ANTIGEN-SPECIFIC HUMAN-IMMUNOGLOBULIN PRODUCTION IN SCID MICE TRANSPLANTED WITH HUMAN PERIPHERAL LYMPHOCYTES IS DEPENDENT ON CD4(-CELLS() CD45RO(+) T)

Severe combined immunodeficient (SCID) mice, lacking mature T and B ce lls and virtually devoid of endogenous serum immunoglobulins, spontane ously produce large amounts of human immunoglobulin after transplantat ion with human peripheral blood lymphocytes (PBL). Moreover, after imm unization with antigen an active immune response resulting in a produc tion of specific antibodies can be induced. Here we report that human T cells must be co-transplanted with B cells into the SCID mice for im munoglobulin production to occur. Resting human B cells could be activ ated to immunoglobulin production in the absence of human monocytes an d a specific antibody response to tetanus toroid (TT) could be induced , suggesting that the human B cells could present antigen to T cells i n the SCID environment. Production of human immunoglobulins, as well a s specific antibodies, was obtained only if CD4(+) T cells of the memo ry phenotype, i.e. expressing CD35RO, were present. No human immunoglo bulin, either of IgM or of IgG isotype, was found in SCID sera if mice were co-transplanted with human B cells and CD45RA expressing CD4(+) T cells. However, FACS analysis revealed that the transplanted CD45RA( +) cells became activated and differentiated towards CD45RO(+) cells w ithin 1-2 weeks. These cells also gained the lymphokine gene expressio n pattern associated with CD45RO(+) cells, as demonstrated by polymera se chain reaction (PCR) analysis, and could support immunoglobulin pro duction in SCID mice transplanted with fresh B cells. In fact, after d ifferentiation of CD4(+) CD45RA(+) T cells towards expression of CD45R O, either in vivo in the SCID mouse or in vitro, these cells could int eract with and activate human B cells to immunoglobulin production. Fu rthermore, in vitro activated and differentiated CD4(+) CD45RA(+) T ce lls from vaccinated donors were also able to support production of TT- specific antibodies provided the antigen was administered.