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. 1983 Jun;80(11):3452–3455. doi: 10.1073/pnas.80.11.3452

Manifold amplification of in vivo immunity in normal and immunodeficient mice by ribonucleosides derivatized at C8 of guanine.

M G Goodman, W O Weigle
PMCID: PMC394062  PMID: 6344084

Abstract

Antigen-specific lymphocyte activation is generally thought to be initiated by the binding of antigen to specific membrane receptors, followed by transduction of a signal across the cell membrane. In addition, at least two supplementary signals apparently are required for induction of specific antibody synthesis. Various exogenous agents have been shown to augment the magnitude of specific responses to antigen. Certain of these adjuvants are polyclonal activators as well. We recently described a new class of activator, the C8-substituted-guanine ribonucleosides, that traverses the cell membrane and bypasses classical triggering mechanisms to activate the lymphocyte at an intracellular site. The current studies demonstrate that this new class of activator exerts powerful in vivo adjuvant activity when administered to mice after antigen. This effect is highly dose- and time-dependent. When nucleoside administration is delayed until 3-4 days after immunization, enhancement of the response persists but the optimal dose of nucleoside decreases by 2 orders of magnitude, indicating that these compounds are highly effective modulators of the immune response well after the initiating events have occurred. Amplification of the antibody response occurs over a wide range of antigen concentrations but is maximal at optimal antigenic concentrations. Enhancement of antibody responses in vivo is absolutely dependent upon derivatization of guanosine at C8; native guanosine is ineffective. When administered after antigen (sheep erythrocytes) to male (CBA/N X CBA/CaJ)F1 mice (which bear the xid B-cell defect) in an effort to bolster their impaired response to this T cell-dependent antigen, the brominated nucleoside induced a degree of responsiveness equivalent to that generated in the normal (female) counterparts injected with antigen and 8-bromoguanosine.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahmed A., Scher I., Sharrow S. O., Smith A. H., Paul W. E., Sachs D. H., Sell K. W. B-lymphocyte heterogeneity: development and characterization of an alloantiserum which distinguishes B-lymphocyte differentiation alloantigens. J Exp Med. 1977 Jan 1;145(1):101–110. doi: 10.1084/jem.145.1.101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Golding H., Foiles P. G., Rittenberg M. B. Partial reconstitution of TNP-Ficoll responses and IgG3 expression in Xid mice undergoing graft-vs-host reaction. J Immunol. 1982 Dec;129(6):2641–2646. [PubMed] [Google Scholar]
  3. Goodman M. G., Weigle W. O. Activation of lymphocytes by a thiol-derivatized nucleoside: characterization of cellular parameters and responsive subpopulations. J Immunol. 1983 Feb;130(2):551–557. [PubMed] [Google Scholar]
  4. Goodman M. G., Weigle W. O. Activation of lymphocytes by brominated nucleoside and cyclic nucleotide analogues: implications for the "second messenger" function of cyclic GMP. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7604–7608. doi: 10.1073/pnas.78.12.7604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Goodman M. G., Weigle W. O. Bromination of guanosine and cyclic GMP confers resistance to metabolic processing by B cells. J Immunol. 1982 Dec;129(6):2715–2717. [PubMed] [Google Scholar]
  6. Goodman M. G., Weigle W. O. Induction of immunoglobulin secretion by a simple nucleoside derivative. J Immunol. 1982 Jun;128(6):2399–2404. [PubMed] [Google Scholar]
  7. Huber B., Gershon R. K., Cantor H. Identification of a B-cell surface structure involved in antigen-dependent triggering: absence of this structure on B cells from CBA/N mutant mice. J Exp Med. 1977 Jan 1;145(1):10–20. doi: 10.1084/jem.145.1.10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. JERNE N. K., NORDIN A. A. Plaque formation in agar by single antibody-producing cells. Science. 1963 Apr 26;140(3565):405–405. [PubMed] [Google Scholar]
  9. Janeway C. A., Jr, Barthold D. R. An analysis of the defective response of CBA/N mice to T-dependent antigens. J Immunol. 1975 Oct;115(4):898–900. [PubMed] [Google Scholar]
  10. Scher I., Berning A. K., Asofsky R. X-linked B lymphocyte defect in CBA/N mice. IV. Cellular and environmental influences on the thymus dependent IgG anti-sheep red blood cell response. J Immunol. 1979 Jul;123(1):477–486. [PubMed] [Google Scholar]
  11. Strauss P. R., Sheehan J. M., Kashket E. R. Membrane transport by murine lymphocytes. I. A rapid sampling technique as applied to the adenosine and thymidine systems. J Exp Med. 1976 Oct 1;144(4):1009–1021. doi: 10.1084/jem.144.4.1009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Subbarao B., Ahmed A., Paul W. E., Scher I., Lieberman R., Mosier D. E. Lyb-7, a new B cell alloantigen controlled by genes linked to the IgCH locus. J Immunol. 1979 Jun;122(6):2279–2285. [PubMed] [Google Scholar]

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