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Generation of High-Affinity Antibody against T Cell-Dependent Antigen in the Ganp Gene-Transgenic Mouse¹

Nobuo Sakaguchi^2,*,¶, Tetsuya Kimura, Shuzo Matsushita, Satoru Fujimura^*, Junji Shibata, Masatake Araki, Tamami Sakamoto, Chiemi Minoda and Kazuhiko Kuwahara^*,||

^* Department of Immunology, Graduate School of Medical Sciences, Division of Clinical Retrovirology and Infectious Diseases, Center for AIDS Research, Division of Bioinformatics, Institute of Resource Development and Analysis, Kumamoto University, and Trans Genic, Kumamoto Japan; ^¶ Core Research for Evolutional Science and Technology Program, Saitama Japan; and ^|| PRESTO, Japan Science and Technology Agency, Saitama, Japan

Generation of high-affinity Ab is impaired in mice lacking germinal center-associated DNA primase (GANP) in B cells. In this study, we examined the effect of its overexpression in ganp transgenic C57BL/6 mice (Ganp^Tg). Ganp^Tg displayed normal phenotype in B cell development, serum Ig levels, and responses against T cell-independent Ag; however, it generated the Ab with much higher affinity against nitrophenyl-chicken gammaglobulin in comparison with C57BL/6. To further examine the affinity increase, we established hybridomas producing high-affinity mAbs and compared their affinities using BIAcore. C57BL/6 generated high-affinity anti-nitrophenyl mAbs (K_D 2.50 x 10^–7 M) of IgG1/1 and contained the V_H186.2 region with W33L mutation. Ganp^Tg generated much higher affinity (K_D > 1.57 x 10^–9 M) by usage of V_H186.2 as well as noncanonical V_H7183 regions. Ganp^Tg also generated exceptionally high-affinity anti-HIV-1 (V3 peptide) mAbs (K_D > 9.90 x 10^–11 M) with neutralizing activity. These results demonstrated that GANP is involved in V region alteration generating high-affinity Ab.

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The JI 2005 174: 4449-4450. [Full Text]  

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				M. Yoshida, K. Kuwahara, T. Shimasaki, N. Nakagata, M. Matsuoka, and N. Sakaguchi GANP suppresses DNA recombination, measured by direct-repeat {beta}-galactosidase gene construct, but does not suppress the type of recombination applying to immunoglobulin genes in mammalian cells Genes Cells, October 1, 2007; 12(10): 1205 - 1213. [Abstract] [Full Text] [PDF]

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