scholarly journals A Strategy for Selective Deletion of Autoimmunity-Related T Cells by pMHC-Targeted Delivery

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1669
Author(s):  
Shalom D. Goldberg ◽  
Nathan Felix ◽  
Michael McCauley ◽  
Ryan Eberwine ◽  
Lou Casta ◽  
...  

Autoimmune diseases such as rheumatoid arthritis are caused by immune system recognition of self-proteins and subsequent production of effector T cells that recognize and attack healthy tissue. Therapies for these diseases typically utilize broad immune suppression, which can be effective, but which also come with an elevated risk of susceptibility to infection and cancer. T cell recognition of antigens is driven by binding of T cell receptors to peptides displayed on major histocompatibility complex proteins (MHCs) on the cell surface of antigen-presenting cells. Technology for recombinant production of the extracellular domains of MHC proteins and loading with peptides to produce pMHCs has provided reagents for detection of T cell populations, and with the potential for therapeutic intervention. However, production of pMHCs in large quantities remains a challenge and a translational path needs to be established. Here, we demonstrate a fusion protein strategy enabling large-scale production of pMHCs. A peptide corresponding to amino acids 259–273 of collagen II was fused to the N-terminus of the MHC_II beta chain, and the alpha and beta chains were each fused to human IgG4 Fc domains and co-expressed. A tag was incorporated to enable site-specific conjugation. The cytotoxic drug payload, MMAF, was conjugated to the pMHC and potent, peptide-specific killing of T cells that recognize the collagen pMHC was demonstrated with tetramerized pMHC-MMAF conjugates. Finally, these pMHCs were incorporated into MMAF-loaded 3DNA nanomaterials in order to provide a biocompatible platform. Loading and pMHC density were optimized, and peptide-specific T cell killing was demonstrated. These experiments highlight the potential of a pMHC fusion protein-targeted, drug-loaded nanomaterial approach for selective delivery of therapeutics to disease-relevant T cells and new treatment options for autoimmune disease.

2013 ◽  
Vol 798-799 ◽  
pp. 1007-1012
Author(s):  
Wen He Zhu ◽  
Wei Zhang ◽  
Yan Li ◽  
Jun Jie Xu ◽  
Shi Jie Lv

Melittin is a novel peptide of biological activity isolated from bee venom. It has potential application value in medicine and agriculture. Here we encoded melittin gene with the EK recognition sequence in the N-terminus into expression vector pGEX-2T.The expressed fusion protein, which is about 29KDa, identified by Western Blot. To facilitate large-scale production of recombinant GST-fusion protein, we optimized different expression conditions to increase the overall production of the fusion protein. The production of the protein had increased about 10-fold when we used an auto-inducing medium. The GST fusion protein showed an equivalent activity with the natural melittin after digested by EK and can inhibited the proliferations of several human cancer lines. The expression system described in this study provides a feasible way for producing melittin in further studies.


2004 ◽  
Vol 70 (6) ◽  
pp. 3292-3297 ◽  
Author(s):  
Gerard M. Gibbs ◽  
Barrie E. Davidson ◽  
Alan J. Hillier

ABSTRACT Piscicolin 126 is a class IIa bacteriocin isolated from Carnobacterium piscicola JG126 that exhibits strong activity against Listeria monocytogenes. The gene encoding mature piscicolin 126 (m-pisA) was cloned into an Escherichia coli expression system and expressed as a thioredoxin-piscicolin 126 fusion protein that was purified by affinity chromatography. Purified recombinant piscicolin 126 was obtained after CNBr cleavage of the fusion protein followed by reversed-phase chromatography. Recombinant piscicolin 126 contained a single disulfide bond and had a mass identical to that of native piscicolin 126. This novel bacteriocin expression system generated approximately 26 mg of purified bacteriocin from 1 liter of E. coli culture. The purified recombinant piscicolin 126 acted by disruption of the bacterial cell membrane.


1998 ◽  
Vol 7 (5) ◽  
pp. 437-448 ◽  
Author(s):  
BRUCE L. LEVINE ◽  
JULIO COTTE ◽  
CAROLYNN C. SMALL ◽  
RICHARD G. CARROLL ◽  
JAMES L. RILEY ◽  
...  

2018 ◽  
Vol 48 (9) ◽  
pp. 823-833 ◽  
Author(s):  
Rajkumar Paul ◽  
Selvarajan Karthik ◽  
Ponnusamy Vimalraj ◽  
Sankaranarayanan Meenakshisundaram ◽  
Perumal Kaliraj

2009 ◽  
Vol 7 (3) ◽  
pp. 339-353 ◽  
Author(s):  
Claudia Jursik ◽  
Michaela Prchal ◽  
Regina Grillari-Voglauer ◽  
Karel Drbal ◽  
Elke Fuertbauer ◽  
...  

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Wai-Ping Lee ◽  
Barbara Willekens ◽  
Patrick Cras ◽  
Herman Goossens ◽  
Eva Martínez-Cáceres ◽  
...  

While emerging evidence indicates that dendritic cells (DC) play a central role in the pathogenesis of multiple sclerosis (MS), their modulation with immunoregulatory agents provides prospect as disease-modifying therapy. Our observations reveal that 1,25-dihydroxyvitamin D3(1,25(OH)2D3) treatment of monocyte-derived DC results in a semimature phenotype and anti-inflammatory cytokine profile as compared to conventional DC, in both healthy controls and MS patients. Importantly, 1,25(OH)2D3-treated DC induce T cell hyporesponsiveness, as demonstrated in an allogeneic mixed leukocyte reaction. Next, following a freeze-thaw cycle, 1,25(OH)2D3-treated immature DC could be recovered with a 78% yield and 75% viability. Cryopreservation did not affect the expression of membrane markers by 1,25(OH)2D3-treated DC nor their capacity to induce T cell hyporesponsiveness. In addition, the T cell hyporesponsiveness induced by 1,25(OH)2D3-treated DC is antigen-specific and robust since T cells retain their capacity to respond to an unrelated antigen and do not reactivate upon rechallenge with fully mature conventional DC, respectively. These observations underline the clinical potential of tolerogenic DC (tolDC) to correct the immunological imbalance in MS. Furthermore, the feasibility to cryopreserve highly potent tolDC will, ultimately, contribute to the large-scale production and the widely applicable use of tolDC.


Author(s):  
C. Ferreras ◽  
B. Pascual-Miguel ◽  
C. Mestre-Durán ◽  
A. Navarro-Zapata ◽  
L. Clares-Villa ◽  
...  

Syndrome coronavirus 2 (SARS-CoV-2) pandemic is causing a second outbreak significantly delaying the hope for the virus’ complete eradication. In the absence of effective vaccines, we need effective treatments with low adverse effects that can treat hospitalized patients with COVID-19 disease. In this study, we determined the existence of SARS-CoV-2-specific T cells within CD45RA– memory T cells in the blood of convalescent donors. Memory T cells can respond quickly to infection and provide long-term immune protection to reduce the severity of COVID-19 symptoms. Also, CD45RA– memory T cells confer protection from other pathogens encountered by the donors throughout their life. It is of vital importance to resolve other secondary infections that usually develop in patients hospitalized with COVID-19. We found SARS-CoV-2-specific memory T cells in all of the CD45RA– subsets (CD3+, CD4+, and CD8+) and in the central memory and effector memory subpopulations. The procedure for obtaining these cells is feasible, easy to implement for small-scale manufacture, quick and cost-effective, involves minimal manipulation, and has no GMP requirements. This biobank of specific SARS-CoV-2 memory T cells would be immediately available “off-the-shelf” to treat moderate/severe cases of COVID-19, thereby increasing the therapeutic options available for these patients.


2020 ◽  
Author(s):  
C Ferreras ◽  
B Pascual-Miguel ◽  
C Mestre-Durán ◽  
A Navarro-Zapata ◽  
L Clares-Villa ◽  
...  

ABSTRACTSARS-CoV-2 is causing a second outbreak so the hope for its complete eradication is far from happening. In the absence of effective vaccines, it is mandatory to find effective treatments with low adverse effects able to treat hospitalized patients with COVID-19 disease. In this work, we determined the existence of SARS-CoV-2 specific T cells within the CD45RA− T memory cells from the blood of convalescent donors. Memory T cells can respond quickly to the infection and provide long-term immune protection to reduce the severity of the COVID-19 symptoms. Also, CD45RA− memory T cells confer protection from other pathogens the donors encountered in their life. This is vital to clear other secondary infections usually developed in hospitalized COVID-19 patients. SARS-CoV-2 specific memory T cells were found within all the CD45RA− subsets CD3+, CD4+, CD8+, and in the central memory and effector memory subpopulations. The procedure to obtain the cells is feasible, easy to implement for small scale manufacture, quick and cost-effective involving minimal manipulation, and without GMP condition requirements. This biobank of specific SARS-CoV-2 memory T cells would be immediately available ‘off-the-shelf’ to treat moderate/severe cases of COVID-19 increasing the therapeutic options available for these patients.


Author(s):  
Maheswara Rao Gokada ◽  
Visweswara Rao Pasupuleti ◽  
Hari Babu Bollikolla

: The novel Coronavirus disease (COVID-19) is an epidemic disease which appeared at the end of the year 2019 in a sudden increase in number and considered as a pandemic disease caused by a viral infection and it has threatened most countries towards the emergency search for new anti-SARS-COV drugs /vaccines. At present, the number of clinical trials is ongoing worldwide on different drugs i.e. Hydroxychloroquine, Remedisvir, Favipiravir that utilizes various mechanisms of actions. A few world countries are currently processing for clinical trials which may result in a positive manner. Favipiravir (FPV) represents one of the feasible treatment options for COVID-19, if trials result seems positive. Favipiravir will be one among the developed authoritative possible drugs to warrant the benefits to mankind with large-scale production in order to meet the demands by the current pandemic Covid-19 outbreak and the future epidemic outbreaks. In this review, the authors tried to explore key molecules, which will be supportive for scheming COVID-19 research.


1993 ◽  
Vol 32 (1) ◽  
pp. 129-131
Author(s):  
Naureen Talha

The literature on female labour in Third World countries has become quite extensive. India, being comparatively more advanced industrially, and in view of its size and population, presents a pictures of multiplicity of problems which face the female labour market. However, the author has also included Mexico in this analytical study. It is interesting to see the characteristics of developing industrialisation in two different societies: the Indian society, which is conservative, and the Mexican society, which is progressive. In the first chapter of the book, the author explains that he is not concerned with the process of industrialisation and female labour employed at different levels of work, but that he is interested in forms of production and women's employment in large-scale production, petty commodity production, marginal small production, and self-employment in the informal sector. It is only by analysis of these forms that the picture of females having a lower status is understood in its social and political setting.


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