Restoration of humoral immunity in vitro in immunodeficient aging mice by C8-derivatized guanine ribonucleosides.

The relative capacities of two classes of immunomodulator to augment the deficient immunity of senescent mice were evaluated. Bacterial lipopolysaccharide (LPS) was used as the prototype for modulators that depend on normal membrane function for signal transduction, and 8-mercaptoguanosine (8MGuo) represents a class of immunomodulator that transverses the cell membrane and induces its effects from an intracellular location. The current studies demonstrate that 8MGuo induces polyclonal immunoglobulin production in cultures from both young and senescent mice, whereas LPS can induce such activity only in cell cultures from young adult mice. Furthermore, LPS was unable to enhance the magnitude of antigen-specific responses in aged mice, in contrast to the marked adjuvant effects of 8MGuo. 8MGuo, but not LPS, provided an effective T cell-like signal that induced responsiveness to a T-dependent antigen in B cells from senescent mice. These B cells thus were able to transduce antigen-specific (first) but not nonspecific (second) signals, provided by agents such as LPS, across the cell membrane. Together, these observations suggest that the C8-derivatized guanine ribonucleosides substantially improve the immunodeficiency of aging by short-circuiting a B cell defect and providing a perceived second signal to lymphocytes from senescent animals.