPC used to reconstitute NSG-HLA-A2-HIS mice. Autologous umbilical cord blood CD14 + monocytes were isolated by MACS and cultured for 3 days in presence of 50 ng/mL hGM-CSF and 5 ng/mL hIL-4.…”

“…A large number of PV and PF cases are diagnosed in the northeastern region of the state of São Paulo each year. [8,9,14] We have investigated some viruses in patients with PV and compared them in patients with PF in this prevalent area for both PV and PF. We decided to study HSV1/2, CMV and EBV to confirm that these viruses are associated with pemphigus, mainly with PV.…”