scholarly journals Mycobacterium leprae-Specific, HLA Class II-Restricted Killing of Human Schwann Cells by CD4+Th1 Cells: A Novel Immunopathogenic Mechanism of Nerve Damage in Leprosy

2001 ◽  
Vol 166 (10) ◽  
pp. 5883-5888 ◽  
Author(s):  
Eric Spierings ◽  
Tjitske de Boer ◽  
Brigitte Wieles ◽  
Linda B. Adams ◽  
Enrico Marani ◽  
...  
Keyword(s):  
Schwann Cells ◽  
Mycobacterium Leprae ◽  
Class Ii ◽  
Nerve Damage ◽  
Hla Class Ii ◽  
Th1 Cells

scholarly journals Structure-Guided Computational Approaches to Unravel Druggable Proteomic Landscape of Mycobacterium leprae

2021 ◽  
Vol 8 ◽  
Author(s):  
Sundeep Chaitanya Vedithi ◽  
Sony Malhotra ◽  
Marta Acebrón-García-de-Eulate ◽  
Modestas Matusevicius ◽  
Pedro Henrique Monteiro Torres ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Schwann Cells ◽  
Protein Structures ◽  
Mycobacterium Leprae ◽  
Data Bank ◽  
Nerve Damage ◽  
Structural Proteomics ◽  
Bacterial Survival ◽  
Functional Sites

Leprosy, caused by Mycobacterium leprae (M. leprae), is treated with a multidrug regimen comprising Dapsone, Rifampicin, and Clofazimine. These drugs exhibit bacteriostatic, bactericidal and anti-inflammatory properties, respectively, and control the dissemination of infection in the host. However, the current treatment is not cost-effective, does not favor patient compliance due to its long duration (12 months) and does not protect against the incumbent nerve damage, which is a severe leprosy complication. The chronic infectious peripheral neuropathy associated with the disease is primarily due to the bacterial components infiltrating the Schwann cells that protect neuronal axons, thereby inducing a demyelinating phenotype. There is a need to discover novel/repurposed drugs that can act as short duration and effective alternatives to the existing treatment regimens, preventing nerve damage and consequent disability associated with the disease. Mycobacterium leprae is an obligate pathogen resulting in experimental intractability to cultivate the bacillus in vitro and limiting drug discovery efforts to repositioning screens in mouse footpad models. The dearth of knowledge related to structural proteomics of M. leprae, coupled with emerging antimicrobial resistance to all the three drugs in the multidrug therapy, poses a need for concerted novel drug discovery efforts. A comprehensive understanding of the proteomic landscape of M. leprae is indispensable to unravel druggable targets that are essential for bacterial survival and predilection of human neuronal Schwann cells. Of the 1,614 protein-coding genes in the genome of M. leprae, only 17 protein structures are available in the Protein Data Bank. In this review, we discussed efforts made to model the proteome of M. leprae using a suite of software for protein modeling that has been developed in the Blundell laboratory. Precise template selection by employing sequence-structure homology recognition software, multi-template modeling of the monomeric models and accurate quality assessment are the hallmarks of the modeling process. Tools that map interfaces and enable building of homo-oligomers are discussed in the context of interface stability. Other software is described to determine the druggable proteome by using information related to the chokepoint analysis of the metabolic pathways, gene essentiality, homology to human proteins, functional sites, druggable pockets and fragment hotspot maps.

scholarly journals A New Peptide Vaccine Ocv-501, Phase 1 Study in Patients with Acute Myeloid Leukemia and In Vitro Pharmacology

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1643-1643
Author(s):  
Tohru Sakura ◽  
Yukio Kobayashi ◽  
Shuichi Miyawaki ◽  
Kazuyuki Toga ◽  
Shinji Sogo ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
Mrna Level ◽  
Pharmaceutical Research ◽  
Class Ii ◽  
Hla Class Ii ◽  
Th1 Cells ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is the most common leukemia in older adults. Chemotherapy is the standard treatment, however, treatment efficacy and tolerability deteriorates with age, and patients are susceptible to relapse after complete remission (CR). Therefore, new therapeutic strategies for preventing relapse after consolidation therapy are urgently needed. Wilms' tumor 1 (WT1) is a promising target of new immunotherapies for acute myeloid leukemia (AML) as well as other cancers. OCV-501 is a helper peptide derived from the WT1 protein. Preclinical studies have shown that it induced OCV-501-specific Th1 responses dose-dependently and stimulated helper activity of the specific Th1 cells in peripheral blood mononuclear cells from healthy donors. OCV-501 also enhanced the increase in WT1-killer peptide-specific cytotoxic T lymphocytes (CTLs). The stimulated OCV-501-specific Th1 clones in an HLA class-II restricted manner formed a complex with HLA class-II protein and showed significant OCV-501-specific cytolytic activity against B-lymphoblastoid cell lines (B-LCL). These results suggested that OCV-501 activates both direct and indirect antitumor (anti-leukemic) cellular immunity, including specific cytotoxic Th1 cells and WT1-peptide-specific CTLs. Based on this, a phase 1 trial was carried out to assess the safety and tolerability as well as efficacy of OCV-501 in elderly AML patients in CR. This was an open label, multi-center trial conducted in Japan. The study involved AML patients who have achieved their first CR with an induction regimen and completed standard consolidation therapy, and have been identified as WT1 mRNA positive, with one of the following HLA class II types: HLA-DRB1*01:01, *04:05, *15:01, *15:02, *08:03, or *09:01. The trial consisted of 3 cohorts at a dose of 0.3 mg in cohort 1, 1 mg in cohort 2, and 3 mg in cohort 3, whereby administration commenced with cohort 1 and progressed to subsequent cohorts, depending on the assessment for dose limiting toxicity (DLT) in the preceding cohort. OCV-501 was administered subcutaneously weekly for 4 weeks, followed by end of treatment and post-treatment examinations after 1 and 4 weeks from the last administration, respectively. Safety and tolerability which included any occurrence of treatment-emergent adverse events (TEAEs) and DLT were assessed, and the maximum tolerated dose (MTD) was determined. Efficacy was evaluated by relapse of AML, WT1 mRNA level and immune response to OCV-501 using delayed-type hypersensitivity (DTH) test. Nine patients were enrolled and all completed the study. No DLT was observed in any of the 3 cohorts. Injection site reactions, including erythema, induration, mass, pain, and pruritus were observed in all patients. However, these drug-related TEAEs were Grade 1 or 2 in severity. There were neither deaths nor serious TEAEs during the treatment period and none of the patients discontinued OCV-501 administration due to TEAE. The result of this trial suggested that OCV-501 once a week for 4 weeks at doses of 0.3, 1, and 3 mg was safe and well-tolerated in AML patients in CR and the MTD was considered to be ≥ 3 mg. In the efficacy analysis, neither relapse nor blast cells were observed in any patients and a reduction in WT1 mRNA level was found in 5 patients. Immunological response was observed in all patients in the OCV-501-specific DTH test. In conclusion, OCV-501, which was suggested to activate both direct and indirect anti-leukemic cellular immunity, showed a favorable safety and tolerability profile in elderly patients who have AML in CR, and the MTD was shown to be ≥ 3 mg. The results suggested the clinical beneficial of this vaccine and further clinical studies are highly warranted. This trial was registered at www.clinicaltrials.gov as NCT 01440920. Disclosures Sakura: Otsuka Pharmaceutical: Research Funding. Kobayashi:Celgene: Research Funding; Pfizer: Research Funding; Ohtsuka Pharmaceutical: Research Funding; Ariad: Research Funding; SymBio Pharmaceuticals: Research Funding. Toga:Otsuka Pharmaceutical: Employment. Sogo:Otsuka Pharmaceutical: Employment. Heike:Sumitomo Dainippon Pharma: Consultancy; Chugai Pharma: Consultancy; Otsuka Pharma: Consultancy.

Novel mechanisms in the immunopathogenesis of leprosy nerve damage: The role of Schwann cells, T cells and Mycobacterium leprae

2000 ◽  
Vol 78 (4) ◽  
pp. 349-355 ◽  
Author(s):  
Eric Spierings ◽  
Tjitske De Boer ◽  
Laurence Zulianello ◽  
Tom HM Ottenhoff
Keyword(s):  
T Cells ◽  
Schwann Cells ◽  
Mycobacterium Leprae ◽  
Nerve Damage

scholarly journals Molecular localization and polymorphism of HLA class II restriction determinants defined by Mycobacterium leprae-reactive helper T cell clones from leprosy patients.

1986 ◽  
Vol 164 (6) ◽  
pp. 1923-1939 ◽  
Author(s):  
T H Ottenhoff ◽  
S Neuteboom ◽  
D G Elferink ◽  
R R de Vries
Keyword(s):  
Immune Response ◽  
T Cell ◽  
T Cell Activation ◽  
Mycobacterium Leprae ◽  
Class Ii ◽  
Hla Class Ii ◽  
Causative Organism ◽  
Th Cells ◽  
Cell Clones ◽  
Ir Genes

MHC class II molecules carry the restriction determinants (RDs) for antigen presentation to antigen-specific Th lymphocytes. This restriction of T cell activation endows those molecules with a key role in the induction and regulation of antigen-specific immune responses. Moreover, class II molecules are the products of class II immune response (Ir) genes. The polymorphism of these Ir genes leads to genetically controlled differences in immuneresponsiveness between different individuals. An important human example is leprosy, in which HLA class II-linked Ir genes determine the immune response against Mycobacterium leprae, the causative organism of the disease. Since the immune response against M. leprae is entirely dependent on Th cells, the HLA class II-linked Ir gene products may well regulate the immune response by controlling the presentation of M. leprae antigens to Th cells. We therefore have investigated the HLA class II RD repertoire of M. leprae-reactive Th cell clones (TLC) by means of extensive panel and inhibition studies with fully class II-typed allogeneic APCs and well-defined HLA class II-specific mAbs. The TLC studied (n, 36) proliferated specifically towards M. leprae, produced IFN-gamma upon activation, and had the CD3+CD4+CD8- phenotype. The results show in the first place that the majority of the RDs for M. leprae reside on DR and not on DP or DQ molecules. This indicates a major role for DR molecules in the immune response to M. leprae and suggests that these molecules are the main products of M. leprae-specific Ir genes. Furthermore, since the expression of DR molecules is much stronger than that of DP and DQ molecules, these findings suggest that the localization of RDs for M. leprae on class II molecules correlates with the quantitative expression of these molecules. The observation that the RDs on DR molecules coded by a DR4 haplotype were situated only on those DR molecules that are known to be highest in expression can be explained in the same way. Second, four distinct RDs related with but not identical to the Dw13 allodeterminant were carried by the DR+DRw53- (alpha beta 1) molecules of a DR4Dw13 haplotype. Since the known amino acid residue differences between the allelic DR4 related Dw beta 1 chains cannot explain the observed RD-polymorphism, this observation suggests that multiple distinct RDs unique for the DR4Dw13 haplotype are expressed by these molecules. Only 2 of 36 TLC were not restricted by DR.(ABSTRACT TRUNCATED AT 400 WORDS)

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