Induction in mature animals

Although it is well-established that a system of negative and positive selection occurs in the thymus, resulting in shaping of a nonself-reactive T cell repertoire, tolerance can also be induced to foreign antigens either in early or late life under the appropriate conditions. The finding that certain Vp specificities of the T cell receptors that are reactive in vitro to self antigens are absent in mice possessing these antigens has led to a number of recent and important studies that have given considerable insight to self-nonself recognition. Later studies using a variety of superantigens which activate an entire T cell population expressing the same Vp T cell receptor, irres pective of antigenic specificity, also demonstrated that in vivo exposure to these superantigens results in the elimination of these cells. The models resulting from such studies yield valuable information concerning immunogenetics of tolerance induction, possible mechanisms of negative and positive selection within the thymus and T cell anergy.

These latter models, however, do not readily lend themselves to understanding the mechanisms of tolerance induction involving the cytokine cascade, antigen presentation, roles of activation events and intracellular biochemical processes as well as the role of antigen processing. Another model, the unresponsive state induced in adult mice to monomeric forms of mammalian gamma globulin, more readily lends itself to the investigation of these latter events. An in vivo model of a central unresponsive state is presented in this review to delineate the conditions required for the induction and maintenance of self tolerance and the role of such induction and maintenance on susceptibility to autoimmunity.

A classical in vivo model of tolerance which mimics a number of aspects of self tolerance has been studied in the past by several groups of workers using monomeric preparations of mammalian gamma globulin. In the model to be discussed below, tolerance is induced to human gamma globulin (HGG) by a single injection of adult mice with deag-gregated (monomeric) HGG (DHGG). Furthermore, tolerance to HGG is also readily induced in neonatal mice. Adult treated mice fail to respond to a subsequent injection of aggregated HGG (AHGG) at both the T helper and B cell levels. However, as much as 2-3 logs less HGG are required to induce tolerance in T helper cells than in B cells (Figure 1). This observation suggests that tolerance to self antigens present in limited concentration may exist in only the T cell compartment, and, thus, has implications in antibody-induced autoimmunity. Although it is not known whether tolerance in this model is the result of anergy or deletion, it is independent of both suppressor cell activity and Fc~/ receptor expression. Of particular interest is that antigen-specific T cell proliferation, T helper function, antibody production and cytokine release are tolerized by prior injection of DHGG. This tolerance is independent of the thymus, since it can be induced in adult thymectomized as well as normal mice. Fol-

Figure 1 Effect of deaggregated human gamma globulin (DHGG) dose on the induction of tolerance to aggregated HGG (AHGG) in mouse T helper cells and B cells.

lowing a single injection of the tolerogen, tolerance to immunogenic challenge is induced in B cells and all subsets of T cells capable of releasing cytokines upon in vitro stimulation. The down side of this model is that purified preparations of HGG (immunoglobulin Gl, IgGl) rendered monomeric by ultracentrifugation (at 4°C) are required. These preparations are relatively unstable and aggregate over a relatively short period of time.

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