Passive antibody administration shows strong potential as a new therapeutic method. In clinical applications, human-derived antibodies with antigen specificity are more useful without putting individuals at risk. Production of human-derived antibodies against given antigens can be obtained from animal models if the human immune system is established in the animals. In fact, past reports revealed that human T and B cells develop from hematopoietic progenitor cells in immunodeficient mice. However, there have been few reports on sufficient induction of antigen-specific antibodies, particularly IgG, in immunodeficient mice reconstituted with human immune cells. In this chapter, we discuss a major shortcoming of induction of antigen-specific IgG antibodies in human immune cells developed in the murine environment based on our data. We demonstrated that human T cell development is restricted by the murine MHC and consequently T cells may not achieve cognate interaction with human B cells. Human B cells developed in the mouse are mainly CD5+B1 cells that preferentially produce IgM. At the same time, human LN transplantation on the spleen enabled NOG mice to produce antigen-specific IgG antibody. These results suggest that if efficient cognate interaction mediated by a certain antigen on MHC class II between human T and B-2 cells occurs, human B cells can produce IgG antibody against a given antigen in the murine environment.