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Biomedical subjects

Y Borel

Publications and source records attributed to Y Borel.

At least 37 records · Page 2Linked to original sources
PubMed1984

Conjugation of DNA fragments to protein carriers by glutaraldehyde: immunogenicity of oligonucleotide-hemocyanin conjugates.

The practical realization of the concept of specific immunotherapy for systemic lupus erythematosus (SLE) has been hampered, thus far, by an inability to link DNA fragments to carrier protein. In this paper, a novel technique is described, in which glutaraldehyde is the linking agent. A 2-stage method was used to link oligonucleotides to a soluble protein carrier, such as keyhole limpet hemocyanin (KLH) or human gamma globulin (HGG), whereas a 1-stage technique was sufficient to link oligonucleotides to sheep red cells. Both the ultraviolet absorbance spectrum and diphenylamine assay demonstrated that oligonucleotides were coupled to soluble protein. The conjugate of oligonucleotide to protein carrier appears to be recognized by anti-DNA antibody since oligonucleotide linked to either KLH or HGG inhibited the binding of anti-DNA antibody in vitro, and oligonucleotide-coupled sheep cells are agglutinating by seropositve sera from lupus patients. In addition, oligonucleotide-KLH raised hemagglutinating antibody to denatured DNA in C57BL/6, DBA/2 or NZB mice, as well as IgG antibody as detected by SPRIA in C57BL/6 and DBA/2 mice. The significance of this new method for the development of an antigen specific therapy of SLE is discussed.

Aldehydes↗
PubMed1984

Influence of intravenous administration of nucleoside-coupled spleen cells on murine lupus nephritis in female (NZB X NZW)F1 mice.

In this study, we examine the influence of the intravenous administration of nucleoside-coupled spleen cells on the spontaneous development of murine lupus nephritis in young and adult BWF1 mice. In both age groups, this treatment failed to affect the autoimmune disease. Rather, in young mice administration of nucleoside-coupled spleen cells accelerates the appearance of anti-DNA antibody suggesting that BWF1 have a specific defect in the immunoregulation of anti-DNA antibody production. The significance of this finding for the pathogenesis of the disease in BWF1 mice is discussed.

Animals↗
PubMed1984

Anti-T cell antibody in juvenile rheumatoid arthritis.

One hundred-and-seven patients with juvenile rheumatoid arthritis (JRA) were studied for the presence or absence of an autoantibody in their sera directed against T cells. Using an indirect immunofluorescence technique on a fluorescence activated cell sorter, 71% of all patients were found to be positive on at least one sample. When studied according to the mode of onset of disease 75% of those with systemic onset, 70% with a pauciarticular, and 68% of those with a polyarticular onset were positive. Longitudinal studies appeared to suggest a correlation with disease activity, particularly in individual patients who were positive, while remission was almost invariably associated with negative testing for anti-T cell antibodies. These findings suggest that the anti-T cell antibody may be a useful diagnostic test in JRA and of benefit in monitoring disease activity and remission of disease.

Adolescent↗
PubMed1984

Increased photosensitivity to near-ultraviolet light in murine SLE.

We investigated whether there is increased susceptibility to near-UVL in murine SLE. Cultured spleen cells from either strain of mice with lupus disease or conventional strains of mice were exposed to different UVL fractions in vitro. The effect of DNA synthesis, release, and repair was examined. DNA synthesis and release was measured as percent of [3H]thymidine (dT) uptake into either total acid-precipitable radioactive material of cell sediment plus supernatant, or that of the medium alone, whereas hydroxyurea-resistant dT incorporation represented DNA repair. The data indicate that all SLE strains, in contrast to all non-SLE strains, show increased DNA synthesis and release after UV-A exposure. In addition, all murine SLE strains demonstrate increased susceptibility to induction of DNA damage by UV-A. The significance of these observations in relation to the clinical activity of SLE after sunlight exposure is discussed.

Animals↗
PubMed1983

Nucleoside-specific suppression in MRL/MP +/+ mice.

The induction of nucleoside-specific nonresponsiveness was further studied in the autoimmune strain MRL/MP +/+ (MRL/n). Experiments were undertaken to determine (i) whether nucleoside-conjugated spleen cells are able to induce specific nonresponsiveness to T-dependent nucleoside antigens in MRL/n mice, and (ii) whether periodic treatment with nucleoside-conjugated spleen cells would retard the development of spontaneous anti-DNA antibodies and associated indicators of autoimmunity. The results show that nonresponsiveness to nucleoside antigens is inducable in male, but not in female, MRL/n mice. Nonresponsiveness in male MRL/n was transferable and mediated by T cells. Treatment of male MRL/n mice with nucleoside-conjugated spleen cells (NSC) appeared to attenuate the progress of autoimmune symptoms in experimental animals. These results are discussed in the context of recent studies exploring the etiology of autoantibody production and the loss of self-tolerance in murine models of autoimmunity.

Animals↗
PubMed1983

H-2-determined kinetic differences for the induction of nucleoside-specific suppression.

The kinetic and the H-2 requirements for the induction of nucleoside-specific suppression were examined in several strains of mice; specifically, whether adenosine (A)-coupled spleen cells given intravenously suppress the primary response to adenosine-KLH. The adenosine system was chosen because C57Bl/6 mice were originally found to be resistant to immune suppression when challenged 5 days after treatment with adenosine-coupled spleen cells. (Raps et al. J. Immunol. 126, 1542, 1981.) It was determined (i) whether A-specific nonresponsiveness is inducible in strains other than C57Bl/6; (ii) whether changes in hapten density on the A-conjugated spleen cells could alter C57Bl/6s ability to become nonresponsive, and (iii) whether there are interstrain differences in the time required to induce A-specific suppressor T cells (Ts). The results show that there are H-2-associated differences in the time required to induce A-specific immune suppression. While A-spleen cells failed to suppress the A-specific response in C67Bl/10 (H-2b), they did induce unresponsiveness in B10.D2 (H-2d on C57Bl/10 background). A 2.5-fold increase in epitope density of adenosine on cells did not influence the kinetics of suppression. C67Bl/6 were resistant to suppression on Day 5, but like the CB6F1, susceptible to unresponsiveness 10 days after treatment. Nonresponsiveness was T-cell-mediated and transferable across IgH-V barriers. Suppression induced by Balb/c donor mice is transferable to Igh-incompatible CAL-20 mice. These results are discussed in the context of genetic restrictions which regulate suppressor T-cell interactions.

Adenosine↗
PubMed1983

Spontaneous increase of DNA turnover in murine systemic lupus erythematosus.

DNA synthesis and release was studied in unstimulated splenocytes of strains of mice known to develop spontaneous systemic lupus erythematosus (SLE)-like disease and in non-SLE age- and sex-matched strains as well. Newly synthesized DNA was measured as total acid-insoluble radioactive material present in cell pellet plus supernatant of unstimulated 0-72 h cell cultures [3H]thymidine-pulsed, whereas DNA release was measured as amount of acid-precipitable radioactivity found in supernatant of those cultures. In all strains known to develop spontaneous murine SLE the amount of newly synthesized DNA was 1.3-2.1-fold increased when compared to normal strains studied concomitantly. Furthermore, a significant increase in DNA release into medium, unrelated to cell viability, was observed in those strains as well. These observations clearly demonstrate different metabolic rates of synthesis and release of DNA in murine SLE. This difference suggests the existence of an underlying mechanism responsible for extracellular DNA abundancy, which may be important for the formation of circulating DNA-anti-DNA immune complexes.

Animals↗
PubMed1983

Hapten-specific carrier-dependent tolerance induction in man in vitro.

We sought to determine whether hapten-specific tolerance can be induced in cultured human lymphocytes in vitro. Unfractionated as well as T and B cells from peripheral blood lymphocytes of healthy human volunteers were cultured with different hapten-carrier conjugates before in vitro challenge with dinitrophenyl (DNP) linked to keyhole limpet hemocyanin. Hapten-specific antibody was detected in the supernatant by solid-phase radioimmunoassay. Both hapten specificity and carrier dependence in addition to the cellular basis of tolerance induction were examined. The results show that hapten-specific tolerance of antibody production was induced by human gamma-globulin (HGG) conjugated to DNP but not by other conjugates of DNP nonhuman gamma-globulin, as well as human serum albumin. Moreover, both T and B cells are involved in tolerance induction to DNP-HGG in vitro. The significance of tolerance in human in vitro for the specific therapy of autoimmune disease is discussed.

Antigens↗
PubMed1983

Systemic lupus erythematosus in childhood: clinical manifestations and improved survival in fifty-five patients.

A retrospective review of 55 patients with systemic lupus erythematosus (SLE) (45 girls and 10 boys) under age 18 (median age of onset; 12.2 years) seen at the Children's Hospital Medical Center (Boston, Mass.) over the past 20 years was done. Clinical presentation was similar to previous series, but atypical presentation was common. Certain unusual presentations (such as isolated hematopoietic abnormalities) often occurred and delayed diagnosis for years in some cases. The frequency of ARA clinical classification of SLE was different in children as compared to adults. We observed depression of lymphocyte count in many patients and encountered elevations of hepatic enzyme levels in others. Of the 55 patients reviewed, 9 have died and 8 have been lost to follow-up. Of the rest, 21 have mild to moderate disease and 17 have inactive or minimally active SLE, after a median length of follow-up of 8.8 years. In severe cases, using either corticosteroids and/or cytotoxic agents, a favorable prognosis was obtained. Our cumulative 5- and 10-year survival of 92 and 85%, respectively, equals or exceeds that of previous reports of childhood SLE.

Child↗
PubMed1983

The role of the epitope density and cross-reactivity between two different purine nucleosides coupled to cells.

Cellular immune responses against nucleic acid antigens were analyzed in BALB/C mice. Delayed-type hypersensitivity (DTH) could be elicited by immunizing and challenging with either guanosine-coupled spleen cells (G-SC) or adenosine-coupled spleen cells (A-SC), and measured by footpad swellings. The epitope density was critical for immunization. This cellular reaction was specific to nucleosides, and cross-immunity was observed between A-SC and G-SC. In addition, cross-unresponsiveness was observed between these two nucleosides. In contrast, soluble carrier proteins coupled with either guanosine or adenosine did not induce cross-reactive immunity or unresponsiveness. The significance of the difference between these two forms of antigens in the ability to induce cross-reactivity is discussed in the context of T versus B-cell recognition in the induction or the expression of the immune response.

Adenosine↗
PubMed1983

In vitro nucleoside specific immune response by lymphocytes from systemic lupus erythematosus.

The in vitro immune response of systemic lupus erythematosus (SLE) lymphocytes to nucleosides conjugated to keyhole limpet hemocyanin (KLH) (A,G,C,T-KLH) was investigated. The nucleosides were chosen not only because they are a part of nucleic acid antigen and involved in autoimmunity, but also because nucleoside covalently bound to either soluble IgG or cells had been shown to induce unresponsiveness in mice. A significant proliferation index was induced in SLE lymphocytes, as compared with normal or rheumatoid arthritis (RA) lymphocytes in vitro [in (A,G,C,T)-KLH, 1 microgram/ml; stimulation index = M +/- SE, SLE 2.10 +/- 0.26, RA 1.06 +/- 0.14, normal 1.12 +/- 0.12 P less than 0.05]. Lymphocytes from SLE patients responded specifically to low doses of (A,G,C,T)-KLH and not to the protein carrier KLH alone. A solid-phase radioimmunoassay was developed to detect nucleoside-specific antibody. SLE lymphocytes spontaneously produced high levels of anti-A,G,C,T antibody. This was further increased by antigenic stimulation, but not with pokeweed mitogen (PWM) stimulation. In contrast normal lymphocytes failed to produce anti-A,G,C,T antibody either spontaneously or in response to antigen. However, normal lymphocytes produced antibody after stimulation with PWM. More importantly, anti-A,G,C,T antibody production by SLE lymphocytes was suppressed by preincubation with A,G,C,T-IgG (A,G,C,T-HGG). The antigen-specific unresponsiveness caused by A,G,C,T-HGG was demonstrated by the observation that preincubation with A,G,C,T-HGG did not affect the production of anti-dinitrophenyl antibody response. The ability to manipulate the altered response of SLE lymphocytes to nucleic acid antigens may have therapeutic implications in these patients.

Adenosine↗
PubMed1983

Selective inhibition of anti-nucleoside-specific antibody production by nucleoside-ricin A conjugate.

The effect of the preincubation of peripheral blood lymphocytes, from SLE patients, with nucleoside-ricin A conjugates on spontaneous A,G,C,T antibody production was examined. Enhanced spontaneous anti-nucleoside-specific antibody (anti-A,G,C,T antibody) production by SLE B cells was selectively inhibited by pretreatment in vitro with nucleosides conjugated to the ricin A chain. The selective suppression was demonstrated by the lack of suppression of the anti-DNP response or of polyclonal IgG production by pretreatment that did suppress anti-A,G,C,T production by the lymphocytes of eight patients with SLE. Furthermore, pretreatment of B cells, but not of T cells, with nucleoside-ricin A conjugates inhibited the A,G,C,T antibody response by these B cells. Thus, (A,G,C,T)-BGG-ricin A conjugates bind directly to the nucleoside-specific B cells via their antigen receptors. This demonstration of the selective elimination of B cells might have therapeutic applications in SLE.

Antibodies, Antinuclear↗
PubMed1983

Direct demonstration of the human suppressor inducer subset by anti-T cell antibodies.

Prior studies indicated that sera of patients with active juvenile rheumatoid arthritis (JRA) contain anti-T cell antibodies reactive with the T4+ inducer population. More important, depletion of this T cell subset with JRA anti-T cell antibodies (JRA+ T cells) and C abrogated T5/T8+ suppressor T cell function. In the present study, we utilized Ig-coated plate techniques and JRA anti-T cell antibodies to fractionate the T4+ population into T4+JRA+ and T4+JRA- subsets and characterize the individual T4+ inducer subset. It was shown that whereas only the T4+JRA- population responded maximally to the soluble antigens, TT and mumps, both T4+JRA+ and T4+JRA- subsets proliferated equally well to mitogens and alloantigens. Furthermore, B cell immunoglobulin production induced by T4+JRA- T cells was approximately twice that induced by the reciprocal T4+JRA+ subset. In contrast, the T4+JRA+ subset alone activated T8+ T cells to become suppressor effector cells. These results suggest that the T4+JRA+ subset is the inducer of suppressor subpopulation whereas the T4+JRA- subset functions maximally as the inducer of B cells. It is believed that the suppressor inducer population may have a central role in the immunoregulatory network in man.

Antibody Formation↗
PubMed1983

The use of haptenated immunoglobulins to induce B cell tolerance in vitro. The roles of hapten density and the Fc portion of the immunoglobulin carrier.

The relationship between the Fc region of trinitrophenylated (TNP)-immunoglobulins (Ig), and their ability to induce tolerance was examined. It was found that adult B cells responding to a T-independent (TI) antigen were tolerized by TNP11 human gamma globulin (HGG), but not by TNP10F(ab')2 fragments of HGG. Increasing the hapten density on the F(ab')2 fragments overcame their inability to induce tolerance. Thus, a TNP17-F(ab')2 was an effective tolerogen. Murine myeloma proteins of different IgG subclasses were similarly tested. A TNP12-IgG2a and a TNP11-IgG1 induced tolerance, whereas two TNP11-12-IgG3 did not. However, a more heavily haptenated TNP18-IgG3 was tolerogenic. These results suggest that lightly haptenated immunoglobulins depend upon Fc receptor binding to induce tolerance in adult B cells. Non-Fc receptor-binding carriers are not tolerogenic unless they are more heavily haptenated. Finally, T cell and macrophage depletion experiments suggest that the tolerogens act directly on the B cells.

Animals↗
PubMed1982

A natural model of immunologic tolerance. Tolerance to murine C5 is mediated by T cells, and antigen is required to maintain unresponsiveness.

A unique experimental model is described, where natural immunologic tolerance to a well-defined soluble native antigen (murine C5) is examined in congenic strains of mice that differ only by the presence or the absence of C5. A highly sensitive hemolytic assay was developed to detect nanogram amounts of C5 as well as an assay of anti-C5 inhibition of C5 hemolytic activity. The latter was more sensitive than immunodiffusion. Two reciprocal approaches were used to study the cellular basis of tolerance in irradiated hosts of either strain. In the first, lymphoid cells from either strain were transferred to irradiated B10.D2OSN hosts that were lacking C5 and so would not hinder detection of anti-C5 antibody upon challenge with murine C5. Second, lymphoid cells from either strain were transferred to irradiated B10.D2NSN hosts, whose native C5 provided the antigenic stimulus. The immune response of whole nonadherent spleen cell suspension as well as mixtures of T and B cells (separated on the basis of surface immunoglobulin) from either strain were studied. In addition, the duration of tolerance and the antigen requirement to maintain it in irradiated C5-deficient hosts repopulated with C5-sufficient spleen cells was examined. The positive control of irradiated C5-deficient hosts repopulated with syngeneic spleen cells showed a primary and secondary response to immunization. In contrast, C5-sufficient spleen cells failed to respond both in the primary and the secondary response. Because the unresponsiveness was not caused by antigen carryover and was not antigen specific, it represents central tolerance. In C5-sufficient irradiated hosts (where immunization was not required and antigen was present in natural form and physiological concentration), transfer of C5-deficient cells mediated a drop in C5 levels to 10-20% of that noted in unreconstituted controls. T and B cell mixing experiments from the two strains into deficient or sufficient hosts demonstrated that tolerance is T cell dependent and that C5-sufficient or -deficient B cells could cooperate with nontolerant C5-sufficient T cells to produce significant anti-C5 antibody or mediate a significant drop in C5 levels. In addition, the presence of antigen was necessary to maintain tolerance. In conclusion, these results show that (a) natural tolerance to C5 is an active process that is T cell dependent and requires the presence of antigen; (b) in this natural model, clonal abortion does not seem to occur; and (c) both tolerant and nontolerant B cells retain the capacity to produce autoantibody.

Animals↗
PubMed1982

Delayed-type hypersensitivity and unresponsiveness to nucleic acid antigen. The role of the epitope density and crossreactivity between nucleoside coupled to cell.

Here we describe a new model to elicit cellular immunity and induce unresponsiveness to nucleic acid antigens. Delayed-type hypersensitivity could be elicited by immunizing and challenging Balb/c mice with either guanosine-coupled spleen cells (G-SC) or adenosine-coupled spleen cells (A-SC) measured by footpad swellings. The epitope density was critical for immunization. This cellular reaction was specific to nucleosides, and crossimmunity was observed beween A-SC and G-SC. In addition, crossunresponsiveness was observed between these two nucleosides. In contrast, soluble carrier proteins coupled with either guanosine or adenosine did not induce crossreactive immunity or unresponsiveness. This emphasizes the dichotomy in both the mechanism and the specificity of unresponsiveness induced by the same ligand bound to two different self molecules (such as cell or igG). Finally, cellular immunity to nucleic acid antigens might be useful in ascertaining its involvement in experimental systemic lupus.

Adenosine↗