Humanized Rag1−/−γc−/− Mice Support Multilineage Hematopoiesis and Are Susceptible to HIV-1 Infection via Systemic and Vaginal Routes

Abstract

Several new immunodeficient mouse models for human cell engraftment have recently been introduced that include the Rag2−/−γc−/−, NOD/SCID, NOD/SCIDγc−/− and NOD/SCIDβ2m−/− strains. Transplantation of these mice with CD34+ human hematopoietic stem cells leads to prolonged engraftment, multilineage hematopoiesis and the capacity to generate human immune responses against a variety of antigens. However, the various mouse strains used and different methods of engrafting human cells are beginning to illustrate strain specific variations in engraftment levels, duration and longevity of mouse life span. In these proof-of-concept studies we evaluated the Balb/c-Rag1−/−γ−/− strain for engraftment by human fetal liver derived CD34+ hematopoietic cells using the same protocol found to be effective for Balb/c-Rag2−/−γc−/− mice. We demonstrate that these mice can be efficiently engrafted and show multilineage human hematopoiesis with human cells populating different lymphoid organs. Generation of human cells continues beyond a year and production of human immunoglobulins is noted. Infection with HIV-1 leads to chronic viremia with a resultant CD4 T cell loss. To mimic the predominant sexual viral transmission, we challenged humanized Rag1−/−γc−/− mice with HIV-1 via vaginal route which also resulted in chronic viremia and helper T cell loss. Thus these mice can be further exploited for studying human pathogens that infect the human hematopoietic system in an in vivo setting.

Cancer stem cell definitions and terminology: the devil is in the details

“…Continued genetic modifications of candidate host mice will probably enable at least some of the species-specific needs to be addressed in the future. These include the possibility of creating transgenic mice that will express species-specific human cytokines, or the use of humanized mice (mice transplanted with human haematopoietic or local tissue components) to create more human-type microenvironments -as has proved useful for certain types of normal human cells [53][54][55][56][57] . Orthotopic injections of CSCs into various target organs may also prove useful, and mimicry of natural tumour immunosurveillance mechanisms may be achievable using injections of specific immune effector cells (TABLE 2).…”

Development of human B cells and antibodies following human hematopoietic stem cell transplantation to Rag2−/−γc−/− mice

“…Although the current humanized mouse models are capable of producing human humoral and cellular immune responses to these pathogens, in general the results have been inconsistent and when they are detected the immune responses are typically weak [6,11,12]. The reasons for these findings are currently unclear, but previous studies have indicated that total human antibody concentrations are much lower in humanized mice than in humans and there may be a defect in classswitching, since IgM concentrations tend to be closer to human concentrations than for IgG [2,13]. One study attempted to immortalize human B cells after immunizing humanized mice and was only able to produce IgM monoclonal antibodies and not IgG producing cells, lending further support to the hypothesis that there is a lack of effective class-switching [14].…”

Human Herpesvirus 6A Infection and Immunopathogenesis in Humanized Rag2−/−γc−/−Mice

“…Peripheral blood was collected by tail bleed and stained with antibodies specific to either human or mouse CD45. Fluorescence-activated cell sorter (FACS) analysis was performed to determine percent peripheral blood engraftment of human cells (38,39).…”