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Biomedical subjects

Y Borel

Publications and source records attributed to Y Borel.

At least 73 records · Page 4Linked to original sources
PubMed1978

Direct evidence for loss of human suppressor cells during active autoimmune disease.

These studies indicate that a regulatory subset of lymphocytes is missing in patients with juvenile rheumatoid arthritis but these patients have antibodies in their serum that react with normal T cells. This regulatory subset of T cells is, however, present in patients whose serum shows little or no reactivity with normal T cells. In addition, patients who are deficient in this regulatory subset of lymphocytes significantly higher numbers of cells secreting Ig as measured by a hemolytic plaque assay. The significance of these observations is twofold: first, they represent a positive relationship among the loss of regulation overproduction of immunoglobulin, and the presence of anti-T cell antibodies and second and perhaps of equal importance, is the indication that serum from patients with autoimmune diseases may give us a readily available reagent with which to dissect further functionally distinct subsets of normal T cells in man.

Adolescent↗
PubMed1978

Treatment of lupus nephritis in adult (NZB + NZW)F1 mice by cortisone-facilitated tolerance to nucleic acid antigens.

Adult female (NZB + NZW)F1 mice were treated with cortisone, cortisone with tolerogen (isologous NZB IgG-nucleosides conjugates) or cortisone with isologous IgG free of nucleosides. Other treatments also included tolerogen or isologous IgG alone, and cortisone together with denatured DNA. All untreated mice died by 10 mo of age. Cortisone prolonged the survival rate. This effect was further improved by combined treatment of cortisone and tolerogen. Prolonged survival was accompanied by a decrease in proteinuria. Other treatments failed to influence either survival or proteinuria. Although cortisone did not prevent the appearance of antibody to denatured DNA, cortisone and tolerogen suppressed them in most of the animals. Preexisting antibody to denatured DNA was reduced by cortisone and cortisone and tolerogen, but not by cortisone and IgG. In contrast, antibody to native DNA bore no relationship to therapy. Animals living beyond 1 yr of age, regardless of the treatment, fall into three histopathological categories: (a) severe nephritis, as in untreated animals, (b) moderate nephritis (with absence of severe alteration of the glomerular basement membrane, i.e. the histological counterpart of prolonged survival), (c) minimal nephritis. In a small number of animals treated with cortisone or cortisone and IgG and in 6/20 animals treated with cortisone and tolerogen, minimal lesions as judged by light, fluorescent, and electron microscopy were found. These last mice were in good health at 15-16 mo of age, twice the life-span of untreated mice. In conclusion, these data suggest that tolerance to nucleic acid antigens facilitated by cortisone offers a promising new approach to treat established murine lupus nephritis.

Animals↗
PubMed1978

Hapten-specific tolerance induced by hapten conjugates of D-glutamic acid, D-lysine (D-Gl) or isologous gamma-globulin: evidence for central B cell tolerance in the presence of carrier-primed helper T cells.

A comparison has been made of the well known hapten-specific tolerance systems induced, respectively, by hapten-D-GL or hapten-isologous gamma-globulin conjugates. The principal question addressed in this study concerned the comparative maintenance of B cell tolerance, induced by one or the other method, after adoptive transfer into carrier-primed, irradiated recipient animals and, in addition, what role, if any, might be played by T lymphocytes in the tolerant donor cell population in maintaining such tolerance. The results clearly show that insofar as the hapten-specific B cell is concerned, no obvious difference exists in the capacity to maintain tolerance adoptive transfer between the hapten-D-GL and hapten-isologous gamma-globulin systems; such cells remained tolerant even in the presence of excess helper T cell activity. Moreover, under the conditions employed, depletion of T lymphocytes from the tolerant donor cell population did not affect the maintenance of hapten-specific B cell tolerance after adoptive transfer to irradiated recipients.

Animals↗
PubMed1977

Nucleoside-specific tolerance suppresses anti-nucleoside antibody forming cells.

Since its original development by Jerne, the haemolytic plaque assay has increased our understanding of antibody formation to a wide variety of antigens, including proteins, lipopolysaccharides, and simple haptens. We have now developed an assay to detect plaque forming cells (PFC) making anti-nucleoside antibodies. Previously we reported the suppression of circulating antibody to DNA determinants by nucleoside-IgG conjugates. Here we show that BALB/c mice can be rendered tolerant in terms of both direct and indirect anti-nucleoside antibody forming cells and that the state of tolerance is nucleoside-specific at the cellular level.

Animals↗
PubMed1976

Effect of anti-carrier antibody on carrier-determined tolerance.

These experiments were originally designed to determine whether an anti-carrier antibody, e.g., anti-allotype could break hapten-specific tolerance in vivo. Tolerance to 2,4-dinitrophenyl (DNP) was induced in C57BL/6J mice using DNP-BALB/c IgG2a conjugate. When anti-allotype serum was injected in C57BL/6J mice one day after a single injection of DNP-IgG2a the mice were not tolerant. In contrast, when tolerance was induced by four weekly injections of tolerogen, the anti-allotype serum had no effect on the tolerant state. This effect was specific for tolerance-inducing carrier. Anti-carrier antibody injected in C57BL/6J mice one day after DNP-IgG2a produced a small but significant anti-DNP response without administration of the immunogen, whereas the tolerogen (DNP-IgG2a) by itself was not immunogenic. Similarly, despite multiple injections of DNP-IgG2a bearing the foreign allotype, only one out of 7 C57BL/6J mice showed a weak anti-carrier response. In contrast, a marked anti-carrier (IgG2a) response was obtained when the anti-allotype antibody was passively administered in C57BL/6J mice. In conclusion, these experiments suggest that tolerance to an antigenic determinant may be broken by an antibody directed not to this determinant, but to another on the same molecule. The significance of this finding in relationship to the mechanism of the carrier-determined tolerance and the breakdown of self-tolerance is discussed.

Animals↗
PubMed1976

Loss of carrier-determined tolerance in vitro with loss of receptor blockade.

Experiments were done to determine whether carrier-determined tolerance is reversible and whether the loss of tolerance is accompanied by the loss of receptor blockade. Spleen cells from mice made tolerant with DNP-isologous IgG remained tolerant when transferred to irradiated syngeneic mice. If these same tolerant spleen cells were incubated for 24 hr or more before transfer the tolerance was lost. Autoradiology was done on the tolerant cells with either 125I anti-DNP or 125DNP-KLH, before and after incubation in vitro. When the cells were tolerant the number of DNP ABC was decreased whereas cells having DNP on their surface were increased. When the cells lost tolerance after in vitro incubation, the hapten-bearing cells were no longer present although the number of cells free DNP receptors increased to normal. These data suggest that in carrier determined tolerance the reactivation of tolerant lymphocytes may involve reversible receptor blockade.

Animals↗
PubMed1976

Nucleoside specificity in the carrier IgG-dependent induction of tolerance.

Induction of tolerance to nucleoside haptens in BALB/c mice with isologous IgG conjugates bearing four nucleosides simultaneously (A, G, C, T)-IgG was confirmed. A mixture of separate nucleoside-IgG tolerogens (A-IgG, G-IgG, C-IgG, and T-IgG) was as effective or more effective that the (A, G, C,T)-IgG form in suppressing the response to (A, G, C, T)-KLH. The nucleosides acted independently and simultaneously, since tolerogens with varying combinations of nucleosides caused specific suppression of the respones to only those nucleosides present on the tolerogen. Nucleoside-IgG conjugates did not suppress the response to denatured DNA-methylated bovine serum albumin, in which larger oligonucleotide determinants predominate. In varying combinations, guanosine was the dominant nucleoside both for immunization and for induction of tolerance. After three or four immunizations, control immunized animals made mainly IgG anti-nucleoside antibodies and this IgG antibody formation was preferentially suppressed in tolerogen-treated animals. Tolerance could be established before the primary or secondary immunization and it then persisted for at least 75 days through a fourth course of immunization. The same dosage of tolerogen did not reverse a strongly established anti-nucleoside antibody production after a tertiary response.

Adenosine↗
PubMed1976

Carrier determined tolerance with various subclasses of murine myeloma IgG.

Groups of BALB/c mice were treated with various conjugates of 2,4 dinitrophenyl (DNP) and BALB/c myeloma proteins belonging to the four subclasses of IgG (IgG1, IgG2, IgG2b, IgG3). Immediately therafter, they were challenged with DNP-keyhole limpet hemocyanin in complete Freund's adjuvant and antibody to the hapten was measured by direct and indirect hemolytic plaque assay. The results show that all subclasses of IgG are effective as tolerance-inducing carriers. However, the ability of induce tolerance is dependent upon the concentration of hapten bound to each myeloma protein. Tolerogenic conjugates suppress both direct and indirect plaque-forming cells in all types of antibodies measured (IgG1, IgG2a, IgG2b, IgGa), whereas, non-tolerogenic conjugate failed to suppress them. The intact molecule of IgG but not its fragments (Fab, F(ab)2', Fc) appear necessary as tolerance-inducing carriers. It is suggested that the ability to induce tolerance is related to the capacity of the tolerogenic conjugates to cause receptor blockade.

Animals↗
PubMed1975

T and B cell in hapten-specific carrier-determined tolerance.

BDF1 mice were made tolerant by a single i.v. injection of 1 mg of DNAP-gamma1 or by weekly i.v. injections of 0.2 mg of DNP-gamma1 given for a month. In both instances, spleen cells of tolerant animals were fractionated to obtain pure populations of T cells (nonimmunoglobulin-bearing cells), referred to as tolerant T cells, and B cells (immunoglobulin-bearing cells) referred to as tolerant B cells (immunoglobulin-bearing cells) referred to as tolerant B cells. The control cells were similarly fractionated to obtain normal T and B cells. Mixtures of tolerant T cells and normal B cells, or conversely, normal T cells and tolerant B cells were used to repopulate lethally irradiated recipients. These recipients were then immunized with dinitrophenyl-keyhole limpet haemocyanin and in certain instances with other antigen horse red blood cells. The immune response to both antigens was measured using the direct hemolytic plaque assay. It was found that both T and B cells were tolerant and that tolerance was hapten specific at both T- and B-cell levels. While B-cell tolerance was demonstrated at a 1/1 T/B ratio, a 4/1 T/B ratio was necessary to show T-cell tolerance. Thus, the hapten-specific carrier-determined tolerance involves not only B cells but also T cells. The implication of this finding for the cellular mechanism of tolerance in an experimental model closely related to self tolerance is discussed.

Animals↗
PubMed1975

Suppression of in vitro antibody response by a serum factor (SAA) in experimentally induced amyloidosis.

Serum from CBA/J mice made amyloidotic by chronic casein injections has been shown to suppress in vitro antibody response to SRBC. Similar suppression was also found with normal mouse serum but to a much lesser degree. This suppressive activity of both amyloidotic serum and normal serum was removed by absorption of the sera with antiserum to protein AA, the major constituent of casein-induced (secondary) amyloid fibrils. This antiserum to the amyloid fibril protein AA (mol wt 8,400 daltons) detects an immunologically cross-reacting serum alpha globulin (SAA) (mol wt approx. 100,000). It is postulated that the serum factor (SAA) is a regulator of antibody response and may be present in elevated amounts as the result of chronic antigenic stimulation.

Alpha-Globulins↗
PubMed1975

Effect on tolerance induction of the mode of attachment of the hapten the carrier.

In this study we have investigated the role played by the mode of attachment of the hapten on autologous IgG in the induction of carrier-determined tolerance. Three conjugates of the dinitrophenyl hapten and mouse gamma-globulin were prepared: 1) DNP-epsilon-lysine-MGG, 2) DNP-azo-MGG (which binds to histidine and tyrosine), 3) DNP-must-MGG (which binds to the carboxyl groups of glutamic or aspartic acid). DNP was also bound to the immunogenic carrier keyhole limpet hemocyanin (KLH) by the three different linkages. The three DNP mouse-gamma-globulin conjugates were used to induce tolerance and immediately thereafter the animals were immunized with various DNP-KLH conjugates. Antibody response was tested by a modiciation of the Jerne plaque assay. It was found that DNP-epsilon-lysine-MGG induced tolerance to both DNP-epsilon-lysine-KLH and to DNP-azo-KLH. In contrast, neither DNP-azo-MGG nor DNP-must-MGG induced tolerance to DNP-epsilon-lysine-KLH or to DNP-azo-KLH and DNP-must-KLH, respectively. Clearance studies showed no differences in the catabolic rate of the various hapten mouse gamma-globulin conjugates as compared to unconjugated MGG. However, although DNP-must-MGG and DNP-azo-MGG were not tolerogenic, they were immunogenic. In conclusion, this study demonstrated that not only the nature of the carrier but the mode of hapten binding to his carrier are critical for the induction of hapten specific tolerance.

Animals↗
PubMed1975

Carrier-determined tolerance in vitro.

A primary immune response to normal BDF1 spleen cells was obtained in vitro to the T-independent antigen TNP-T4 coliphage. This anti-TNP response was suppressed by exposing the spleen cells for 6 hr to TNP bound either to isologous or heterologous gamma-globulin. The suppression was hapten specific. In contrast, TNP-albumin conjugates did not induce tolerance in vitro.

Animals↗