CD40 stimulation promotes human secondary immunoglobulin responses in HuPBL-SCID chimeras

Antibodies to CD40 have been demonstrated to promote B-cell growth and differentiation in vitro. In order to determine if CD40 stimulation could promote antigen-specific human immunoglobulin (Ig) production in vivo, we examined the effects of anti-human CD40 MoAb in an in vivo system where human peripheral blood lymphocytes (huPBL) were engrafted into mice with severe combined immune deficiency (SCID). The huPBL-SCID mice were then given various doses of diphtheria-tetanus toxoid (DT) vaccine and were examined for the presence of human DT-specific antibodies by ELISA. Surprisingly, treatment with anti-CD40 significantly lowered background DT responses versus untreated chimeras in unimmunized huPBL-SCID mice. However, after immunization, huPBL-SCID mice treated with anti-CD40 MoAb responded to a significantly greater extent in response to the vaccine compared with control huPBL-SCID mice, although total Ig levels were sometimes lower in anti-CD40-treated mice. The predominant Ig isotype induced after immunization was IgG. Thus, CD40 stimulation promotes human secondary IgG responses in huPBL-SCID mice. These data demonstrate that CD40 stimulation is capable of promoting antigen-specific human B-cell responses in vivo.