Humoral Immunity in Mice Transplanted with Hematopoietic Stem Cells Derived from Human Umbilical Cord Blood Recapitulates That of Human Infants

Abstract

Immunodeficient mice transplanted with human hematopoietic stem cells (HSCs) have been referred to as "Human Immune System" (HIS) mice and are a translational platform for studying human immune responses in vivo. Human HSC sources used in generating HIS mice include fetal liver (FL), umbilical cord blood (CB), and adult bone marrow (BM). Since HSCs from FL, CB, and BM are produced at various stages of human development, we tested whether mice transplanted with these three HSCs differ in their immune responses. We found that compared with CB HSCs or FL HSCs, adult BM HSCs reconstitute the immune system poorly. The resulting HIS mice do not mount an antibody response to Borrelia hermsii infection and as a consequence suffer persistently high levels of bacteremia. While both CB and FL HSCs yield comparable levels of immune reconstitution of HIS mice resulting in robust anti-B. hermsii immune responses, FL HSC-transplanted mice exhibited a discernable difference in their human B cell maturity as identified by an increased frequency of CD10 immature B cells and relatively smaller lymphoid follicles compared with CB HSC-transplanted mice. Although CB HSC-transplanted mice generated robust antibody responses to B. hermsii and specific protein antigens of B. hermsii, they failed to respond to Salmonella typhi Vi polysaccharide, a classical T cell-independent antigen. This situation resembles that seen in human infants and young children. Therefore, CB HSC-transplanted mice may serve as a translation platform to explore approaches to overcome the impaired antipolysaccharide responses characteristic of human infants.

Improved multilineage human hematopoietic reconstitution and function in NSGS mice

“…This may be due to higher levels of primitive HSCs and multi-potent progenitors and fewer B progenitors in FL relative to UCB [14]. FL xenografts have been reported to display more immature B cells and smaller follicular structures compared to UCB engrafted mice, while BM HSCs generate comparatively poor levels of engraftment with reduced functionality [15].…”

Identification of collaborative cross mouse strains permissive to Salmonella enterica serovar Typhi infection

“…Several research groups demonstrated that CD34 + human hematopoietic stem cell-engrafted NOD/SCID/IL-2Rγc null or NOD/SCID/IL-2Rγc null mice, referred to as “Human Immune System” or “humanized” mice are susceptible to S. Typhi infection 20 – 22 . Although humanized mice have the potential to understand typhoid pathogenesis, the humoral immunity of these mice is immature and such mice do not respond to ViPS immunization 23 , 24 . Therefore, the “humanized” mouse model in its current form is not appropriate for understanding immune responses to S. Typhi.…”

Collaborative Cross mice are permissive to Salmonella enterica serovar Typhi infection

“…Several research groups demonstrated that CD34 + human hematopoietic stem cell-engrafted NOD/SCID/IL-2Rgc null or NOD/SCID/IL-2Rgc null mice, referred to as "Human Immune System" or "humanized" mice are susceptible to S. Typhi infection [20][21][22] . Although humanized mice have the potential to understand typhoid pathogenesis, the humoral immunity of these mice is immature and such mice do not respond to ViPS immunization 23,24 . Therefore, the "humanized" mouse model in its current form is not appropriate for understanding immune responses to S. Typhi.…”