Human antibody response in human peripheral blood leukocyte/severe combined immunodeficient chimeric model is dependent on B and T cell costimulation via CD40/CD40 ligand.

We have used a human/severe combined immunodeficient (SCID) mouse chimeric model (in which human PBLs are engrafted into SCID mice) to investigate in vivo the role of the CD40/CD40 ligand (CD40L) interaction in the generation of humoral immunity by engrafted human cells. It is established in this work that the thymic dependent, multiclonal, humoral immune response of human lymphocytes to mouse erythrocyte protein Ags is inhibited significantly when CD40/CD40L ligation is prevented in vivo. Suppression of the response was observed with administration of neutralizing Abs specific for either CD40 or CD40L, or with the soluble fusion protein human CD40-Fc. Human anti-mouse erythrocyte Abs and the total human Ig levels in the sera of the SCID mice were suppressed for up to 10 wk when the neutralizing agents were administered at the time of human leukocyte engraftment, i.e., coincident with Ag stimulation, and subsequently at 2 and 4 days after Ag stimulation. These results are the first to demonstrate the ability of CD40/CD40L blocking agents to inhibit the human Ag-specific humoral immune response in vivo, and they sustain the notion that these blocking agents may be utilized clinically to eliminate immune responses associated with autoimmunity or allergy. In addition to confirming the importance of the CD40/CD40L interaction of T and B cells in vivo, it is established in this work that the mouse erythrocyte-specific humoral immune response of the lymphocytes in the human PBL/SCID mouse model is a bona fide T cell-dependent response, and that this is a viable model with which to study human lymphocyte activation in vivo. These results also suggest that the costimulatory activation of human B and T cells is not dependent on the microenvironment of the germinal centers.