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.
Highlights
Humanized mice constructed by engrafting human tissues/cells into immunodeficient mice have greatly advanced research with viruses such as HIV since human target cells are provided in a physiological setting permitting the study of human disease pathogenesis, immunity and testing of antivirals in vivo [1,2,3]
We have shown that a new strain of immunodeficient mice, Rag12/2cc2/2 mice, permits efficient engraftment with human fetal liver derived CD34+ hematopoietic progenitor cells giving rise to multilineage human hematopoiesis
Infection of these mice with HIV-1 leads to chronic viremia and subsequent CD4 helper T cell loss
Summary
Humanized mice constructed by engrafting human tissues/cells into immunodeficient mice have greatly advanced research with viruses such as HIV since human target cells are provided in a physiological setting permitting the study of human disease pathogenesis, immunity and testing of antivirals in vivo [1,2,3]. Artemis is an endonuclease involved in the DNA recombination event required to generate T and B cell receptors. The second common category of mutations leading to immunodeficiency is the lack of the common gamma chain (cc) which is an integral part of receptors required for the response to the cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. This leads to a failure in various cell types to mature and/or expand, including T cells, B cells, and natural killer (NK) cells [11,12,13]. A disadvantage with the NOD strain is high incidence of lymphomas leading to a shortened lifespan
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
