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Methods of producing humanized non-human mammals

A mammalian, non-human technology, applied in the field of manufacturing humanized non-human mammals, which can solve the problems of poor, undetectable and non-functional NK cells and myeloid cells

Inactive Publication Date: 2012-10-10
MASSACHUSETTS INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

B cell reconstitution is robust and T cell reconstitution is adequate, but both B and T cells are nonfunctional
Furthermore, reconstitution of NK cells and myeloid cells is often poor or undetectable

Method used

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  • Methods of producing humanized non-human mammals
  • Methods of producing humanized non-human mammals
  • Methods of producing humanized non-human mammals

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0104] Expression of human cytokines in humanized mice (Humice) significantly enhanced reconstitution of specific human blood cell lineages.

[0105] Materials and Methods

[0106] HSC isolation, construction of humanized mice, and hydrodynamic gene delivery. Human cord blood was obtained from the Singapore Cord Blood Bank. Cord blood mononuclear cells (MNC) were separated by a Ficoll-diatrizoate density gradient. RosetteSep was used according to the manufacturer's scientific protocol (Stem Cell Technologies) system to purify CD34+ cells. CD34 + The purity of the cells was >95%. To expand HSCs, purified CD34 + Cells were cultured for 11 to 14 days (Zhang CC, Kaba M, Iizuka S, Huynh H, Lodish HF (2008) Blood 111:3415-3423). Humanized mice were generated using unexpanded and expanded HSCs.

[0107] NSG mice were purchased from Jackson Laboratories and maintained under specific pathogen-free conditions in the animal laboratories of Nanyang Technological University and Na...

example 2

[0131] Expression of human cytokines enhances human T and B cell reconstitution and function in humanized mice

[0132] Reconstitution of human T and B cells was adequate in humanized mice, but they did not display optimal function. For example, although human CD8 has been detected after viral challenge + T cell responses, these CD4 + T cell function is abnormal; human B cell-mediated antibody responses are absent in humanized mice. As shown here, abnormalities in human T-cell and B-cell responses are also due to poor cross-reactivity of mouse cytokines with human cells in mice. Shown here is that injection of plasmids encoding human GM-CSF and IL-4 into humice results in human CD209 + Reconstitution of dendritic cells, which are considered the primary antigen-presenting cells against T cells, is enhanced. In addition, IL-4 has also been shown to promote cell proliferation, survival, and immunoglobulin class switching to IgG and IgE in human B cells, and acquisition of a T...

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Abstract

Provided herein are methods of reconstituting functional human blood cell lineages in a non-human mammal comprising introducing human hematopoietic stem cells (HSCs) and nucleic acid encoding one or more human cytokines into an immunodeficient non-human mammal. The non-human mammal is maintained under conditions in which the nucleic acid is expressed and the human HSCs differentiate into functional human blood cell lineages in the non-human mammal, thereby reconstituting functional human blood cell lineages in the non-human mammal. Also provided are methods of producing human antibodies directed against an immunogen in a non-human mammal, hybridomas that secrete the monoclonal antibodies as well as antibodies (e.g., polyclonal antibodies; monoclonal antibodies) produced by the B cells and non-human mammals produced by the methods.

Description

[0001] related application [0002] This application claims the benefit of US Provisional Application No. 61 / 221,438, filed June 29, 2009. The entire teachings of one or more of the above applications are hereby incorporated by reference. Background of the invention [0003] There is a great need to study the human immune response to pathogen infection in a synthetic and controlled manner in small animal models. Significant efforts have been invested in the past two decades to reconstitute severe combined immunodeficiency (scid) mice lacking T and B lymphocytes with cells of the human blood lineage (Shultz LD, Ishikawa F, Greiner DL (2007) Nat RevImmunol 7:118-130). However, early attempts were unsuccessful due to poor engraftment in recipient mice, rapid disappearance of human T and B cells, or rapid development of hematopoietic malignancies. Achieved by using recipient mice lacking not only T and B cells (due to scid mutations or recombination-activating gene (Rag) mutati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N5/071
CPCA01K67/0271A01K2267/0381C07K16/2893A01K2227/105A01K2267/0331A61K39/3955A01K2207/12A61K2039/505A01K67/027C07K2317/24A61K2300/00
Inventor 陈清风陈建竹
Owner MASSACHUSETTS INST OF TECH
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