Article

Creation of "humanized" mice to study human immunity.

Diabetes Division, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Current protocols in immunology / edited by John E. Coligan ... [et al.] 06/2008; Chapter 15:Unit 15.21. DOI: 10.1002/0471142735.im1521s81
Source: PubMed

ABSTRACT "Humanized" mice are a promising translational model for studying human hematopoiesis and immunity. Their utility has been enhanced by the development of new stocks of immunodeficient hosts, most notably mouse strains such as NOD-scid IL2rgamma(null) mice that lack the IL-2 receptor common gamma chain. These stocks of mice lack adaptive immune function, display multiple defects in innate immunity, and support heightened levels of human hematolymphoid engraftment. Humanized mice can support studies in many areas of immunology, including autoimmunity, transplantation, infectious diseases, and cancer. These models are particularly valuable in experimentation where there is no appropriate small animal model of the human disease, as in the case of certain viral infections. This unit details the creation of humanized mice by engraftment of immunodeficient mice with hematopoietic stem cells or peripheral blood mononuclear cells, provides methods for evaluating engraftment, and discusses considerations for choosing the appropriate model system to meet specific goals.

2 Followers
 · 
106 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Multiple sites can be used for the engraftment of primary human cells and tissues into murine hosts. For example, leukemias are usually best engrafted intravenously, but they can also be engrafted directly into the bone marrow cavity. Some solid tumors such as colon tumors grow successfully following subcutaneous engraftment, sometimes requiring provision of a Matrigel artificial basement membrane. In certain cases (e.g., human bladder cancer and ductal breast carcinoma), the use of the autochthonous site (bladder and mammary duct, respectively) is often most efficient, whereas the tumors can grow poorly when transplanted subcutaneously or heterochthonously. Here, we present a protocol for the surgical implantation of tissues under the kidney capsule. The kidney is especially suited for the transplantation of normal as well as malignant cells and tissues. It is very accessible, and transplanted tissues are well contained under the renal capsule in a highly vascularized site. Furthermore, the retroperitoneal location of the kidney, together with its separation from other organs, is advantageous both for imaging and biopsy.
    Cold Spring Harbor Protocols 07/2014; 2014(7):pdb.prot078089. DOI:10.1101/pdb.prot078089 · 4.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Since their description and identification in leukemias and solid tumors, cancer stem cells (CSC) have been the subject of intensive research in translational oncology. Indeed, recent advances have led to the identification of CSC markers, CSC targets, and the preclinical and clinical evaluation of the CSC-eradicating (curative) potential of various drugs. However, although diverse CSC markers and targets have been identified, several questions remain, such as the origin and evolution of CSC, mechanisms underlying resistance of CSC against various targeted drugs, and the biochemical basis and function of stroma cell-CSC interactions in the so-called ‘stem cell niche.’ Additional aspects that have to be taken into account when considering CSC elimination as primary treatment-goal are the genomic plasticity and extensive subclone formation of CSC. Notably, various cell fractions with different combinations of molecular aberrations and varying proliferative potential may display CSC function in a given neoplasm, and the related molecular complexity of the genome in CSC subsets is considered to contribute essentially to disease evolution and acquired drug resistance. In the current article, we discuss new developments in the field of CSC research and whether these new concepts can be exploited in clinical practice in the future.
    Journal of Hematology & Oncology 02/2015; 8(1). DOI:10.1186/s13045-015-0113-9 · 4.93 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute graft-versus-host disease (aGVHD) is a life-threatening complication following allogeneic haematopoietic stem cell transplantation (HSCT), occurring in up to 30–50% of patients who receive human leucocyte antigen (HLA)-matched sibling transplants. Current therapies for steroid refractory aGVHD are limited, with the prognosis of patients suboptimal. Mesenchy-mal stem or stromal cells (MSC), a heterogeneous cell population present in many tissues, display potent immunomodulatory abilities. Autologous and allogeneic ex-vivo expanded human MSC have been utilized to treat aGVHD with promising results, but the mechanisms of therapeutic action remain unclear. Here a robust humanized mouse model of aGVHD based on deliv-ery of human peripheral blood mononuclear cells (PBMC) to non-obese dia-betic (NOD)-severe combined immunodeficient (SCID) interleukin (IL)-2rg null (NSG) mice was developed that allowed the exploration of the role of MSC in cell therapy. MSC therapy resulted in the reduction of liver and gut pathology and significantly increased survival. Protection was dependent upon the timing of MSC therapy, with conventional MSC proving effective only after delayed administration. In contrast, interferon (IFN)-g-stimulated MSC were effective when delivered with PBMC. The beneficial effect of MSC therapy in this model was not due to the inhibition of donor PBMC chimer-ism, as CD45 + and T cells engrafted successfully in this model. MSC therapy did not induce donor T cell anergy, FoxP3 + T regulatory cells or cause PBMC apoptosis in this model; however, it was associated with the direct inhibition of donor CD4 + T cell proliferation and reduction of human tumour necrosis factor-a in serum.

Preview

Download
0 Downloads
Available from