Papers by Candida Fratazzi MD
PubMed, Dec 1, 1987
Ten patients are described who, in addition to other allergic symptoms, suffered from arthralgia.... more Ten patients are described who, in addition to other allergic symptoms, suffered from arthralgia. Dietary exclusion relieved the symptoms and specific food challenge reproduced them. IgG anti-IgE autoantibodies were high in patients with arthralgia in the serum and in the synovial fluid as compared with normals and the majority of patients with rheumatoid arthritis, traumatic arthralgia, and osteoarthritis used as controls. In three food-allergic patients IgG anti-IgE was detectable in a complexed form in the serum samples examined before and after food challenge. The finding of IgG anti-IgE autoantibody in a group of patients with allergic arthralgia is quite exciting. It raises the possibility of distinguishing a subgroup of arthralgic patients not having a classical rheumatoid arthritis, who may have a definable external exacerbating cause for their symptoms. A larger detailed survey is now in progress.
PubMed, 1988
An IgG type of antibody directed against IgE has been studied in serum from healthy and allergic ... more An IgG type of antibody directed against IgE has been studied in serum from healthy and allergic individuals. The technique used is based on a solid phase paper radioimmunoassay in which the discs were sensitized with purified IgE myeloma. After incubation with patients' serum, human IgG labeled with iodine 125 was added. The anti-IgE antibodies were partially blocked by endogenous IgE in the serum and heating the serum samples at 56 degrees C disrupted the immune complexes (ie, IgG-aIgE:IgE), thereby increasing the detectable levels of IgG anti-IgE. The specificity of anti-IgE autoantibody was confirmed by both competitive inhibition and absorption experiments, using IgG, IgM, IgA, IgE, and rabbit anti-human IgG. Significantly raised levels of anti-IgE autoantibody were found in patients suffering from atopic disorders in comparison to the controls. These observations may suggest that the anti-IgE autoantibody could play a certain role in the modulation of IgE-mediated immune system and the pathogenesis of atopic diseases.
Clinical Immunology and Immunopathology, Dec 1, 1996
ence of IL-7. A significant augmentation of LFA-1 and The low-affinity receptor for IgE, CD23, ha... more ence of IL-7. A significant augmentation of LFA-1 and The low-affinity receptor for IgE, CD23, has been de-VLA-4 was observed in cells cultured in the presence scribed in several pathological conditions. However, of IL-7. Taken together these findings point to the likelihood that IL-7 is responsible for the observed quanti-the factors involved in the upregulation or downregutative difference in the level of adhesion molecules and lation of this receptor are still debated. We studied the may open a new role of CD23 in the immune regulation. effect of interleukin 7 (IL-7) on the production of CD23
JAMA, Apr 25, 2023
ImportanceThe effect of rationally defined nonpathogenic, nontoxigenic, commensal strains of Clos... more ImportanceThe effect of rationally defined nonpathogenic, nontoxigenic, commensal strains of Clostridia on prevention of Clostridioides difficile infection (CDI) is unknown.ObjectiveTo determine the efficacy of VE303, a defined bacterial consortium of 8 strains of commensal Clostridia, in adults at high risk for CDI recurrence. The primary objective was to determine the recommended VE303 dosing for a phase 3 trial.Design, Setting, and ParticipantsPhase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted from February 2019 to September 2021 at 27 sites in the US and Canada. The study included 79 participants aged 18 years or older who were diagnosed with laboratory-confirmed CDI with 1 or more prior CDI episodes in the last 6 months and those with primary CDI at high risk for recurrence (defined as aged ≥75 years or ≥65 years with ≥1 risk factors: creatinine clearance <60 mL/min/1.73 m2, proton pump inhibitor use, remote [>6 months earlier] CDI history).InterventionsParticipants were randomly assigned to high-dose VE303 (8.0 × 109 colony-forming units [CFUs]) (n = 30), low-dose VE303 (1.6 × 109 CFUs) (n = 27), or placebo capsules (n = 22) orally once daily for 14 days.Main Outcomes and MeasuresThe primary efficacy end point was the proportion of participants with CDI recurrence at 8 weeks using a combined clinical and laboratory definition. The primary efficacy end point was analyzed in 3 prespecified analyses, using successively broader definitions for an on-study CDI recurrence: (1) diarrhea consistent with CDI plus a toxin-positive stool sample; (2) diarrhea consistent with CDI plus a toxin-positive, polymerase chain reaction–positive, or toxigenic culture–positive stool sample; and (3) diarrhea consistent with CDI plus laboratory confirmation or (in the absence of a stool sample) treatment with a CDI-targeted antibiotic.ResultsBaseline characteristics were similar across the high-dose VE303 (n = 29; 1 additional participant excluded from efficacy analysis), low-dose VE303 (n = 27), and placebo (n = 22) groups. The participants’ median age was 63.5 years (range, 24-96); 70.5% were female; and 1.3% were Asian, 1.3% Black, 2.6% Hispanic, and 96.2% White. CDI recurrence rates through week 8 (using the efficacy analysis 3 definition) were 13.8% (4/29) for high-dose VE303, 37.0% (10/27) for low-dose VE303, and 45.5% (10/22) for placebo (P = .006, high-dose VE303 vs placebo).Conclusions and RelevanceAmong adults with laboratory-confirmed CDI with 1 or more prior CDI episodes in the last 6 months and those with primary CDI at high risk for recurrence, high-dose VE303 prevented recurrent CDI compared with placebo. A larger, phase 3 study is needed to confirm these findings.Trial RegistrationClinicalTrials.gov Identifier: NCT03788434
PubMed, Feb 1, 1993
The rising prevalence of infection with the human immunodeficiency virus type 1 (HIV-1) in young ... more The rising prevalence of infection with the human immunodeficiency virus type 1 (HIV-1) in young women will increase the number of infected children worldwide. Because HIV-1 seems to be transmitted mostly intrapartum, fetal infection probably occurs mainly via skin or mucous membrane exposure. A model for this route of fetal infection has been established in primates. After injecting the simian immunodeficiency virus (SIV) into amniotic fluid during late gestation, six of seven rhesus monkeys were born infected. All infected neonates were viable and showed signs of disease, such as low birth weights, lymphadenopathy, and rashes. Cytotoxic T-cell responses to SIV were absent in neonates, but present in mothers. The high fetal infection rate allows studies of lentiviral immunopathogenesis during ontogeny and the development of strategies to prevent maternal HIV-1 transmission.
Journal of Leukocyte Biology, Nov 1, 1999
Mycobacterial diseases are a major public health concern. In the case of tuberculosis, the proble... more Mycobacterial diseases are a major public health concern. In the case of tuberculosis, the problem has been acerbated due to the emergence of drug-resistant strains of Mycobacterium tuberculosis, and Mycobacterium avium is the major opportunistic pathogen in HIV-1 infection in the United States. M. tuberculosis and M. avium replicate in human macrophages and induce apoptosis. Incubation of freshly added uninfected autologous macrophages with apoptotic M. avium-infected macrophages results in 90% inhibition of bacterial growth. Apoptosis also prevents the release of intracellular components and the spread of mycobacterial infection by sequestering the pathogens within apoptotic bodies. Consistent with the model that host cell apoptosis is a defense mechanism against mycobacteria is the finding that the virulent M. tuberculosis strain H37Rv induces substantially less macrophage apoptosis than the attenuated strain H37Ra. Evasion of apoptosis by this pathogen is achieved by enhanced release of sTNFR2 by H37Rv-infected macrophages and subsequent formation of inactive TNF-␣-TNFR2 complexes. These observations contribute to the hypothesis that apoptosis of the host macrophage is an important defense mechanism in mycobacterial infections, which prevents the spread of the infection.
International Archives of Allergy and Immunology, 1993
The low-affinity Fc receptor for IgE, CD23/FcεRII, has been expressed in T cell lines an... more The low-affinity Fc receptor for IgE, CD23/FcεRII, has been expressed in T cell lines and pathologic T cells, but its presence on normal human T cells is still debated. We studied the expression of CD23/FcεRII on purified T cells from normal peripheral blood mononuclear cells (PBMC) or tonsil T cells stimulated with 10 μg/ml phytohemagglutinin A (PHA) or phorbol-12myristate-13acetate (PMA) Ca2+. Using two-dimensional flow cytometry, the tonsil T-cell-enriched population showed > 10% of CD23/FcεRII expression when coexpressed with the CD3 antigen. CD4+ T cells appear to be principally involved in the expression of CD23/FcεRII, although we were unable to detect a clear expression of CD23/FcεRII in PBMC that were activated with either PHA or PMA Ca2+. PHA stimulation resulted in the release of IgE binding factor (IgEBF). The induction of CD23/FcεRII expression in PHA- and PMA-Ca2+-activated T cells was enhanced by IL-4, but not by IgE or IL-6. IL-4 also augmented the PHA- and PMA-Ca2+-induced release of IgEBF. The addition of supernatant from the Epstein-Barr virus (EBV)-infected cell line to PHA-or PMA-Ca2+-stimulated tonsil T cells did not increase CD23/FcεRII expression. The expression of CD23/FcεRII mRNA was detected in RNA prepared from a tonsil T-cell-enriched population by Northern blot analysis.Copyright © 1993 S. Karger AG, Basel
Regular and Young Investigator Award Abstracts
Journal of Experimental Medicine, Jul 10, 2000
We studied the role of CD43 (leukosialin/sialophorin), the negatively charged sialoglycoprotein o... more We studied the role of CD43 (leukosialin/sialophorin), the negatively charged sialoglycoprotein of leukocytes, in the binding of mycobacteria to host cells. CD43-transfected HeLa cells bound Mycobacterium avium , but not Salmonella typhimurium or Shigella flexneri. Quantitative bacteriology showed that macrophages (M) from wild-type mice (CD43 ϩ / ϩ) bound M. avium , Mycobacterium bovis (bacillus Calmette-Guérin), and Mycobacterium tuberculosis (strain H37Rv), whereas M from CD43 knockout mice (CD43 Ϫ / Ϫ) did not. Fluorescence microscopy demonstrated that the associated M. avium had been ingested by the CD43 ϩ / ϩ M. The inability of CD43 Ϫ / Ϫ M to bind M. avium could be restored by addition of galactoglycoprotein (Galgp), the extracellular mucin portion of CD43. The effect of Galgp is not due to opsonization of the bacteria, but required its interaction with the M ; other mucins had no effect. CD43 expression by the M was also required for optimal induction by M. avium of tumor necrosis factor (TNF)-␣ production, which likewise could be reconstituted by Galgp. In contrast, interleukin (IL)-10 production by M. avium-infected M was CD43 independent, demonstrating discordant regulation of TNF-␣ and IL-10. These findings describe a novel role of CD43 in promoting stable interaction of mycobacteria with receptors on the M enabling the cells to respond specifically with TNF-␣ production.
Molecular Immunology, Oct 1, 1991
Three rat monoclonal antibodies specific for mouse IgE (C12B9, 2363, and BIE3) were established b... more Three rat monoclonal antibodies specific for mouse IgE (C12B9, 2363, and BIE3) were established by using monoclonal anti-DNP mouse IgE (mIgE) as immunogen. These antibodies, as well as a fourth, (RlE4) were characterized. It was found that one antibody (C12B9) recognizes an allotypic determinant (Igh-7a) found on the C, chain of mIgE. Antibody cross-blocking studies and epitope mapping studies using recombinant mIgE indicated that 3 antibodies (C12B9, RlE4 and 2363) were directed against the C,3 domain while one (BlE3) was directed against the C,4 domain. A highly specific sandwich RIA for mIgE was developed using these antibodies. Use of these monoclonal anti-mIgE antibodies in conjunction with recombinant chimeric mIgE-human IgG, molecules, demonstrated that the C,3 domain is important in the binding of mIgE to the murine B cell Fc,RII as well as to the murine mast cell Fc,RI. The presence of the C,4 domain influenced the binding of the recombinant IgE to the FqRII; in contrast to the C,4 domain had no effect on binding to the Fc,RI.
Blood, Nov 16, 2005
AIMS: Evaluation of safety and clinical activity of Gene-Activated ® human glucocerebrosidase (GA... more AIMS: Evaluation of safety and clinical activity of Gene-Activated ® human glucocerebrosidase (GA-GCB) as a new intravenous enzyme replacement therapy (ERT) for patients with type I Gaucher disease participating in a 9 month, open-label Phase I/II clinical study. BACKGROUND: GA-GCB is human glucocerebrosidase (GCB) produced in a well-characterized, continuous human cell line using proprietary gene activation technology. GA-GCB has an identical amino acid sequence to the naturally occurring human enzyme and contains terminal mannose residues that target the enzyme to macrophages, the primary target cells in Gaucher disease. Nine month study results of GA-GCB treatment will be presented. METHODS: Twelve adult patients (7 females /5 males) with type I Gaucher disease with clinically significant anemia, thrombocytopenia, hepatomegaly and/or splenomegaly, were enrolled in a 9 month Phase I/II clinical trial. Patients received GA-GCB every other week for a total of 40 weeks (20 infusions). A staggered dose escalation of GA-GCB was performed in the first 3 patients: these patients received 15 U/kg at the first infusion, 30 U/kg at the second infusion, and then 60 U/kg IV every other week for a total of 20 IV infusions. The remaining 9 patients received 60 U/kg beginning with their first dose. Anti-GA-GCB antibodies were tested in all patients during the 9 months of treatment. All patients were routinely evaluated for hemoglobin, platelets, liver and spleen volumes, infusion reactions and adverse events. In addition, serum samples were analyzed for disease biomarkers: chitotriosidase and CCL18. RESULTS: Eleven of the 12 patients who were enrolled in the trial have been treated for nine months. One patient withdrew consent after three injections for reasons not related to treatment. Dose escalation from 15 U/kg to 60 U/kg was well tolerated in the first three patients. The remaining patients received 60 U/kg every other week throughout the course of the study. Anti-GA-GCB antibody test results were negative for all patients. Mean hemoglobin and platelet values, below the normal range at baseline, improved after 9 months of GA-GCB treatment to levels consistent with the therapeutic goals for ERT in Gaucher disease (Seminars in Hematology 2004). Analysis of the liver and spleen volumes decreased following 9 months of treatment. In addition, serum chitotriosidase and CCL18 levels decreased over the 9 months of GA-GCB treatment. CONCLUSION: ERT with GA-GCB was well tolerated and demonstrated clinical activity in well-established clinical markers in patients with type 1 Gaucher disease when administered IV every other week at 60 U/kg over 9 months. Results suggest that GA-GCB holds promise as a new therapeutic option for ERT in Gaucher disease.
Pharmaceutical Sciences Encyclopedia, Mar 15, 2010
Clinical & Experimental Allergy, Nov 1, 1997
SummaryBackground The low affinity receptor for IgE, CD23, has been described in several patholog... more SummaryBackground The low affinity receptor for IgE, CD23, has been described in several pathological conditions. However, the factors involved in the upregulation or downregulation of this receptor are still debated.Methods and Results We studied the effect of interleukin 7 (IL‐7) on the expression of CD23 in normal PBT cells stimulated with PMA + Ca2. The data indicate that activated PB‐T cultured in the presence of IL‐7 showed an increased expression of CD23. The induction of IL‐7 on CD23 production appears to be independent of IL‐2, IL‐4, IL‐9, IL‐15. Indeed, the addition of specific MoAbs anti‐IL‐2, IL‐4, IL‐9, IL‐15 oranti‐IL2R was unable to block the effect of IL‐7 on CD23. The addition of IL‐7 to a specific subset CD4+CD23+ was able to augment the adhesiveness of T cells to parenchymal cell monalayers. The use of different cytokine (IL‐2, IL‐4, IL‐9, IL‐15) resulted in no increase of adhesiveness. In contrast the addition of IL‐7 to a different T‐cell subset (i.e. CD4+CD23‐) was unable to rescue the lack of adhesiveness observed in these cells. Blocking experiments with MHM6 MoAb were able to drastically reduce the adhesiveness observed in CD4+FCD23+ subsets. The presence of LFA‐1 and VLA‐4 adhesion molecules were responsible for the augmented adhesiveness of activated CD4+CD23+ T cells cultured in the presence of IL‐7. Blocking experiments with anti‐LFA‐1, VLA‐4. anti‐LFA‐1β plus VLA‐4α MoAbs or anti‐ICAM‐1 MoAb added to the monolayers resulted in a complete inhibition of adhesion to parenchymal monolayers. In contrast, the addition of anti‐IL‐7 oranti‐IL‐7R MoAbs were able to block the augmented adhesiveness of CD4+CD23+ cells to monolayers observed in the presence of IL‐7.Conclusions Taken together these findings point to the likelihood that IL‐7 is responsible for the observed quantitative difference in the level of adhesion molecules and may open a new role of CD23 in the immune regulation.
Gastroenterology, May 1, 2022
Clinical Immunology and Immunopathology, 1998
The present study was undertaken to investigate the growth of mitogen activated T cells (7), and ... more The present study was undertaken to investigate the growth of mitogen activated T cells (7), and regulating interaction of IL-7 and sCD23 on human peripheral specific functions of human T lymphocytes (8-17). blood T cell activation and CTL differentiation. Puri-Soluble CD23 (sCD23) was reported to control the fied T lymphocytes were stimulated with mitogen plus synthesis of mouse IgE (18), sustain the proliferation IL-2 and subcultured for 7 days with IL-7 and/or sCD23. of B (19) and T cells (20-24), and be released from The combination of IL-7 and sCD23 synergistically en-PBMC of viral diseases (22, 25-27). The role of CD23 hanced the proliferation of both CD4 / and CD8 / T has recently been reexamined and it appeared that cells. CD8 / T cells, however, were usually more responsome CD23 activities are IgE independent (28-32). Resive to IL-7 and sCD23. This synergy was observed on cent data indicate a function for CD23 in the regulation both subsets of T cells. Furthermore, these cytokines of the production of two potent macrophages activating synergistically augment the CTL activity of CD8 / T factors, i.e., IFN-g and TNF-a (33). cells in both mitogen-and antigen-activated T cells. Several reports showed the presence of receptor for MAbs anti-IL-2 or anti-IL-2R (CD25) and anti-IL-12 had IL-7 or CD23 on cells of the lymphoid lineage and on no effect on T cell proliferation and CD8 / cytotoxic mitogen-activated T cells (20, 21, 23). It was also sugactivity induced by IL-7 and sCD23. We analyzed the gested that the presence of these receptors correlates effect on IFN-g induction by CD8 / T cells and found with the ability of stimulated T lymphocytes to proliferthat IL-7 alone was incapable of inducing detectable levels of IFN-g production, but together with sCD23 it ate in response to soluble cytokines (20, 23, 34, 35). enhanced the production of IFN-g. We also found that However, little is known about regulation of their ex-IFN-g was not required for enhanced CTL activity of pression by different cytokines. CD8 / T cells, because rabbit anti-IFN-g did not block The present study has been undertaken to investithe synergistic effects of either cytokine. The data gate the combined effects of IL-7 and sCD23 on T cell demonstrate that the synergistic stimulatory activity activation and CTL differentiation. In this paper, we of IL-7 and sCD23 may be of significance in the human demonstrate that: (i) IL-7 combined with sCD23 re-CTL development and provide an alternative mechasulted in a synergistic increase of T cell proliferation; nism of stimulating T cells for use in immunotherapy. (ii) the combination of IL-7 and sCD23 appeared to ᭧ 1998 Academic Press specifically augment the cytotoxic activity of CD8 / T Key Words: CD23; IL-7; influenza virus; T cells; CTL; cells; (iii) the augmentation of T cell proliferation and mitogen. cytotoxic activity occurred in an IL-2-and IL-12-independent manner; and (iv) the synergistic effect of IL-7 and sCD23 on the augmentation of CD8 / CTL activity MATERIALS AND METHODS from precursor CTLs involves intricate interactions with antigen via the T cell receptor-CD3 complex and Antigens and antibodies. Concanavalin A (ConA) the action of soluble factors (3-5). was from Sigma Chemical Co. (St. Louis, MO). In-Interleukin 7 (IL-7) has initially been described as terleukin 2 (IL-2) (200 pM) (Pharmacia, U.S.A.) and IL-7 (1000 U/ml) (Sterling Wintrop, Malvern, PA) were used to stimulate T cells.
Journal of women's health, 1993
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Papers by Candida Fratazzi MD