Effect of donor and recipient immunization protocols on primary and secondary human antibody responses in SCID mice reconstituted with human peripheral blood mononuclear cells

Abstract

We have examined the ability of mice with severe combined immunodeficiency (SCID mice) reconstituted with human peripheral blood mononuclear cells (PBMC) to generate human antibody responses after specific immunization. SCID mice reconstituted with cells from a keyhole limpet hemocyanin (KLH)-naive donor are unable to generate specific human antibody responses after immunization with that antigen. After KLH immunization, SCID mouse recipients of human PBMC from a KLH-immune subject develop specific human antibody levels exceeding those of the donor. Human antitetanus antibody titers in reconstituted, immunized mice are also equivalent to those of the donor, provided that the mice are immunized within days of human cell transplantation. The ability of reconstituted mice to generate high titers of specific human antibody is lost within 35 days of human cell reconstitution, even though titers of total human immunoglobulin (Ig) are preserved. SCID mice reconstituted with tetanus-immune donor cells fail to generate IgA responses after booster immunization, and IgM responses are low or nonexistent. These data indicate that early exposure of the adoptive recipients of human cells to antigen is required to transfer specific human humoral responses. These findings are also consistent with a requirement for persistence of antigen for the maintenance of B-cell memory. The ability to achieve specific human antibody levels equivalent to those obtained with humans indicates that reconstituted mice may be useful for the evaluation of human antibody-mediated mechanisms of resistance to infection. The data indicate, however, that cells from immunized donors will have to be used for such studies.