Tolerogenic or immunogenic activity of hapten‐conjugated polysaccharides correlated with cellular localization

Abstract

Dinitrophenylated (DNP) conjugates of Ficoll, hydroxyethyl starch, levan, dextran, type 3 pneumococcal capsular polysaccharide SIII, pectin, alginic and hyaluronic acid at various epitope densities were tested for their capacity to inhibit secondary IgG anti-DNP antibody responses using an in vivo transfer system. Some aminobenzylarsonate conjugates were examined similarly. Conjugates of the acidic polysaccharides were markedly more effective than those of uncharged polysaccharides. Conjugated with high epitope densities were particularly tolerogenic. DNP conjugates of Ficoll and hydroxyethyl starch elicited prolonged IgM responses over a wide dose range, and there are indications in the literature that conjugates of dextran do likewise. All the polysaccharide conjugates, labeled with radioiodine, persisted in the body for long periods (half-lives 8.5--63 days), and all were cleared rapidly from, but remained detectable in the blood for many days. Gross tissue distributions varied markedly from one conjugate to another, and autoradiography revealed unexpected differences in cellular localization. Despite substantial retention in the liver, some uncharged polysaccharides were localized only in parenchymal and not in Kupffer cells. In the spleen, only the acidic polysaccharides were predominantly localized in red pulp macrophages, and the neural polysaccharides were detectable exclusively, and in the case of Ficoll, hydroxyethyl starch and some dextrans very intensely in macrophages of the marginal zone of the white pulp. It is suggested that retention of thymus-independent antigens in marginal-zone macrophages favors, whereas trapping in red-pulp macrophages diminishes immunogenicity, and that tolerogenic effectiveness depends upon a balance between tolerization of B cells by free antigen and stimulation by antigen presented by marginal-zone macrophages. The distinction between functionally different macrophages in the spleen is elaborated in the following report.

Characterization of two monoclonal antibodies (UCL4D12 and UCL3D3) that discriminate between human mantle zone and marginal zone B cells

“…Two functions have been ascribed to marginal zone cells. In earlier work it was shown that these cells are important in immune responses to thymusindependent (T12) antigens (Humphrey, 1981), a result in agreement with the observation that splenectomized individuals who are depleted of marginal zone cells, respond poorly to thymus independent antigens (Amlot & Hayes, 1985). More recently extensive studies in the rat have led to the suggestion that the marginal zone contains memory B cells Kumararatne & MacLennan, 1981;Zhang et al, 1988).…”

“…It is likely that somatic mutation events leading to production of high affinity antibodies take place in this site (MacLennan & Gray, 1986). The third population of B cells is that of the splenic marginal zone which contains a mixture of cells at intermediate stages between small lymphocytes and plasmablasts, as well as macrophages (Humphrey, 1981). These B cells express sIgM but not sIgD and have avid Fc and C3 receptors , Liu, Oldfield & MacLennan, 1988.…”

T-Cell-Independent Responses toBorrelia burgdorferiAre Critical for Protective Immunity and Resolution of Lyme Disease

“…Additionally, even though the presence of T cells hastened class switching, they did not cause a pronounced fall in antibody titer after peak production had been reached, suggesting the absence of a TD regulatory event and potentially reflecting the presence of persisting antigen. Antigen persistence is a characteristic trait of most if not all TI antigens, probably reflecting their complex nature and resistance to degradation, as well as their tendency to be associated with per- sistent infection (20), which are all characteristics of B. burgdorferi infection (7).…”

Repeated injection of PEGylated solid lipid nanoparticles induces accelerated blood clearance in mice and beagles

“…For most T-cell-independent type 2 antigens, the prolonged contact of the antigens with membrane immunoglobulin and persistent B-cell signaling is common in inducing a humoral immune response in the absence of helper T cells. 37,38 Consequently, in addition to the density of PEG, it is rational to speculate that extended circulation time also plays an important role in the induction of the ABC phenomenon. Regarding 5 mol% PEG SLNs, because of the only slightly prolonged circulation time, inefficient contact of the PEGylated SLNs with membrane immunoglobulin stimulated B-cells and resulted in secretion of a small amount of anti-PEG IgM, with only a weaker immune response and insignificant ABC phenomenon.…”