C-8-Substituted Guanosine Analogues are Novel Immunostimulants and Differentiating Agents for Neonatal, Normal and X-Linked Immune Defective (xid) B Lymphocytes

Abstract

It was recently demonstrated that bromination or thiolation of guanosine at the C-8 position endowed it with potent biological activities, including the capacity to induce blast transformation of murine B lymphocytes and to enhance the secretion of specific antibody when administered with antigen. The guanosine, which is itself inhibitory to murine B cells, can also be converted to an immunostimulatory molecule after substitution at its C-8 position with methoxy or hydroxy groups. The present paper demonstrates that 8-hydroxyguanosine and 8-methoxyguanosine can also act as potent in vitro immunoadjuvants and the bromo or thio group is not essential for conferring biological activity to this nucleoside. Substitution of guanosine at C-8 position with -NH₂, -OH and -OCH₃ groups has differential effects in influencing B-cell activation and differentiation.

Invitro responses of B lymphocytes or spleen cells from neonatal mice and from xid immune defective (CBA/N × DBR/2) F₁ male mice to TNP-Ficoll were investigated. B cells from these mice are immunologically immature and unresponsive to antigen challenge with polysaccharide antigens including haptenated Ficoll. In the presence of 8-mercaptoguanosine, TNP-Ficoll induced TNP-specific responses in xid B cells and neonatal B cells equal in magnitude to those generated in cells from control mice. It is suggested that C-8 substituted guanosine analogues may function as differentiating factors for B lymphocytes. The use of these analogues should prove to be powerful probes for investigating the triggering mechanisms underlying the proliferation and differentiation pathways of B lymphocyte at the molecular level.