Pathogen reduction with riboflavin and ultraviolet light induces a quasi‐apoptotic state in blood leukocytes

Tran, Johnson Q.; Muench, Marcus O.; Heitman, John W.; Jackman, Rachael P.

doi:10.1111/trf.15516

Cited by 7 publications

(5 citation statements)

References 74 publications

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“…Prior studies have shown UV1R-treated WBCs take on apoptotic characteristics, and processing of these apoptotic-like cells may drive the tolerogenic phenotype we observed. 22,[82][83][84] Our findings are consistent with studies demonstrating that allogeneic platelets can give rise to T-cell responses [50][51][52][53][54] but clarify the kinetics and quality of the alloimmune response. We demonstrate that the primary alloresponse includes CD4 1 T cells with both T helper type 1 (Th1) and Th2 phenotypes, 26 whereas the recall response skews toward a Th1 phenotype.…”

Section: Discussionsupporting

confidence: 89%

“…21 Furthermore, UV1R-treated PRP induces a quasi-apoptotic state in human and mouse leukocytes that may lead to processing of these cells in a tolerogenic manner. 22 Both platelets and contaminating leukocytes contribute to the alloantibody responses in platelet transfusion. 23,24 Alloantibody responses result from complex interactions of innate and adaptive cellular responses that involve antigen-presenting cells (APCs) such as macrophages (Mfs), conventional dendritic cells (cDCs), and B cells, and their cognate T cells.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, while the effect of PRT or UV light on blood components has been evaluated in vitro, 21,[55][56][57][58][59][60] in vivo studies have focused predominantly on alloantibody outcomes, with little known about cellular responses. 18,21,22,61 Immune tolerance, including induction of T regulatory cells (T reg cells), has been associated with other UV treatment strategies in humans and animal models, [62][63][64][65][66][67][68] suggesting similar mechanisms may be induced by PRT.…”

Section: Introductionmentioning

confidence: 99%

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Pathogen-reduced PRP blocks T-cell activation, induces Treg cells, and promotes TGF-β expression by cDCs and monocytes in mice

2020

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Alloimmunization against platelet-rich plasma (PRP) transfusions can lead to complications such as platelet refractoriness or rejection of subsequent transfusions and transplants. In mice, pathogen reduction treatment of PRP with UVB light and riboflavin (UV+R) prevents alloimmunization and appears to induce partial antigen-specific tolerance to subsequent transfusions. Herein, the in vivo responses of antigen-presenting cells and T cells to transfusion with UV+R-treated allogeneic PRP were evaluated to understand the cellular immune responses leading to antigen-specific tolerance. Mice that received UV+R-treated PRP had significantly increased transforming growth factor β (TGF-β) expression by CD11b+ CD4+ CD11cHi conventional dendritic cells (cDCs) and CD11bHi monocytes (P < .05). While robust T-cell responses to transfusions with untreated allogeneic PRP were observed (P < .05), these were blocked by UV+R treatment. Mice given UV+R-treated PRP followed by untreated PRP showed an early significant (P < .01) enrichment in regulatory T (Treg) cells and associated TGF-β production as well as diminished effector T-cell responses. Adoptive transfer of T-cell–enriched splenocytes from mice given UV+R-treated PRP into naive recipients led to a small but significant reduction of CD8+ T-cell responses to subsequent allogeneic transfusion. These data demonstrate that pathogen reduction with UV+R induces a tolerogenic profile by way of CD11b+ CD4+ cDCs, monocytes, and induction of Treg cells, blocking T-cell activation and reducing secondary T-cell responses to untreated platelets in vivo.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pathogen-reduced PRP blocks T-cell activation, induces Treg cells, and promotes TGF-β expression by cDCs and monocytes in mice

2020

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“…On the one hand, exogenous riboflavin facilitates the ability of immune cells to protect the host from infection. For instance, riboflavin regulates the accumulation, infiltration, migration, and development of macrophages and PMNs [ 98 , 123 , 124 ]. Under some conditions, pathogens are disseminated through immune cells (such as macrophages and PMNs) [ 125 ].…”

Section: Anti-infection Effect Of Exogenous Riboflavinmentioning

confidence: 99%

The promise of endogenous and exogenous riboflavin in anti-infection

et al. 2021

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To resolve the growing problem of drug resistance in the treatment of bacterial and fungal pathogens, specific cellular targets and pathways can be used as targets for new antimicrobial agents. Endogenous riboflavin biosynthesis is a conserved pathway that exists in most bacteria and fungi. In this review, the roles of endogenous and exogenous riboflavin in infectious disease as well as several antibacterial agents, which act as analogues of the riboflavin biosynthesis pathway, are summarized. In addition, the effects of exogenous riboflavin on immune cells, cytokines, and heat shock proteins are described. Moreover, the immune response of endogenous riboflavin metabolites in infectious diseases, recognized by MHC-related protein-1, and then presented to mucosal associated invariant T cells, is highlighted. This information will provide a strategy to identify novel drug targets as well as highlight the possible clinical use of riboflavin.

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“…Our hypothesis that tumour cells treated by this process might be capable of enhanced presentation of tumour antigen necessary for invoking an enhanced anti‐tumour response was driven by observations that platelets treated by this process maintain protein synthesis [10] as well as by the fact that white blood cells treated by this process exhibit a quasi‐apoptotic state [11].…”

Section: Introductionmentioning

confidence: 99%

A novel cancer immunotherapy utilizing autologous tumour tissue

et al. 2020

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Background With the recent interest in personalized medicine for cancer patients and immune therapy, the field of cancer vaccines has been resurrected. Previous autologous, whole cell tumour vaccine trials have not produced convincing results due, in part to poor patient selection and inactivation methos that are harsh on the cells. These methods can alter protein structure and antigenic profiles making vaccine candidates ineffective in stimulating immune response to autochthonous tumour cells. Materials and methods We investigated a novel method for inactivating tumour cells that uses UVA/UVB light and riboflavin (vitamin B2) (RF + UV). RF + UV inactivates the tumour cells' ability to replicate, yet preserves tumour cell integrity and antigenicity. Results Our results demonstrate that proteins are preserved on the surface of RF + UV-inactivated tumour cells and that they are immunogenic via induction of dendritic cell maturation, increase in IFNc production and generation of tumour cell-specific IgG. Moreover, when formulated with an adjuvant ('Innocell vaccine') and tested in different murine tumour primary and metastatic disease models, decreased tumour growth, decreased metastatic disease and prolonged survival were observed. In addition, immune cells obtained from tumour tissue following vaccination had decreased exhausted and regulatory T cells, suggesting that activation of intra-tumoural T cells may be playing a role leading to reduced tumour growth. Conclusions These data suggest that the RF + UV inactivation of tumour cells may provide an efficacious method for generating autologous whole tumour cell vaccines for use in cancer patients.

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Pathogen reduction with riboflavin and ultraviolet light induces a quasi‐apoptotic state in blood leukocytes

Cited by 7 publications

References 74 publications

Pathogen-reduced PRP blocks T-cell activation, induces Treg cells, and promotes TGF-β expression by cDCs and monocytes in mice

Pathogen-reduced PRP blocks T-cell activation, induces Treg cells, and promotes TGF-β expression by cDCs and monocytes in mice

The promise of endogenous and exogenous riboflavin in anti-infection

A novel cancer immunotherapy utilizing autologous tumour tissue

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