Chapter 9 : Humanized Mice for Studying Human Immune Responses and Generating Human Monoclonal Antibodies

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The potential uses of human pathogen-specific antibodies are enormous in terms of both diagnostics and therapeutics. Early applications used polyclonal sera for prophylaxis and therapies, but problems such as allergic reactions, cost, and difficulty in their generation have led to the use of mouse-derived monoclonal antibodies that were humanized by various methods ( ). These methods involved substituting part or all of the murine antibody backbone with its human equivalent to derive chimeric or fully humanized antibodies. Less labor-intensive methods used transgenic mice harboring human immunoglobulin genes for immunization to derive human antibodies ( ). While this has hastened human antibody generation, some limitations exist, such as differences in the maturation processes between the mouse B cells expressing human antibodies and human B cells secreting human antibodies. Therefore, an ideal way to produce authentic affinity-matured human antibodies is to identify and harness the specific antibody-producing human B-cell clones themselves. Conventional methods involved immortalizing antigen-specific B cells from individuals who either recovered from a disease or were vaccinated with a desired antigen to derive stable antibody-producing cells. Alternatively, more recent high-throughput methods involved rescuing the specific antibody genes from either specific plasma cells or memory B cells ( ). While these methods have now become routine, they both require collecting B cells from suitable human subjects. In addition to the paucity of specific pathogen-exposed human subjects when needed and the existence of low numbers of antigen-specific cells, there are other practical and ethical considerations. One such consideration is the derivation of antibodies against dangerous pathogens such as Ebola virus. These limitations pointed out the need for a more practical experimental system that permits isolation of large quantities of antigen-specific B cells against any pathogen or antigen of interest. In this regard, newer-generation humanized mice harboring a transplanted human immune system with a capacity to yield antigen-specific B and plasma cells are expected to fill this need ( ) and are discussed here.

Citation: Akkina R. 2015. Humanized Mice for Studying Human Immune Responses and Generating Human Monoclonal Antibodies, p 157-171. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0003-2012
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Figure 1

Schematic for generation of Hu-HSC RG (Rag-hu) and BLT mice.

Citation: Akkina R. 2015. Humanized Mice for Studying Human Immune Responses and Generating Human Monoclonal Antibodies, p 157-171. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0003-2012
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Figure 2

Intrahepatic injection of CD34 hematopoietic stem cells (HSCs) into newborn immunodeficient RG mouse.

Citation: Akkina R. 2015. Humanized Mice for Studying Human Immune Responses and Generating Human Monoclonal Antibodies, p 157-171. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0003-2012
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Figure 3

Schematic for deriving human monoclonal antibodies using Hu mice.

Citation: Akkina R. 2015. Humanized Mice for Studying Human Immune Responses and Generating Human Monoclonal Antibodies, p 157-171. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0003-2012
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Summary of current Hu mouse models

Citation: Akkina R. 2015. Humanized Mice for Studying Human Immune Responses and Generating Human Monoclonal Antibodies, p 157-171. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0003-2012

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