Effect of Tolerance and Immunity on Antibody Affinity

We have described a model of immunological tolerance induced, in adult mice, by a single injection of a moderate dose of a hapten-protein conjugate. The data suggest that the mechanism of this tolerance state is the production of small amounts of high affinity antibody in response to the tolerance-inducing antigen injection. This antibody acts to inhibit the response to a subsequent challenge with antigen in complete Freund's adjuvant by a mechanism comparable to that of passive antibody-medicated immune suppression. It was shown that a small but high affinity. Tolerance was not terminated by transfer of normal syngeneic spleen or peritoneal cells into tolerant animals. Spleen cells from tolerant mice, when transferred into lethally irradiated, syngeneic animals, produced a PFC response which is greater in magnitude and tolerance state had a significant degree of carrier specificity which was shown to be comparable to the carrier specificity of antibody-mediated immune suppression. hus, evidence was presented to show that one mechanism of tolerance in adult animals in the suppressive effect of small amounts of high affinity antibody formed in response to the tolerizing injection of antigen.

Section: Methodscontrasting

confidence: 52%

“…Consequently, B-cell tolerance has been found to be associated with a marked depression in antibody affinity (13,(15)(16)(17)(18) . The tolerant state described in the current work is thus distinctive in that it is associated with an increase in antibody affinity .…”

Section: Discussionmentioning

confidence: 99%

Demonstration of an antibody-mediated tolerance state and its effect on antibody affinity.

Birnbaum¹,

Weksler²,

Siskind³

1975

“…In the current and subsequent experiments, this was taken as evidence of carrier-specific tolerance. Primary suppression was consistently maximal between days 7 and 21, and began to wane by the 4th wk after tolerance induction, and was no longer detectable by day [35][36][37][38][39][40] in most experiments.…”

Section: Resultsmentioning

confidence: 99%

Suppressor T cell memory. II. The role of memory suppressor T cells in tolerance to human gamma globulin.

Loblay¹,

Groth²,

Pritchard-Briscoe³

et al. 1983

The precise mechanism(s) of immunological tolerance to both self-and non-selfantigens remains unclear, despite substantial advances in the understanding of cellular and molecular immunology over the past three decades. Current hypotheses may be divided into two broad (but not necessarily mutually exclusive) categories: (a) those involving direct, antigen-induced clonal inactivation of specific T and/or B cells, and (b) those in which suppressor T cells (Ts) 1 are held to be responsible for specific unresponsiveness. The first category includes classical clonal deletion as described originally by Burnet (1) and modified subsequently by Bretscher and Cohn (2) in their "two signal" hypothesis. According to the latter, contact of an antigen-reactive cell with antigen alone (signal one) in the absence of a second triggering signal from a collaborating cell (signal two) leads to irreversible inactivation of the cell concerned. Related to this are certain variations (3, 4) of Lederberg's original hypothesis of selftolerance (5) which stated that developing lymphocytes are more sensitive than mature cells to antigen-induced inactivation. In some in vitro models receptor blockade has also been invoked as a mechanism for clonal inactivation (6), although this appears to be reversible (7) and its significance in vivo is uncertain.In the second category of hypotheses, antigen-specific (or in some cases idiotypespecific) suppressor cells are held to be responsible for initiating and maintaining tolerance. Although Ts have been shown to be present in a wide variety of unresponsive states (8-13), their precise role in the induction and/or maintenance of unresponsiveness remains controversial. One of the major reasons for this uncertainty is the repeated observation that the kinet.ics and magnitude of suppressive activity do not parallel the time course and degree of tolerance (14-16). Thus some investigators have come to regard the presence of Ts as a regulatory epiphenomenon of little or no relevance to the mechanism of immunological unresponsiveness (15,17,18).In this communication, Ts specific for the protein antigen human gamma globulin (HGG) have been shown to exist in two distinct functional states in tolerant animals, effector cells and memory cells. The activity of the former is readily apparent in standard adoptive mixing experiments shortly after tolerance induction, but their *

“…It is generally held that selection of precursor B cells to differentiate and to synthesize antibody is primarily dependent on the effective concentration of antigen in the micro-environment of B cells, and thus B cells with high affinity for antigen are more easily selected to proliferate and to expand their progeny (5)(6)(7)(8). Therefore, the affinity of produced antibody is primarily determined by the thermodynamic relationship between antigen and receptor of precursor B cells.…”

Section: Suppression Of Relative Avidity Of Pfc For Hapten By Carriermentioning

confidence: 99%

Selective Roles of Thymus-Derived Lymphocytes in the Antibody Response

Takemori

Tada

1974

Our preceding studies indicated that thymus-derived lymphocytes (T cells) primed with a carrier antigen suppressed antibody responses by bone marrowderived lymphocytes (B cells) against a hapten coupled to the homologous carrier, when they were transferred into immunized recipients (1). The degree of suppression in IgM and IgG antibody responses differed depending primarily on the time when suppressor T cells were transferred to the recipients. Thus, it appeared that susceptibility of B cells to the regulatory influence of T cells is inherently different according to the differentiation stages of B cells following antigenic stimulation. The results are in accordance with the widely noted distinction between IgM and IgG antibody responses with respect to their dependency on T cells (2-4).Another important facet observed in the above T-cell-mediated suppression of antibody response is the strict specificity of both T and B cells for the immunizing antigen: to elicit effective suppression T cells must be primed by the carrier on which haptens are coupled. These observations suggest that T cells would specifically influence the emergence and selection processes of B cells by antigen, resulting in the observed preferential suppression of certain populations of antibody-forming cells. It has been generally accepted that antihapten antibodies are heterogeneous with respect to their affinity for hapten, which probably reflects the heterogeneity among B cells (5-8). It has also been noted that the intrinsic affinity of IgM antibodies is usually lower than that of IgG antibodies (9-11). In view of these immunochemical bases, the present experiments were undertaken to study what subpopulations of B cells with regards to the affinity of produced antibody are, in fact, selectively suppressed by the carrier-specific T cells. Materials and MethodsMost essential experimental details have already been described in the preceding paper (1), and only a few points are added here.