SummaryInjection of adult mice with high doses of monomeric human gamma globulins (dHGG) has been previously shown to produce a state of peripheral tolerance in both B and T cells. To gain insight into the mechanism of induction and maintenance of adult tolerance in this model, we have analyzed the pattern of lymphokines produced by control and tolerant animals in response to the tolerogen. The data presented indicate that HGC~specific, interleukin 2 (IL-2)-and interferon 3' (IFN'q')'producing T cells (thus referred to as T helper type 1 [Thl] cells) are rendered unresponsive after in vivo administration of soluble HGG. In contrast, antigenic stimulation of T cells isolated from tolerant adult mice leads to increased production of IL-4 in vitro. In vivo challenge ofdHGGtreated adult animals with hapten-coupled HGG (p-azophenylarsonate [ARS]-HGG) induced a significant ARS-specific antibody response, suggesting that tolerance induction in this model does not completely abrogate tolerogen-specific Th activity in vivo. In agreement with the in vitro data, hapten-specific antibody response of tolerant animals is characterized by a selective deficiency in the IFN-q,-dependent IgG2a subclass. Injection of immunogenic forms of HGG into tolerant animals also produced an IL-4-dependent increase in total serum IgE levels, indicative of an increased activity of HGG-specific Th2 cells in these animals. The finding that tolerance induction differentially affects Th subpopulations suggests that crossregulation among lymphocyte subsets may play a role in the induction and/or maintenance of acquired tolerance in adults.A prime aim in the treatment of allograft rejection and autoimmune disorders is to convert antigen recognition by a mature immune system into a state of specific immune unresponsiveness. Although induction of immune tolerance in adults meets difficulties, antigen-specific unresponsiveness in mature lymphocytes has been induced in vivo by intravenous administration of allogeneic (1) or Mls-disparate cells (2), hapten-coupled syngeneic cells (3, 4), soluble antigen (5), and antigen-pulsed, chemically modified, syngeneic cells (6). In most cases described, induction of unresponsiveness does not require a thymic environment (7,8), and appears to be mediated by clonal anergy rather than clonal deletion (2, 9).Th unresponsiveness can be induced in vitro by confronting mature lymphocytes with antigen-pulsed, purified MHC molecules (10), chemically (6) or UV-treated APC (11), high doses of antigen (12), or Ib2 (13).It is noteworthy that, in most systems described to date, different sensitivities to tolerance induction in vitro have been noticed when murine helper clones producing distinct patterns of lymphokines were studied. In particular, only IL-2-producing CD4 + clones (14,15), and more recently CD8 § , Ib2-producing clones (16), have been shown to be susceptible to anergy induction by chemically damaged APC. Ib4-producing clones (Th2 cells) appear to be resistant to in vitro tolerance induction under the same experim...

Injection of high doses of monomeric human gamma globulins (dHGG) in naive, adult mice causes antigen-specific tolerance of B cell and Th1 lymphocytes, while inducing the selective expansion of antigen-specific Th2 cells. Several parameters of tolerance induction were analyzed in this work, in order to establish whether B cell tolerance and Th1 unresponsiveness were functionally related in this in vivo model. By varying the antigen form and site of injection, we demonstrate in this work that Th1 unresponsiveness to HGG is not a consequence of peripheral B cell tolerance. In particular, mice pretreated with heat-aggregated antigen (HAHGG) or F(ab')2 HGG were found to develop a strong humoral response while displaying a defective Th1 response. In fact, these animals developed a strong Th2 response in vivo, demonstrating that selective expansion of antigen-specific Th2 cells in this model is not a consequence of B cell tolerance or antigen capture by Fc receptor-expressing cells. We conclude that while B cell tolerance in this model is only observed in response to deaggregated antigen, injection of all forms of adjuvant-free, protein antigens induces T helper precursor cells to differentiate into Th2-type helper cells in vivo irrespectively of the B cell tolerance status.

The immune response of A/J mice against p-azophenylarsonate (Ars)-keyhole limpet hemocyanin (KLH) is characterized by the dominance, late in primary and during the secondary, of a recurrent idiotype called CRIA, encoded by a canonical combination of Ig gene segments. In this study, A/J mice were given Ars coupled to deaggregated human gamma globulins (dHGG) within 24 h after delivery. The offsprings from these mice were then exposed as adults to Ars-KLH. These animals developed an unusual immune response. The level of anti-Ars antibodies was nearly normal but a dramatic shift in repertoire was observed: the cross-reactive idiotype which is the hallmark of the anti-Ars response in A/J mice was completely absent. The idiotype could be recovered by injection of anti-idiotypic antibodies alone, with no need of lipopolysaccharide coupling. Therefore the presence of antigen at birth can lead to a strong perturbation of idiotype selection. Similar results were obtained with neonatal treatment using anti-IgM antibodies. After recovery of suppression, A/J mice can mount an anti-arsonate response of normal level but devoid of the dominant idiotype.

A. B CELL SUBSETSIn the field of B cell biology, many immunologists believe that any immune response may only be explained by the laws of clonal selection acting on a set of committed B lymphocytes which undergo extensive somatic mutations after antigen arrival [ 1, 21. In this view, there is no special problem of selection of available repertoires. After self non-self discrimination, available repertoires are simply those repertoires which have immunoglobulin receptors of high affinity for the antigen.Recent findings indicate that this simple Darwinian view is insufficient to understand the functioning of the immune system.There is now suggestive evidence that different subsets of B lymphocytes exist. This fragmentation of the B lymphocyte world calls for a new synthesis.At least four types of B lymphocytes have been described: a. Tolerant B lymphocytes: In many systems, anti-self lymphocytes are not clonally deleted but rather survive as anergic cells for the lifetime of the animal. This leaves us with a basic question: Why is the immune system keeping its tolerant inactivated B lymphocytes? What is their role, if any? It seems possible that these tolerant B lymphocytes play a key role in the maintenance of the tolerant state. They inform the immune system about their state. Anergic B lymphocytes are the best APC, for self antigens and being unable to furnish the costimulatory signal, they might be able to anergize T or B lymphocytes displaying affinity for the same antigen. They might also play a role in the establishment of available repertoires (see below) [3, 41. b. CD5 positive lymphocytes: Recent results suggest that they constitute a separate B cell lineage, whose embryological origin is traced to the omentum. They seem to play a major role in the synthesis of the so-called normal immunoglobulins [5, 61. c. + d. Two other subsets of B lymphocytes have been described. The primary set gives 259 Int Rev Immunol Downloaded from informahealthcare.com by UB Giessen on 11/01/14 For personal use only. Int Rev Immunol Downloaded from informahealthcare.com by UB Giessen on 11/01/14 For personal use only. Int Rev Immunol Downloaded from informahealthcare.com by UB Giessen on 11/01/14 For personal use only.

The anti‐arsonate immune response of A/J mice is characterized by the occurrence of several recurrent idiotypes with a different temporal pattern of expression. The CRI‐A idiotype is typically a memory idiotype since it appears late in the primary and dominates the secondary as well as subsequent immune responses. The CRI‐C idiotype is present throughout the responses, including the primary one. Naive adult A/J mice treated repeatedly with anti‐μ or anti‐δ monoclonal antibodies exhibit a completely different balance of HSAlow and HSAhigh B cell subsets and an opposite idiotype profile after immunization with p‐azophenylarsonate coupled to hemocyanin. Anti‐μ  treatment leads to a striking enhancement of the HSAlow cell subset associated with an earlier important synthesis of CRI‐A+ antibodies, while anti‐δ treatment enhances significantly the HSAhigh compartment with a strong decrease of CRI‐A and persistence of CRI‐C1 antibodies. Semiquantitative PCR analysis reveals that the presence of CRI‐A transcripts is associated with the HSAlow compartment, while CRI‐C transcripts are mainly associated with HSAhigh B cell subsets. This has been demonstrated with spleen cells of adult A/J mice treated with anti‐μ or anti‐δ antibodies and also with purified B cell subsets of unimmunized adult A/J mice and on neonatal spleen cells. It appears that the memory (CRI‐A) idiotype is selected into the HSAlow B cell subset before antigen arrival.