Neonatal exposure to a self-peptide-immunoglobulin chimera circumvents theuse of adjuvant and confers resistance to autoimmune disease by a novel mechanism involving interleukin 4 lymph node deviation and interferon gamma-mediated splenic anergy

Induction of neonatal T cell tolerance to soluble antigens requires the use of incomplete Freund's adjuvant (IFA). The side effects that could be asso ciated with IFA and the ill-defined mechanism underlying neonatal tolerance are setbacks for this otherwise attractive strategy for prevention of T ce ll-mediated autoimmune diseases. Presumably, IFA contributes a slow antigen release and induction of cytokines influential in T cell differentiation. Immunoglobulins (Igs) have long half-lives and could induce cytokine secret ion by binding to Fc receptors on target cells. Our hypothesis was that pep tide delivery by Igs may circumvent the use of IFA and induce neonatal tole rance that could confer resistance to autoimmunity. To address this issue w e used the proteolipid protein (PLP) sequence 139-151 (hereafter referred t o as PLP1), which is encephalitogenic and induces experimental autoimmune e ncephalomyelitis (EAE) in SJL/J mice. PLP1 was ex-pressed on an Ig, and the resulting Ig-PLP1 chimera when injected in saline into newborn mice confer s resistance to EAE induction later in life. Mice injected with Ig-PLP1 at birth and challenged as adults with PLP1 developed T cell proliferation in the lymph node but not in the spleen, whereas control mice injected with Ig -W, the parental Ig not including PLP1, developed T cell responses ill both lymphoid organs. The lymph node T cells from Ig-PLP1 recipient mice were d eviated and produced interleukin (IL)-4 instead of IL-2, whereas the spleen cells, although nonproliferative, produced IL-2 but not interferon (IFN)-g amma. Exogenous IFN-gamma, as well as IL-12, restored splenic proliferation in an antigen specific manner. IL-12-rescued T cells continued to secrete IL-2 and regained the ability to produce IFN-gamma. In vivo, administration of anti-IL-4 antibody or IL-12 restored disease severity. Therefore, adjuv ant-free induced neonatal tolerance prevents autoimmunity by all organ-spec ific regulation of T cells that involves both immune deviation and a new fo rm of cytokine-dependent T cell anergy.