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C Bona

Publications and source records attributed to C Bona.

At least 55 records · Page 3Linked to original sources
PubMed1995

[Critical course of a case of idiopathic pulmonary fibrosis].

The authors present a case of idiopathic pulmonary fibrosis with an unusual onset in the form of acute interstitial pneumonia. On being admitted to hospital the 53-year-old woman presented an altered breathing pattern which initially required oxygen therapy using Venturi's oxygen mask followed by sedation and mechanical ventilation with appropriate FiO2 to guarantee adequate pO2 and arterial saturation. For diagnostic purposes bronchiolar and alveolar lavage was immediately performed together with transbronchial biopsy during the course of fibrobronchoscopy. The results of these tests revealed a syndrome of interstitial pneumonia and widespread alveolar lesion with an enhanced lymphocyte population. Antibac-terial and immunosuppressive therapy (6-methylprednisolone and cyclophosphamide) commenced on the basis of these tests caused a temporary improvement in blood-gas parameters and parenchymal thickening. But in spite of treatment the patient's cardiocirculatory and respiratory conditions deteriorated, causing death. This case report raises a number of different questions regarding both diagnosis and treatment. With regard to diagnosis it is worth underlining the absence of hyaline membrane, pathognomonic of widespread alveolar lesions, in biopsies removed while the patient was still alive. With regard to treatment, in addition to specific antibiotic and immunosuppressive therapy, the authors consider that surfactants might be of some help given that widespread alveolar damage can be attributed to pulmonary fibrosis.

Female↗
PubMed1994

Autoantibodies in scleroderma and tightskin mice.

There is much evidence to suggest that scleroderma in human patients is caused by a fundamental defect in the immune system. In tightskin mice, the scleroderma syndrome is associated with autoimmunity, particularly autoantibodies interacting with scleroderma target antigens.

Animals↗
PubMed1994

Antibody response elicited by T-dependent and T-independent antigens in gene targeted kappa-deficient mice.

Animal models substantially contribute to the understanding of the pathogenesis of various human diseases, including those associated with genetic defects. Our study investigated the characteristics of antibody responses elicited by T-dependent and T-independent antigens in mice rendered kappa-deficient by targeted deletion of the J kappa C kappa gene segments. It is known that in normal murine species the kappa repertoire dominates the antibody repertoire (kappa/lambda ratio = 95:5). Our results indicate that the kappa gene deletion causes the alternative usage of lambda 1 (93%) and lambda 2 (7%) light chains, confirming previous studies demonstrating that in kappa-deficient mice all B cells express Ig lambda receptors. The anti-trinitrophenylbenzene (TNP) response in K-/- mice was compensated for by lambda 1 and lambda 2 bearing Igs. However, isoelectric focusing analysis of anti-TNP antibodies showed a considerably more restricted pattern of lambda anti-TNP antibodies in K-/- as compared with kappa antibodies in normal mice. No major differences were observed in the affinity for the hapten of kappa or lambda 1 or lambda 2 mAbs obtained from 129/Sv and K-/- mice. Furthermore, lambda 1 and lambda 2 chains can reconstitute the expression of an idiotype (460Id) borne on kappa anti-TNP antibodies. The 460Id was detected both in polyclonal and monoclonal anti-TNP antibodies obtained from K-/- mice. Our results clearly showed that the kappa anti-TNP repertoire is compensated by the lambda repertoire even though the latter is clonally restricted in K-/- mice.

Animals↗
PubMed1994

Immunogenicity of microbial peptides grafted in self immunoglobulin molecules.

The advent of genetic engineering has allowed for the expression and production of recombinant proteins carrying short immunogenic epitopes of foreign antigens. These antigenized molecules represent valuable tools to investigate the molecular basis of antigen fragmentation, generation and presentation of peptide to lymphocytes, the induction of epitope specific immunity and potentially the development of a new generation of vaccines. Recently, we expressed viral epitopes on immunoglobulin molecules by replacing the D segment of a variable region of the heavy chain (VH) gene with a B cell epitope from the V3-loop of HIV-1 envelope protein, as well as a cytotoxic T lymphocyte (CTL) and a T helper epitope from influenza virus nucleoprotein and hemagglutinin, respectively. The T cell peptides generated from the immunoglobulin molecules produced by cells transfected with chimeric V genes, activated specific T cells as they do when generated from viral proteins. Possible practical applications for the development of prophylactic and immunotherapeutic reagents are envisioned for immunoglobulin molecules bearing foreign epitopes.

Amino Acid Sequence↗
PubMed1993

Autoantibodies directed against different classes of Fc gamma R are found in sera of autoimmune patients.

Serum samples from 147 patients with different systemic autoimmune diseases (SLE, Sjögren's syndrome, and progressive systemic sclerosis) were tested for anti-Fc gamma R activity using mouse rFc gamma RII in an ELISA. High reactivity compared to normal individuals was found for patients with all three diseases. The anti-Fc gamma R antibody was purified from several serum samples by affinity chromatography on a Sepharose column coupled with denatured, murine rFc gamma RII. Both IgM and IgG antibodies were found. To analyze the specificity of the affinity-purified autoantibody, cells (human neutrophils, IFN-gamma-stimulated neutrophils, monocytes, and the THP-1 monocytic cell line) that express different combinations of Fc gamma R (CD64, CD32, CD16) were stained with the affinity purified Ig. Ig directed against all three types of Fc gamma R were found. The results may reflect on the role of Fc gamma R-specific antibodies in the pathology of autoimmune diseases.

Animals↗
PubMed1993

Presentation of a viral T cell epitope expressed in the CDR3 region of a self immunoglobulin molecule.

Synthetic peptides corresponding to microbial epitopes stimulate T cell immunity but their immunogenicity is poor and their half-lives are short. A viral epitope inserted into the complementarity-determining region 3 (CDR3) loop of the heavy chain of a self immunoglobulin (Ig) molecule was generated from the Ig context and was presented by I-Ed class II molecules to virus-specific, CD4+ T cells. Chimeric Ig-peptide was presented 100 to 1000 times more efficiently than free synthetic peptide and was able to prime virus-specific T cells in vivo. These features suggest that antigenized Ig can provide an improved and safe vaccine for the presentation of microbial and other peptides.

Amino Acid Sequence↗
PubMed1993

In vivo priming effect during various stages of ontogeny of an influenza A virus nucleoprotein peptide.

In vivo priming of cytotoxic T lymphocytes (CTL) by an influenza virus nucleoprotein (NP) peptide was studied at various stages of development. Adult mice immunized twice with the NP peptide in complete Freund's adjuvant and incomplete Freund's adjuvant, respectively, produce significant CTL responses. Neonates immunized at birth with large amounts of NP peptide and boosted twice with the peptide during adulthood, also mount a weak but significant CTL response. By contrast, offspring from mothers immunized with the NP peptide at days 15, 17, and 19 of pregnancy showed unresponsiveness to the peptide subsequent to a similar regimen of peptide immunization at the age of 1 month. The data indicate that the contact of T cell precursors with antigen during fetal life induces CTL tolerance, whereas, after birth the precursors are not susceptible to tolerogenic signals.

Animals↗
PubMed1993

Monoclonal antibodies to heparan sulfate inhibit the formation of thrombin-antithrombin III complexes.

As components of the cell surface and extracellular matrix, heparan sulfate proteoglycans play an important role in the function of most organs, including the vasculature. Autoimmunity to heparan sulfate (HS) glycosaminoglycan epitopes may play a role in tissue injury. Tight skin (TSK) mice suffer a disease resembling scleroderma, an autoimmune disease associated with alterations in the extracellular matrix of the skin and other organs, as well as vascular injury. Studies of autoimmunity to HS were performed in TSK mice employing a solid-phase radioimmunoassay for the detection of anti-HS antibody. An increase in the clonal frequency of hybridomas secreting anti-HS antibody was noted in TSK mice compared to that in control mice. Liquid-phase competitive inhibition specificity studies of IgM and IgG anti-HS monoclonal antibodies demonstrated little cross-reactivity with other glycosaminoglycans. Some cross-reactivity, albeit at lower affinity, with phosphorylated antigens including DNA, cardiolipin, and RNA polymerase were noted. Negatively charged sulfate groups and carboxyl groups played a role in the immunodominant site. Monoclonal antibodies to HS inhibited the binding of HS to antithrombin III and the formation of thrombin-antithrombin III complexes. These results demonstrate autoimmunity to HS in TSK mice. The results also indicate that HS is a high-affinity antigen of pathological significance for anti-DNA and anti-phospholipid antibodies. Thrombosis induced by polyclonal anti-phospholipid antibodies may be mediated by a subset of these antibodies with high affinity for HS. Anti-HS antibodies may promote a procoagulant state by the blockade of HS binding to antithrombin III, inhibiting the accelerated formation of thrombin-antithrombin III complexes.

Animals↗
PubMed1993

An Fc gamma RIII (CD16)-specific autoantibody from a patient with progressive systemic sclerosis.

Polyspecific and organ specific autoimmune diseases are often accompanied by prolonged clearance of immune complexes. In mice, impaired macrophage Fc gamma receptor function may be associated with autoantibody against Fc gamma receptors. To extend these observations to autoimmune human disease, we transformed with EBV peripheral lymphocytes from a patient with terminal progressive systemic sclerosis and screened for clones secreting anti-Fc gamma receptor Ig. A clone, N55, which secretes a high affinity anti-Fc gamma receptor IgG2 antibody was obtained. The Fab fragment of N55 bound to human neutrophils, NK cells, but not to monocytes, consistent with specificity for Fc gamma RIII (CD16). N55 Fab competed weakly for the binding of anti-Fc gamma RIII mAb 3G8 to neutrophils but did not have any effect on staining with the anti-Fc gamma RII mAb, IV.3. N55 Fab did not bind to peripheral monocytes, but did bind to monocytes incubated with TGF-beta (24 h) to induce Fc gamma RIII. The specificity of N55 IgG for Fc gamma RIII was confirmed by ELISA using secreted recombinant Fc gamma RIIA and Fc gamma RIIIB protein to coat microtiter wells. N55 IgG triggered the release from neutrophils of beta-glucuronidase, arylsulfatase and alkaline phosphatase. Such antibody may play a pathogenic role in progressive systemic sclerosis.

Alkaline Phosphatase↗
PubMed1993

Defining criteria for autoimmune diseases (Witebsky's postulates revisited)

With new knowledge gained from molecular biology and hybridoma technology, as well as the original Witebsky postulates, we propose that three types of evidence can be marshalled to establish that a human disease is autoimmune in origin. They include direct evidence from transfer of pathogenic antibody or pathogenic T cells; indirect evidence based on reproduction of the autoimmune disease in experimental animals; and circumstantial evidence from clinical clues.

Animals↗
PubMed1993

Induction of antihemagglutinin antibodies by polyclonal antiidiotype antibodies.

Antiidiotypic antibodies can be envisioned as an alternative approach in the development of vaccines against influenza virus, which exhibits natural antigenic variations. In our work, we obtained two polyclonal cross-reactive anti-Id antibodies against PY102, VM113, and VM202 mAbs, which in turn are specific respectively for PR8 virus and laboratory-induced virus variants (PY102-V1 and VM113-V1). With these cross-reactive anti-Id antibodies, we were able to elicit anti-HA antibodies in mice. In comparing the anti-HA antibody response in animals injected with anti-Id antibodies to those immunized with PR8 influenza virus, we demonstrated that the HI titer was higher after virus immunization and that the PR8 virus boost was more efficient in this group. Our results showed that the polyclonal cross-reactive anti-Id antibodies were more efficient than the individual anti-Ids at eliciting responses. At the same time, we demonstrated that PR8-primed T cells, cultured with B cells from animals immunized with anti-Id antibodies, were able to produce anti-PR8 antibodies subsequent to stimulation with influenza virus.

Animals↗
PubMed1993

Priming of cytotoxic T lymphocytes at various stages of ontogeny with transfectoma cells expressing a chimeric Ig heavy chain gene bearing an influenza virus nucleoprotein peptide.

The amino acid residues 147-161 of the nucleoprotein (NP) of influenza virus represent a T cell epitope recognized by cytotoxic T cells (CTLs) in association with Kd class I molecules. When SP2/0 myeloma B cells are transfected with a chimeric heavy chain gene bearing this particular NP(147-161) peptide, they are lysed by CTLs specific for the NP(147-161) peptide. Cells that are transfected with this heavy chain chimera and the parental light chain secreted a soluble Ig-NP chimera and were also lysed by the CTLs. Herein, we present evidence that transfectoma cells are able to induce in vitro proliferation of NP specific CTL, whereas immobilized Ig-NP chimeras do not. Furthermore, the transfectoma cells expressing the chimeric heavy chain prime NP specific CTLs in adult as well as in newborn mice, while SP2/0 cells coated with NP(147-161) synthetic peptide do not. These data indicate that the NP peptide needs to be cleaved from the Ig context in order to be presented to T cells and that only endogenously generated NP peptide is immunogenic.

Amino Acid Sequence↗
PubMed1993

Chimeric influenza virus induces neutralizing antibodies and cytotoxic T cells against human immunodeficiency virus type 1.

Expression vectors based on DNA or plus-stranded RNA viruses are being developed as vaccine carriers directed against various pathogens. Less is known about the use of negative-stranded RNA viruses, whose genomes have been refractory to direct genetic manipulation. Using a recently described reverse genetics method, we investigated whether influenza virus is able to present antigenic structures from other infectious agents. We engineered a chimeric influenza virus which expresses a 12-amino-acid peptide derived from the V3 loop of gp120 of human immunodeficiency virus type 1 (HIV-1) MN. This peptide was inserted into the loop of antigenic site B of the influenza A/WSN/33 virus hemagglutinin (HA). The resulting chimeric virus was recognized by specific anti-V3 peptide antibodies and a human anti-gp120 monoclonal antibody in both hemagglutination inhibition and neutralization assays. Mice immunized with the chimeric influenza virus produced anti-HIV antibodies which were able to bind to synthetic V3 peptide, to precipitate gp120, and to neutralize MN virus in human T-cell culture system. In addition, the chimeric virus was also capable of inducing cytotoxic T cells which specifically recognize the HIV sequence. These results suggest that influenza virus can be used as an expression vector for inducing both B- and T-cell-mediated immunity against other infectious agents.

Amino Acid Sequence↗
PubMed1993

Engineered immunoglobulin molecules as vehicles for T cell epitopes.

The variable regions (V) of immunoglobulins (Ig) bear antigenic determinants that can stimulate both humoral and cellular immune responses subsequent to hetero, allo or iso-immunization. The expression of these determinants by Igs usually correlates with the presence of specific amino acid residues within the CDR loops of the V regions. Since the CDR loops varies in length, we reasoned that they would represent permissive sites to insert foreign peptides and create antigenized Igs expressing selected determinants. Taking advantage of these properties and the fact that Igs are self and long-lived molecules, we expressed a CTL and a helper epitope of influenza virus nucleoprotein and hemagglutinin respectively, within the heavy chain CDR3 loop of an anti-arsonate antibody. We found that foreign peptides comprised of 11 to 15 amino acid residues can be expressed within the V region of the heavy chain without alteration of pairing with the light chain. More striking, the cellular processing machinery is able to generate the peptides from the Ig context which were then recognized by specific T cells. Furthermore, the engineered Igs are able to induce T cell responses specific for the inserted peptide and for influenza virus. The use of engineered Ig molecules as vehicles for T and B cell peptides might represent a valuable strategy to generate safe, long lived reagents able to stimulate strong specific immune responses. This would then overcome the short half life of synthetic peptides based vaccines and the side effects seen in case of recombinant viral proteins or inactivated viruses based vaccines.

Animals↗
PubMed1992

Cells expressing an H chain Ig gene carrying a viral T cell epitope are lysed by specific cytolytic T cells.

The epitope corresponding to amino acid residues 147-161 of the nucleoprotein (NP) of influenza A virus is recognized by CTL in association with H-2Kd class I Ag. Herein, we engineered an Ig molecule carrying this CTL epitope by replacing the diversity gene segment of the H chain V region of an anti-arsonate antibody with an oligonucleotide that encodes the CTL epitope. The chimeric H chain gene was expressed either alone or together with the parental L chain in the nonsecreting BALB/c myeloma B cell line, SP2/0. The Ig produced by cells transfected with both the chimeric H chain and parental L chains genes expressed the NP epitope but lost the original arsonate binding activity. In addition, SP2/0 cells expressing the chimeric H chain either alone or together with the parental L chain were lysed by class I restricted NP-epitope specific CTL. By contrast, SP2/0 cells pulsed with soluble chimeric Ig molecules were not lysed by the specific CTL. These observations indicate that: 1) this particular CTL epitope can be expressed on Ig molecules without altering the H and L chain pairing; 2) this CTL epitope can be generated from this chimeric Ig in which it is surrounded by flanking regions distinct from those of the viral NP; and 3) the generation of this CTL epitope from the Ig molecule requires the endogenous pathway as do viral proteins.

Amino Acid Sequence↗