Ontogeny of B-lymphocyte function. III. In vivo and in vitro studies on the ease of tolerance induction in B lymphocytes from fetal, neonatal, and adult mice

Abstract

It has generally been felt that tolerance can be induced more readily in neonatal than in adult animals. While this is clearly true in allograft tolerance induction (1), it has been less obvious with other antigens. Thus, Siskind et al.(2) and Howard and Hale (3) found no difference between neonatal and adult mice in regard to tolerance induction with polysaccharide antigens and Dresser (4) found that the dose of aggregate-free bovine gamma globulin (BGG) 1 required to induce tolerance in mice was the same in neonatal and adult animals. It has been unclear as to whether immature lymphocytes are or are not more sensitive to tolerance induction than are mature lymphoid cells. Recently, in vitro studies (5-7) have shown that tolerance could be induced in vitro in B lymphocytes from immature donors at antigen concentrations far lower than that required for tolerance induction in mature B lymphocytes.In the studies reported here a cell transfer system was employed so that the susceptibility of B cells to tolerance induction could be assayed in the absence of T cells and in a constant, adult, in vivo environment. It was found that with two hapten-carrier conjugates neonatal cells were indeed more susceptible to tolerance induction, both in vivo and in vitro, than were adult B cells. However, with BGG as antigen no difference was detected between B cells from 17-day fetal mice, neonatal mice, and adult mice with regard to the ease of tolerance induction either in vivo or in vitro. The results thus suggest that the relative ease of tolerance induction in immature B cells may be limited to moderately polyvalent antigens such as hapten-carrier conjugates.

In vitro model for natural tolerance to self-antigens. Inhibition of the development of surface-immunoglobulin-negative lymphocytes into T-dependent responsive B cells by antigen.

“…Numerous reports have documented the extreme sensitivity of neonatal B cells to multivalent antigens compared with adult B cells (5,20,(26)(27)(28)(29)(30). Likewise, in this study it was found that neonatal unfractionated spleen cells and s-Ig-positive B cells were sensitive to tolerogen with an ~60-70% reduction in responsive B cells, although adult unfractionated spleen cells and adult s-Ig-positive B cells remained refractory to tolerogen.…”

The Role of Receptor IgM and IgD in Determining Triggering and Induction of Tolerance in Murine B Cells1

“…The one major caveat in suggesting that the in vilro model reflects in vivo differentiation is the recent finding of Szewczuk & Siskind (1977). Hence, the issue raised by Szewczuk & Siskind (1977) is not yet resolved. They therefore questioned the physiological significance of in vitro models in which polyvalent antigens, such as heavily conjugated DNP-HgG are employed.…”

“…Thus, studies by Szewczuk & Siskind (1977) and by Howard & Hale (1976) indicate that adult and neonatal B cells responding to TI antigens are equally susceptible to tolerance induction. Thus, studies by Szewczuk & Siskind (1977) and by Howard & Hale (1976) indicate that adult and neonatal B cells responding to TI antigens are equally susceptible to tolerance induction.…”

Immunosenescence and Immune Response in Organ Transplantation

“…The numbers of memory B cells (CD27+) are increased with aging [27]. An increased proportion of mature B cells may also account for the increased resistance to tolerance induction in the elderly [28–31]. …”