In vivo induction of tolerance in murine CD4+ cell subsets.

Abstract

SummaryThe induction of tolerance in mice to preparations of deaggregated human gamma globulin (DHGG) results in in vitro antigen-specific unresponsiveness in CD4 + T cells as well as in both the T helper 1 (Thl) and Th2-1ike subpopulations. Whereas both CD45RB hi and CD45RB l~ cells from lymph nodes of HGG/complete Freund's adjuvant-immunized mice (control) proliferated in vitro to HGG, both subpopulations from mice previously tolerized with DHGG failed to respond. Furthermore, CD4 + T cells from control, but not from DHGG-injected mice, secreted high levels of interleukin 2 (IL-2) after in vitro stimulation with HGG. Although significant levels of IL-4 in supernatants of control CD4 + cells stimulated with HGG were detected in some, but not all, experiments, significant levels of IL-4 were never detected in supernatants of HGGstimulated tolerant CD4 + cells. The demonstration that serum IgG1 anti-HGG is preferentially produced in a few tolerant mice that exhibit a leaky tolerant state suggests that tolerance induction may be more dif~cult to induce in IL-4-than in IL-2-producing cells.A solid and long-lasting tolerant state can be induced in adult mice by a single injection of deaggregated human gamma globulin (DHGG) 1 (for a review see reference 1). Although tolerance is induced in both T and B cells, the dose of tolerogen required for B cell tolerance is 2-3 log10 greater than that for T cell tolerance (for a review see reference 1). The tolerant state in T cells is of long duration, whereas in B cells it is of relatively short duration (2). Induction of tolerance in T cells is independent of the thymus and is not controlled by regulating T cells (3). Although the in vivo induction of tolerance in the T cells can be interfered with by generators of IL-1 or IL-1 itself (4, 5), once induced, the tolerant state cannot be terminated by these reagents. In addition to the in vivo induction of tolerance, tolerance has been induced in HGG-specific T cell clones using either DHGG (6, 7) or inappropriate antigen presentation (8-10). Whereas tolerance in Thl clones is induced in terms of both proliferation and T cell help, tolerance in Th2 clones is induced at only the T helper level (10, 11). Whether the in vivo induction of tolerance occurs in all CD4 + cell populations has recently been questioned. Data have been reported that imply that DHGG induces tolerance in IL-2-producing T cells, but induces responsiveness in IL-4-producing cells, resulting in IL-4 production and T helper activity (12).1Abbreviations used in tkis paper: DHGG, deaggregated human gamma globulin; HGG, human gamma globulin.In this report, the susceptibility of CD4 § cells and their subsets to the induction of tolerance to DHGG was assessed. Our results demonstrate that when mice are exposed to HGG as a tolerogen before immunization, such that the in vitro antigen-specific proliferation of CD4 + T cells is totally abrogated and serum antibody levels are dramatically reduced, antigen-specific proliferation of both Thl-and Th2-1ike subsets is abroga...

Induction of Peripheral T Cell Tolerance by Antigen-Presenting B Cells. I. Relevance of Antigen Presentation Persistence

“…It is, indeed, well known that i.v. injection of high doses of soluble Ags can induce tolerance of Ag-specific CD4 ϩ and CD8 ϩ T cells (25). The importance of the balance between Ag dose and specific T cells has also been stressed in experiments performed in TCR Tg animals in which, given the high frequency of Ag-specific T cells, peripheral tolerance by injection of soluble Ags can be reached only if the number of T cells is decreased by anti-CD4 Ab treatment (26).…”

Immune Tolerance Split between Hepatitis B Virus Precore and Core Proteins

“…Monomeric HBeAg is significantly less immunogenic than particulate HBcAg at the T-and B-cell levels even when formulated in adjuvants (29). Furthermore, monomeric secreted antigens tend to be more tolerogenic than immunogenic in general (41,52).…”

Prevention of collagen-induced arthritis (CIA) by treatment with polyethylene glycol-conjugated type II collagen; distinct tolerogenic property of the conjugated collagen from the native one

“…Alternatively, the distinct tolerogenic properties of PEG-conjugated proteins may be explained as a consequence of changes in chemical properties; PEG modification is shown to increase resistance to proteolytic degradation and decrease plasma clearance rates [11,12,42], the properties considered to be important for the tolerogenic capacity of proteins [21]. However, the precise mechanism for the different tolerogenic property of PEG-conjugated proteins remains to be elucidated, and investigation is in progress in our laboratories.…”

“…Other investigators have reported an additional immunological change in proteins due to the PEG modification; proteins could be rendered not only nonimmunogenic but also tolerogenic [18,19]. However, the necessity or benefit of the PEG conjugation of antigens to induce tolerance has been left undetermined, since, as mentioned above, unconjugated native proteins are also capable of inducing tolerance when the treatments are properly scheduled [1,2,20,21]. It is therefore important to compare the tolerogenic activity of PEG-protein conjugates with that of the native counterparts.…”