scholarly journals Presence of Human T-Cell Responses to the Mycobacterium leprae 45-Kilodalton Antigen Reflects Infection with or Exposure to M. leprae

2001 ◽  
Vol 8 (3) ◽  
pp. 604-611 ◽  
Author(s):  
Anne Macfarlane ◽  
Rafael Mondragon-Gonzalez ◽  
Francisco Vega-Lopez ◽  
Brigitte Wieles ◽  
Josefina de Pena ◽  
...  
Keyword(s):  
T Cell ◽  
Pulmonary Tuberculosis ◽  
Mycobacterium Leprae ◽  
The Other ◽  
Recombinant Antigens ◽  
Diagnostic Potential ◽  
Human T Cell ◽  
Tuberculoid Leprosy ◽  
Leprosy Patients ◽  
Ifn Γ

ABSTRACT The ability of the 45-kDa serine-rich Mycobacterium leprae antigen to stimulate peripheral blood mononuclear cell (PBMC) proliferation and gamma interferon (IFN-γ) production was measured in leprosy patients, household contacts, and healthy controls from areas of endemicity in Mexico. Almost all the tuberculoid leprosy patients gave strong PBMC proliferation responses to the M. leprae 45-kDa antigen (92.8%; n = 14). Responses were lower in lepromatous leprosy patients (60.6%;n = 34), but some responses to the 45-kDa antigen were detected in patients unresponsive to M. lepraesonicate. The proportion of positive responses to the M. leprae 45-kDa antigen was much higher in leprosy contacts (88%; n = 17) than in controls from areas of endemicity (10%; n = 20). None of 15 patients with pulmonary tuberculosis gave a positive proliferation response to the 45-kDa antigen. The 45-kDa antigen induced IFN-γ secretion similar to that induced by the native Mycobacterium tuberculosis30/31-kDa antigen in tuberculoid leprosy patients and higher responses than those induced by the other recombinant antigens (M. leprae 10- and 65-kDa antigens, thioredoxin, and thioredoxin reductase); in patients with pulmonary tuberculosis it induced lower IFN-γ secretion than the other recombinant antigens. These results suggest that the M. leprae 45-kDa antigen is a potent T-cell antigen which is M. leprae specific in these Mexican donors. This antigen may therefore have diagnostic potential as a new skin test reagent or as an antigen in a simple whole-blood cytokine test.

scholarly journals A Postgenomic Approach to Identification ofMycobacterium leprae-Specific Peptides as T-Cell Reagents

2000 ◽  
Vol 68 (10) ◽  
pp. 5846-5855 ◽  
Author(s):  
Hazel M. Dockrell ◽  
Shweta Brahmbhatt ◽  
Brian D. Robertson ◽  
Sven Britton ◽  
Uli Fruth ◽  
...  
Keyword(s):  
United Kingdom ◽  
T Cell ◽  
Mononuclear Cells ◽  
Diagnostic Tools ◽  
T Cell Epitopes ◽  
Human T Cell ◽  
Hla Dr ◽  
Tuberculoid Leprosy ◽  
Leprosy Patients ◽  
Ifn Γ

ABSTRACT To identify Mycobacterium leprae-specific human T-cell epitopes, which could be used to distinguish exposure to M. leprae from exposure to Mycobacterium tuberculosis or to environmental mycobacteria or from immune responses followingMycobacterium bovis BCG vaccination, 15-mer synthetic peptides were synthesized based on data from the M. lepraegenome, each peptide containing three or more predicted HLA-DR binding motifs. Eighty-one peptides from 33 genes were tested for their ability to induce T-cell responses, using peripheral blood mononuclear cells (PBMC) from tuberculoid leprosy patients (n = 59) and healthy leprosy contacts (n = 53) from Brazil, Ethiopia, Nepal, and Pakistan and 20 United Kingdom blood bank donors. Gamma interferon (IFN-γ) secretion proved more sensitive for detection of PBMC responses to peptides than did lymphocyte proliferation. Many of the peptides giving the strongest responses in leprosy donors compared to subjects from the United Kingdom, where leprosy is not endemic, have identical, or almost identical, sequences in M. leprae and M. tuberculosis and would not be suitable as diagnostic tools. Most of the peptides recognized by United Kingdom donors showed promiscuous recognition by subjects expressing differing HLA-DR types. The majority of the novel T-cell epitopes identified came from proteins not previously recognized as immune targets, many of which are cytosolic enzymes. Fifteen of the tested peptides had ≥5 of 15 amino acid mismatches between the equivalent M. leprae and M. tuberculosissequences; of these, eight gave specificities of ≥90% (percentage of United Kingdom donors who were nonresponders for IFN-γ secretion), with sensitivities (percentage of responders) ranging from 19 to 47% for tuberculoid leprosy patients and 21 to 64% for healthy leprosy contacts. A pool of such peptides, formulated as a skin test reagent, could be used to monitor exposure to leprosy or as an aid to early diagnosis.

scholarly journals From Genome-Based In Silico Predictions to Ex Vivo Verification of Leprosy Diagnosis

2009 ◽  
Vol 16 (3) ◽  
pp. 352-359 ◽  
Author(s):  
Annemieke Geluk ◽  
John S. Spencer ◽  
Kidist Bobosha ◽  
Maria C. V. Pessolani ◽  
Geraldo M. B. Pereira ◽  
...  
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
Immunoglobulin M ◽  
Diagnostic Tools ◽  
Cell Responses ◽  
Household Contacts ◽  
Diagnostic Potential ◽  
Human T Cell ◽  
Leprosy Patients

ABSTRACT The detection of hundreds of thousands of new cases of leprosy every year suggests that transmission of Mycobacterium leprae infection still continues. Unfortunately, tools for identification of asymptomatic disease and/or early-stage M. leprae infection (likely sources of transmission) are lacking. The recent identification of M. leprae-unique genes has allowed the analysis of human T-cell responses to novel M. leprae antigens. Antigens with the most-promising diagnostic potential were tested for their ability to induce cytokine secretion by using peripheral blood mononuclear cells from leprosy patients and controls in five different areas where leprosy is endemic; 246 individuals from Brazil, Nepal, Bangladesh, Pakistan, and Ethiopia were analyzed for gamma interferon responses to five recombinant proteins (ML1989, ML1990, ML2283, ML2346, and ML2567) and 22 synthetic peptides. Of these, the M. leprae-unique protein ML1989 was the most frequently recognized and ML2283 the most specific for M. leprae infection/exposure, as only a limited number of tuberculosis patients responded to this antigen. However, all proteins were recognized by a significant number of controls in areas of endemicity. T-cell responses correlated with in vitro response to M. leprae, suggesting that healthy controls in areas where leprosy is endemic are exposed to M. leprae. Importantly, 50% of the healthy household contacts and 59% of the controls in areas of endemicity had no detectable immunoglobulin M antibodies to M. leprae-specific PGL-I but responded in T-cell assays to ≥1 M. leprae protein. T-cell responses specific for leprosy patients and healthy household contacts were observed for ML2283- and ML0126-derived peptides, indicating that M. leprae peptides hold potential as diagnostic tools. Future work should concentrate on the development of a sensitive and field-friendly assay and identification of additional peptides and proteins that can induce M. leprae-specific T-cell responses.

scholarly journals Antigen-Specific T-Cell Responses of Leprosy Patients

2008 ◽  
Vol 15 (11) ◽  
pp. 1659-1665 ◽  
Author(s):  
Malcolm S. Duthie ◽  
Wakako Goto ◽  
Greg C. Ireton ◽  
Stephen T. Reece ◽  
Lucas H. Sampaio ◽  
...  
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
Significant Proportion ◽  
T Cell Responses ◽  
Potential Candidate ◽  
Peripheral Blood Mononuclear ◽  
Cell Responses ◽  
Human T Cell ◽  
Leprosy Patients ◽  
Ifn Γ

ABSTRACT The identification of human T-cell antigens of Mycobacterium leprae could improve treatment and help to disrupt the transmission of leprosy by directing diagnosis and vaccine programs. This study screened a panel of M. leprae recombinant proteins for T-cell recall responses, measured by gamma interferon (IFN-γ) production, among leprosy patients. After initial studies using peripheral blood mononuclear cells from leprosy patients, we transitioned our studies to simple whole-blood assays (WBA), which are more applicable in field or clinical settings. T-cell responses generated in WBA using blood from individuals in Goiânia, Brazil, demonstrated that several M. leprae antigens (ML0276, ML0840, ML1623, ML2044, and 46f) elicited >0.5 IU/ml IFN-γ, and these proteins were classified as immunogenic and leprosy specific. Several of these individual antigens were recognized by cells from >60% of Brazilian paucibacillary (PB) leprosy patients, and ML0276, ML0840, ML1623, and 46f complemented each other such that 82% of PB patients had strong (>1.25 IU/ml IFN-γ) responses to at least one of these proteins. These proteins were also recognized by cells from a significant proportion of the household contacts of multibacillary leprosy patients, but in contrast, few responses were observed in active tuberculosis patients or healthy control groups from areas of endemicity. Our results indicate several potential candidate antigens which may be useful for either leprosy diagnosis or vaccination and demonstrate the utility of leprosy WBA that can be applied broadly in clinical or field settings.

Mycobacterium Leprae-reactive T-cell clones isolated from polar lepromatous and tuberculoid leprosy patients

1987 ◽  
Vol 138 (5) ◽  
pp. 723-735 ◽  
Author(s):  
P. Launois ◽  
P. Shankar ◽  
D. Wallach ◽  
B. Flageul ◽  
F. Cottenot ◽  
...  
Keyword(s):  
T Cell ◽  
Mycobacterium Leprae ◽  
T Cell Clones ◽  
Cell Clones ◽  
Tuberculoid Leprosy ◽  
Leprosy Patients

scholarly journals Rational Combination of Peptides Derived from Different Mycobacterium leprae Proteins Improves Sensitivity for Immunodiagnosis of M. leprae Infection

2008 ◽  
Vol 15 (3) ◽  
pp. 522-533 ◽  
Author(s):  
Annemieke Geluk ◽  
Jolien van der Ploeg ◽  
Rose O. B. Teles ◽  
Kees L. M. C. Franken ◽  
Corine Prins ◽  
...  
Keyword(s):  
T Cell ◽  
Early Stage ◽  
T Cell Responses ◽  
Hla Class I ◽  
Mycobacterium Leprae ◽  
Diagnostic Tools ◽  
Cell Responses ◽  
Diagnostic Potential ◽  
Leprosy Patients ◽  
Hla Binding

ABSTRACT The stable incidence of new leprosy cases suggests that transmission of infection is continuing despite the worldwide implementation of multidrug therapy programs. Highly specific tools are required to accurately diagnose asymptomatic and early stage Mycobacterium leprae infections which are the likely sources of transmission and cannot be identified by using the detection of antibodies against phenolic glycolipid I. One of the hurdles hampering T-cell-based diagnostic tests is that M. leprae antigens cross-react at the T-cell level with antigens present in other mycobacteria, like M. tuberculosis or M. bovis bacillus Calmette-Guerin (BCG). Using comparative genomics, we previously identified five candidate proteins highly restricted to M. leprae which showed promising features with respect to application in leprosy diagnostics. However, despite the lack of overall sequence homology, the use of recombinant proteins includes the risk of detecting T-cell responses that are cross-reactive with other antigens. To improve the diagnostic potential of these M. leprae sequences, we used 50 synthetic peptides spanning the sequences of all five proteins for the induction of T-cell responses (gamma interferon) in leprosy patients, healthy household contacts (HHC) of leprosy patients, and healthy controls in Brazil, as well as in tuberculosis patients, BCG vaccinees, and healthy subjects from an area of nonendemicity. Using the combined T-cell responses toward four of these peptides, all paucibacillary patients and 13 out of 14 HHC were detected without compromising specificity. The peptides contain HLA binding motifs for various HLA class I and II alleles, thereby meeting an important requirement for the applicability of diagnostic tools in genetically diverse populations. Thus, this study provides the first evidence for the possibility of immunodiagnostics for leprosy based on mixtures of peptides recognized in the context of different HLA alleles.

AB0268 HUMAN T-CELL LEUKAEMIA VIRUS TYPE 1 MAY INVALIDATE T-SPOT.TB RESULTS AMONG RHEUMATOID ARTHRITIS PATIENTS: A RETROSPECTIVE OBSERVATIONAL STUDY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1432.1-1433
Author(s):  
K. Umekita ◽  
Y. Hashiba ◽  
R. Kudou ◽  
S. Miyauchi ◽  
M. Kimura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Type ◽  
Peripheral Blood ◽  
Medical Records ◽  
Cell Leukaemia ◽  
Leukaemia Virus ◽  
Human T Cell ◽  
Ifn Γ

Background:In clinical rheumatology, interferon-γ release assays (IGRAs) have been reported as a useful diagnostic test for latent tuberculosis infection (LTBI) before beginning the administration of biologics such as anti-TNF therapies (1). CD4-positive T cells are the main target in Human T-cell leukaemia virus type 1 (HTLV-1) infection. Several reports suggest that the reaction of tuberculin skin test (TST) is attenuated in HTLV-1-positive individuals compared with that in HTLV-1-negative individuals (2). However, it remains unclear whether IGRAs are reliable for detecting TB infection among HTLV-1-positive RA patients.Objectives:The present study aimed to investigate the usefulness of the T-SPOT.TBassay in HTLV-1-positive RA patients. In addition, the association between the existence of IFN-γ producing T cells and HTLV-1 proviral loads (PVLs) in HTLV-1-positive RA patients was analysed on the basis of the T-SPOT.TBassay results.Methods:We reviewed the medical records of 75 HTLV-1-negative and 29 HTLV-1-positive RA patients were suspected cases of LTBI and evaluated using the T-SPOT.TBassay as a clinical practice from April 2012 to July 2019. The results of T-SPOT.TBwere collected from medical records, retrospectively. Peripheral blood samples were obtained from HTLV-1-positive RA patients for the analysis of HTLV-1 PVLs values. The study protocol was approved by the research ethics committees of our hospitals.Results:Approximately 55% of the HTLV-1-positive RA patients showed invalid results for the T-SPOT.TBassay (p < 0.0001); the cause of invalid results was a spot-forming count of >10 spots in the negative controls of the T-SPOT.TBassay among HTLV-1-positive RA patients. Among HTLV-1-positive RA patients, HTLV-1 PVL values were significantly higher in 16 patients who showed invalid results than in 13 patients who did not (p = 0.003). There were no between-group differences in female patient ratio, age, RA disease activity and therapeutic regimens. IFN-γ producing cells were detected in the peripheral blood of HTLV-1-positive RA patients without stimulation with TB-specific antigens.Conclusion:The incidence of invalid results for the T-SPOT.TBassay has been reported to be as low as 0.6% (3). The results of this assay for screening of LTBI in HTLV-1-positive RA patients should be interpreted with caution. Furthermore, our results show that an increase in IFN-γ producing T cell numbers due to HTLV-1 infection in RA patients may affect the pathogenesis of RA.References:[1]Iannone, F., et al.J. Rheumatol. Suppl.91, 41-46 (2014).[2]Tachibana, N., et al.Int. J. Cancer42, 829-831 (1988).[3]Rego, K., et al.Tuberculosis (Edinb.)108, 178-185 (2018).Acknowledgments:We would like to thank Dr Yuki Hashikura and Ms Yuki Kaseda of the University of Miyazaki for their technical support in this work. We would also like to acknowledge Ms Yumiko Kai at the Institute of Rheumatology, Zenjinkai Shimin-no-Mori Hospital, for her help in data management.A part this work was supported by a grant from the Practical Research Project for Rare/Intractable Diseases of the Japan Agency for Medical Research and Development (Grant No. JP19ek0109356), a Health and Labor Sciences Research Grant on Rare and Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan (Grant No. 19FC1007), and a Grant-in-Aid for Clinical Research from Miyazaki University Hospital.Disclosure of Interests:Kunihiko Umekita Paid instructor for: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Speakers bureau: Bristol-Myers Squibb, Yayoi Hashiba: None declared, Risa Kudou: None declared, Shunichi Miyauchi: None declared, Masatoshi Kimura: None declared, Motohiro Matsuda: None declared, Chihiro Iwao: None declared, Yumi Kariya: None declared, Takeshi Kawaguchi: None declared, Katoko Takajo: None declared, Koushou Iwao: None declared, Yuuki Rikitake: None declared, Ichiro Takajo: None declared, Toshihiko Hidaka Paid instructor for: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Speakers bureau: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Akihiko Okayama: None declared

Antitumor Effects of JBD57 in Human Multiple Myeloma Cells in Vitro

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5175-5175
Author(s):  
Juliana Pereira ◽  
Debora Levy ◽  
Jorge Luis Maria Ruiz ◽  
Felipe Vieira Rodrigues Maciel ◽  
Dalton de Alencar Fisher Chamone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Cell Viability ◽  
Uterine Sarcoma ◽  
The Other ◽  
Time Dependent ◽  
Dependent Manner ◽  
Human T Cell ◽  
Rpmi 8226

Abstract JBD57 is a nucleoside/nucleotide analogue that in human cells causes depletion of mitochondrial DNA by disrupting oxidative phosphorylation pathways leading to toxic accumulation of nonesterified fatty acids, dicarboxylic acids and free radicals. Human 26S proteasome is also a target for JBD57. Here we evaluated JBD57 citotoxicity in several human tumor cell lines in vitro. Human MM cell line RPMI 8226/S (CCL-155), human T-cell lymphoblastic-like (Jurkat) and human T-cell leukemia (1301) were grown in RPMI 1640 medium; uterine sarcoma (MES-S (CRL-1976) cells were grown in McCoy medium; HUV-EC-C (CRL-1730) cells were grown in 199/EBSS medium. Media were supplemented with 10 % FBS. Cells were incubated at 37°C in a water-jacketed incubator with 5 % CO2. To evaluate JBD57 citotoxicity in RPMI 8226/S, MES-S, Jurkat, 1301 and HUV-EC-C cells, 104cells/well were grown in flat-bottomed 96-well tissue culture plates for 24, 48 and 72 hr; JBD57 was added to the media in several concentrations (0μM, 32.25μM, 62.5μM, 125μM, 250μM and 500μM). At the end of the experimental periods, cell viability was determined by the MTT method. JBD57 inhibited the growth of MM cell line RPMI 8226/S in a dose- and time-dependent manner. Cell viability decreased progressively with increasing concentrations of JBD57 as well as with increasing time periods. The IC50 (inhibitory concentration at 50%) was 125 μM at 72 hr. The viability of the MM cells after 72 hr incubation with JBD57 500μM was 33%, whereas 100% viability was observed when no drug was added. On the other hand, JBD57 did not affect cell viability of any of the other studied cell lines (uterine sarcoma, Jurkat, 1301 and HUVEC-C). JBD57 promotes a significant human MM cell death in a dose and time dependent manner but do not affect neither normal cell HUV-EC-C nor the tumoral cells MES-S, Jurkat and 1301, at least in the studied conditions. These results suggest that the potent antitumoral activity of JBD57 observed against MM cells could be potentially useful in the treatment of multiple myeloma.

scholarly journals Functionally restricted, allospecific, human helper T cell lines that amplify either B cell or cytolytic T cell responses.

1983 ◽  
Vol 157 (5) ◽  
pp. 1675-1680 ◽  
Author(s):  
S M Friedman ◽  
G S Thompson
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Cell Lines ◽  
Cytotoxic T Lymphocytes ◽  
The Other ◽  
Helper T Cells ◽  
Cell Responses ◽  
Histocompatibility Complex ◽  
Human T Cell ◽  
T Cell Lines

Using a panel of partially cloned, OKT4+, DRw-1-specific, alloproliferative human T cell lines, we have identified two functionally restricted and reciprocating types of helper T cells. One provides major histocompatibility complex-restricted help for plaque-forming cell responses by DRw 1+ allogeneic B cells; the other preferentially amplifies the generation of allospecific cytotoxic T lymphocytes (CTL) from CTL precursors that have been suboptimally triggered by alloantigen.

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