ANERGY OF ANTIGEN-SPECIFIC T-LYMPHOCYTES IS A POTENT MECHANISM OF INTRAVENOUSLY INDUCED TOLERANCE

Intravenous (i.v.) injection of an antigen before immunization has bee n shown to be a potent way to induce suppression at the T-cell level. In this study we demonstrate an almost complete suppression of arthrit is (using antigen-induced arthritis as a model) by i.v. injection of 1 00 mu g hen egg lysozyme (HEL) 7 days before immunization. Underlying mechanisms, including suppression by CD8(+) T lymphocytes, suppression by T-helper 2 (Th2) or anergy of antigen-specific T lymphocytes, were studied. In vivo treatment with either anti-CD8 or anti-interleukin-4 (IL-4) could not abrogate i.v.-induced tolerance. Lymphocyte stimulat ion assays showed reduced antigen-specific proliferative responses and IL-2 production in tolerized mice. The possible role of soluble suppr essive cytokines was examined in vitro by adding anti-IL-4, anti-IL-10 or anti-transforming growth factor-beta (TGF-beta). Neutralization of these factors could not diminish suppression. Finally, anergy of anti gen-specific T lymphocytes was tested as a possible mechanism for i.v. -induced tolerance. Results demonstrated that reduced proliferative T- cell responses were reversible: incubation of tolerized lymph node cel ls for 5 days in added recombinant (r)IL-2 fully restored proliferativ e capacity back to normal. We therefore conclude that the main mechani sm of i.v.-induced tolerance in our model is anergy of antigen-specifi c T lymphocytes.