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C Carnaud

Publications and source records attributed to C Carnaud.

At least 19 recordsLinked to original sources
PubMed1992

Acquired allo-tolerance to major or minor histocompatibility antigens indifferently contributes to preventing diabetes development in non-obese diabetic (NOD) mice.

Diabetes in NOD mice represents the end stage of a genetically-programmed autoimmune process mediated by T lymphocytes and directed against insulin-producing beta cells. We have shown in a previous study that the course of the disease is significantly inhibited in NOD mice which have been made tolerant at birth to foreign histocompatibility antigens. This early T cell manipulation results in a significant delay of disease onset, reduced overall incidence and less severe alterations of islet cells. In order to characterize better the nature of the foreign tolerogenic determinants responsible for this protection, we have now examined separately the contribution of MHC and non-MHC antigens. Two lines of congenic mice were used as donors of tolerogenic cells, NOD.H-2b, which differ from NOD by the MHC-encoded antigens only, and B10.H-2g7, which differ by all the minor histocompatibility antigens encoded by the B10 background, but which share with NOD mice the same MHC haplotype. Our results show that NOD recipients of F1 semi-compatible cells become specifically tolerant to the set of alloantigens to which they were neonatally exposed. Unresponsiveness, assessed by lack of CTL generation, is profound and specific. Yet, despite the fact that distinct sets of alloreactive T cell precursors are silenced, mice made tolerant indifferently to major or minor histocompatibility antigens are significantly protected against overt diabetes. These results could mean that each set of MHC and non-MHC encoded determinants can independently cross-tolerize a sufficient proportion of the autoreactive repertoire to slow the natural course of the disease. Alternatively, neonatally-acquired tolerance might induce polyclonal activation of the immune system resulting in the suppression or the immunodeviation of potentially harmful, autoreactive T cell clones.

Animals↗
PubMed1991

Host humoral and cellular immune mechanisms in the continued suppression of Friend erythroleukemia metastases after interferon alpha/beta treatment in mice.

DBA/2 mice were injected intravenously with 2 x 10(6) 3C18 Friend erythroleukemia cells (FLC), a cell line resistant to interferon alpha/beta (IFN-alpha/beta). Although daily administration of mouse IFN-alpha/beta markedly increased the mean survival time, most IFN-treated mice continued to harbor FLC in different organs. To investigate the mechanisms responsible for this persistent suppression of FLC growth in IFN-treated mice, we undertook a series of adoptive transfer experiments with sera and spleen cells. Sera from FLC-injected, IFN-treated mice were very effective in conferring protection on DBA/2 mice even when injected systemically (intravenously) 18-24 h before intravenous challenge with FLC. These sera also exhibited antitumor activity when injected subcutaneously or intraperitoneally together with FLC. The protective factor in serum was shown to be an immunoglobulin. FLC-injected, IFN-treated mice developed antibodies to FLC demonstrable by radioimmunoassay and complement-dependent cytotoxicity. Sera from these mice recognized a specific 65-kD FLC membrane antigen(s) not detectable on membrane extracts from RBL-5 or ESb tumor cells, or on normal spleen cells. FLC-injected, IFN-treated mice also developed a specific cellular response demonstrable by transfer of protection with spleen cells injected intravenously or subcutaneously. Analysis of the responsible spleen cell populations indicated that the effector cells were neither T nor B cells. These results demonstrating the importance of host humoral and cellular immune mechanisms in the persistent suppression of FLC in IFN-treated mice may be relevant to the use of IFN-alpha/beta in patients in whom tumors may regress and tumor cells may then remain latent for extended periods of time.

Animals↗
PubMed1991

CD8+ T cell homing to the pancreas in the nonobese diabetic mouse is CD4+ T cell-dependent.

The adoptive transfer of type I diabetes in nonobese diabetic mice requires the contribution of both CD4+ and CD8+ T cells. To further elucidate the cellular pathway(s) of beta-cell destruction and the responsibility of each subset, high doses of committed T cells from diabetic mice purified to single subsets, were injected into syngeneic nonobese diabetic neonates. The recipients of single or mixed subsets were followed for clinical manifestations of diabetes and examined at 30 days of age for in situ lesions. None of the animals injected with either CD4+ or CD8+ T cells became overtly diabetic during the 30 days of observation whereas 8 of 23 mice inoculated with a mixture of the two subsets developed glycosuria and hyperglycemia. However, insulitis was found in 6 of the 13 mice injected with CD4+ T cells whereas only 1 of the 9 mice injected with CD8+ T cells showed marginal infiltration of the pancreas. The lesions initiated by CD4+ T cells alone were considerably less severe than those induced by the mixture of both subsets, corroborating the fact that overt disease did not occur in the former group. Together, these results suggest a distinct function for each diabetogenic T cell subset. CD4+ T cells, which have the capacity to home to the pancreas, promote in turn the influx of CD8+ effector T cells that do not by themselves accumulate in this organ. These results illustrate a novel form of T-T cell interactions leading to organ specific autoimmune lesions.

Animals↗
PubMed1991

Prevention of diabetes in NOD mice treated with antibody to murine IFN gamma.

The NOD mouse is studied as an animal model of human insulin-dependent diabetes mellitus (IDDM). To evaluate the role of IFN gamma in the pathogenesis of the disease, we have studied the effect of anti-IFN gamma mAb on the expression of insulitis and clinical diabetes. Treatment of mice with anti-IFN gamma mAb prevented the induction of early IDDM by cyclophosphamide as well as the adoptive transfer of diabetes by spleen cells from diabetic NOD mice. The protection against induction of diabetes by cyclophosphamide was observed in animals treated with the anti-IFN gamma mAb within 24 h following the first cyclophosphamide injection but not in animals in which mAb treatment was started 7 days later. Transfer of disease was prevented both in adult irradiated and in newborn recipients. The absence of clinical signs in these mice was corroborated by a significant reduction of both the extent and severity of insulitis. Over-expression of Ia antigen on endothelial cells lining the islets was also considerably reduced in mice treated with mAb. These data strongly suggest a role for IFN gamma during the autoimmune process leading to beta cell destruction in diabetes and prompt further investigation of the use of such antibodies in the immunoprevention of IDDM.

Animals↗
PubMed1990

Anti-tumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend erythroleukemia cells. VIII. Role of the immune system in the inhibition of visceral metastases.

DBA/2 mice were injected i.v. with IFN alpha/beta-resistant 3CI8 Friend erythroleukemia cells (FLC) which metastasize to the liver and spleen. IFN alpha/beta treatment of FLC-injected mice increased their survival time and these mice developed a resistance to a second challenge with FLC. The efficacy of IFN alpha/beta in increasing the survival time was compared between normal immunocompetent and immunodeficient mice. The anti-tumor action of IFN was markedly reduced or abolished in newborn DBA/2 mice, in adult athymic nu/nu and beige DBA/2 mice, and in BALB/c scid/scid mice. To determine the phenotype of the effector cells involved, FLC-injected DBA/2 mice were treated with antibodies to asialo-GMI, CD4, or CD8 antigens, or with cyclosporin A or silica. IFN alpha/beta treatment proved much less effective in these mice, indicating that a variety of effector cell types participated in the IFN-induced suppression of visceral metastases. Thus, an intact immune system appears to be essential to obtain optimal therapeutic effects of IFN alpha/beta in this experimental model.

Animals↗
PubMed1990

The nonobese diabetic mouse model. Independent expression of humoral and cell-mediated autoimmune features.

Nonobese diabetic (NOD) mice present concomitant signs of cell-mediated and humoral autoimmunity. Whereas the involvement of the cell-mediated manifestations in the pathogenesis of diabetes has been clearly demonstrated, the origin and the relevance of the humoral manifestations is still unclear. In the present study, we have tried to determine whether the humoral manifestations observed in NOD mice were secondary to the cell-mediated antiislet reaction, or whether they resulted from an autonomous polyclonal activation of B cells, a possibility suggested by the notorious presence of antilymphocyte antibodies with thymocytotoxic properties, in the serum of old NOD females. To discriminate between the two alternatives, we have followed the titers of thymocytotoxic autoantibodies in aging males and females, as well as in F1 hybrids where the organ-specific disease is recessive, and in back-crossed mice where the susceptibility genes responsible for insulitis and diabetes have segregated. In addition to thymocytotoxic antibodies, we have also screened the sera of these animals for hyperglobulinemia, antiinsulin, and anti-DNA autoantibodies that are classically associated with polyclonal B cell activation in autoimmune strains of mice. The results indicate that these humoral anomalies are clearly disconnected from the occurrence of diabetes and even of insulitis. Lymphocytotoxic antibodies appear several weeks after the onset of insulitis in NOD mice, are not correlated with disease occurrence and have no predictive value for its onset. The humoral manifestations that include, beside thymocytotoxic antibodies, antiinsulin antibodies, hyperglobulinemia, but no anti-DNA antibodies, are found at the same frequency in F1 mice as in parental mice in spite of the fact that the former are practically free of insulitis lesions. These anomalies are also randomly distributed among back-crossed mice independently of the presence and the severity of the organ-specific lesions. Altogether, these results suggest that NOD mice, like other autoimmune strains, suffer from a genetically inherited defect of B cell regulation resulting in the hyperproduction of natural autoantibodies.

Age Factors↗
PubMed1990

Natural thymocytotoxic autoantibodies in non-obese diabetic (NOD) mice: characterization and fine specificity.

The NOD mouse is a model of human juvenile type I diabetes mellitus. As in humans and in the BB rat model, the development of diabetes in NOD mice is accompanied by evident manifestations of cell-mediated and humoral autoimmunity. Beside autoantibodies directed at putative islet cell antigens, NOD sera contain antibodies with specificity for lymphocyte cell-surface determinants. Here we demonstrate that these anti-lymphocyte antibodies have the same characteristics of target cell specificity, of isotype, and of temperature reactivity, as do natural thymocytotoxic autoantibodies (NTA) from lupic NZB mice, or from mice undergoing polyclonal B cell activation. We also demonstrate that the thymocytotoxic activity of NOD sera is not due to cross-reactive anti-insulin antibodies. Biochemical characterization of the determinants recognized by these anti-lymphocyte antibodies reveals two membrane-associated proteins of 28 and 33 kD, partially similar to the two peptides recognized by NTA from NZB mice (30 and 33 kD). Altogether, these results suggest that NOD mice develop manifestations of polyclonal B cell activation similar to those observed in lupus-prone mice. The relationship of these anomalies with the organ-specific pancreatic disease remains to be properly evaluated.

Animals↗
PubMed1989

Neonatal induction of allogeneic tolerance prevents T cell-mediated autoimmunity in NOD mice.

Diabetes in the NOD mouse strain is a genetically programmed T cell-mediated autoimmune process that is directed against an as yet unknown antigen target(s) on pancreatic beta cells. To investigate whether the course of the autoimmune disease could be altered by immune manipulations of the T cell repertoire, we have induced allogeneic tolerance by injecting F1 semiallogeneic spleen cells into NOD neonates. This procedure resulted in a significant protection against both insulitis and diabetes. However, although it requires the induction of tolerance, as shown by the failure of non-tolerizing irradiated cells to prevent autoimmunity, protection appeared to be independent of the major histocompatibility complex haplotypes of the F1 spleen cells injected at birth, e.g. (C57BL/6 x NOD)F1, (CBA/Ca x NOD)F1 or (BALB/c x NOD)F1 cells. In addition, a similar degree of protection was induced, whether the tolerant state, as assessed by mixed lymphocyte reaction studies in vitro, was of short duration, approximately 6 weeks, or lasted for more than 12 weeks. Putative veto or suppressor functions of chimeric T cells were ruled out, since mice tolerized with T cell-depleted F1 spleen cells were equally protected. We conclude that the expression of spontaneous T cell-mediated autoimmunity can be modulated by immune manipulations at birth. Whether the protection observed in the present experiments resulted from the production of one or several specific holes in the autoimmune T cell repertoire, i.e. cross-tolerance, or whether it resulted from nonspecific disturbances of the emerging T cell repertoire remains to be elucidated.

Age Factors↗
PubMed1989

Enhancement of natural killer cell activity by Nocardia opaca fractions.

Three molecules derived from Nocardia opaca bacteria, NDCM, NWSMP, and PG, have been shown to express immunomodulating properties. The present study was aimed at assessing the effects of these derivatives on natural killer (NK) activity. Two experimental protocols were adopted, consisting of incubating whole or Percoll fractionated NK cells in vitro with those substances, and the other in which the derivatives were administered in vivo to mice and the activity assessed later. Incubation of spleen cells in vitro with NWSMP or its precursor NDCM promoted NK activity. This effect could be observed after only 2 h of incubation and continued until day 2. Percoll fractions 1-3, which contain most of the NK activity, were enhanced to a similar extent. Band 4, which is usually devoid of such activity, remained unresponsive even after contact with the N. opaca derivatives. PG was practically ineffective upon all the subsets. The results of experiments in vivo correlated with those obtained in vitro in that NWSMP and NDCM, but not PG, promoted NK activity. Bands 1-3 were similarly enhanced, the effect was observed after short treatment times, and could be partially cancelled by the concomitant administration of anti-interferon antibodies (anti-IFN Ab). All these findings suggest that the promoting effects of N. opaca derivatives are mediated through alpha/beta IFN. In contrast to the results observed on spleen NK cells, NK cells from the peritoneum displayed susceptibility mainly to PG, and much less to NWSMP or NDCM. The administration of PG to mice in vivo had a particularly marked promoting effect upon the cytotoxic activity of peritoneal cells. One logical explanation for the difference observed between PG and NWSMP or NDCM may be related to the specific IFN inducing properties of these compounds as well as to the different responsiveness of the NK cells present in the spleen and peritoneal cavity.

Animals↗
PubMed1979

Selective depression of the xenogeneic cell-mediated lympholysis in systemic lupus erythematosus.

The immunological responsiveness of a panel of 17 patients with systemic lupus erythematosus (SLE) was studied in an in vitro model of xenogeneic sensitization against mouse lymphoid cells. Generation of cytotoxic thymus-derived (T) cells evaluated by a chromium release assay against labeled target cells was found to be drastically impaired in these lupus patients. Such depression was independent of drug therapy at the time of the study, clinical status, and other immunological parameters such as antibodies against native DNA, complement levels, cryoglobulinemia, circulating immune complexes, or T- and bone marrow-derived (B)-cell numbers. In contrast to the cytotoxic response, the proliferative responses to phytohemagglutinin, to allogeneic lymphocytes, and to xenogeneic lymphocytes were not significantly different from those of normal individuals. The latter response was shown to be H-2 restricted with the primed lymphocyte test. These results suggest the presence of a selective defect in the generation or in the expression of killer cells rather than a deficiency in antigen recognition by T cells. The role of serum factor(s) was examined by educating the lymphocytes of normal subjects in the presence of serum from SLE patients. Such manipulation affected both the generation of killer cells and the proliferative response. Finally our observations indicate that depression of cell-mediated immunity in SLE patients may be associated with several mechanisms including a cellular one, specifically affecting the generation of killer T cells, and a humoral one possibly as a result of antilymphocytic antibodies and(or) immune complexes.

Adult↗
PubMed1977

Increased stimulatory capacity of spleen cells from adult thymectomized mice in mixed lymphocyte reactions.

Conflicting results have been reported concerning the effect of adult thymectomy (A-Tx) on the mixed lymphocyte reaction (MLR) response. Our purpose was to test the reverse question, namely the effect of A-Tx on the stimulatory capacity of mouse lymphocytes carrying allelic disparities at the Mls and the H-2 loci. Spleen cells from A-Tx CBA donors were found to be significantly more stimulating than cells from normal donors. That A-Tx could eliminate suppressor T cells involved in MLR regulation or in preventing back stimulation is not likely according to our data. An increment in expression or in accessibility of Mls or H-2 antigenic determinants induced by A-Tx is no more likely, since a smilar increase in lymphocyte proliferation was observed in syngeneic cultures. The most probable explanation remains that A-Tx discloses a strongly stimulatory subpopulation, perhaps acting in part nonspecifically. The hypothesis of an enrichment in B cells versus a loss of T cells is not compatible with our findings, since B-cell-enriched fractions from various origins never attained the stimulating ability disclosed by A-Tx cells. Moreover, the cell involved is theta-positive, although slightly nylon-wool-adherent, and thus shares several properties with immature T cells involved in auto-rosette formation.

Aging↗
PubMed1976

Thymic factors.

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Animals↗
PubMed1975

Spleen-cell reactivity against transplanted neurogenic rat tumors induced by ethylnitrosourea: uncovering of tumor specificity after removal of complement-receptor-bearing lymphocytes.

Spleen cells from BDIX-rats bearing either GVlAl-tumor (a syngeneic mixed glioma) or NVlAc-tumor (a cloned syngeneic neurinoma of the peripheral nervous system) were cytotoxic to both tumor cells in vitro. However, the tumors displayed individually distinct antigenic specificities by in vivo rejection tests. Their in vitro cross-reactivity disappeared when a particular subpopulation of the spleen cells was used. The procedure of lymphocyte purification included three consecutive steps: treatment with carbonyl iron and magnetism, passage through a nylon wool column, and finally removal of complement receptor-bearing cells present in the colum-excluded population. Cross-reactivity between the syngeneic tumors persisted after the first two steps of lymphocyte purification. In contrast, specific cytotoxic reactions were observed against each individual tumor subsequent to the removal of the remaining C3 receptor-positive but surface Ig-negative cells. While killer cells were present in normal spleen-cell populations, these were almost completely eliminated by passage through the nylon wool column.

Animals↗