Erythrophagocytosis by plasmacytoid dendritic cells and monocytes is enhanced during inflammation

Richards, Amanda L.; Hendrickson, Jeanne E.; Zimring, James C.; Hudson, Krystalyn E.

doi:10.1111/trf.13497

Cited by 33 publications

(54 citation statements)

References 44 publications

(85 reference statements)

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“…The identity and context of phagocytes that ingest the antigenloaded RBCs could lead to different outcomes, in terms of both antigen presentation and stimulation of an immune response (40)(41)(42). Phagocytosis triggers elaborate signals that might either induce tolerance or an immune response (9,10).…”

Section: Discussionmentioning

confidence: 99%

Engineered erythrocytes covalently linked to antigenic peptides can protect against autoimmune disease

Pishesha

Bilate

Wibowo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

130

117

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Significance Immune-mediated diseases are prevalent, debilitating, and costly. Unfortunately, current treatments rely on nonspecific immunosuppression, which also shuts down a protective immune response. To circumvent this, we exploited the noninflammatory natural means of clearance of red blood cells (RBCs), in combination with sortase-mediated RBC surface modification to display disease-associated autoantigens as RBCs’ own antigens. We found that this strategy holds promise for prophylaxis and therapy, as shown in a mouse model of multiple sclerosis and of type 1 diabetes.

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Section: Discussionmentioning

confidence: 99%

Engineered erythrocytes covalently linked to antigenic peptides can protect against autoimmune disease

Pishesha

Bilate

Wibowo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

130

117

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“…Not all transfusion recipients make detectable alloantibodies to foreign RBC antigens (“non-responders”). In the absence of inflammation, mice transfused with RBCs expressing transgenic human glycophorin A (hGPA) antigen did not produce detectable anti-hGPA immunoglobulins in contrast to the same protocol in the setting of inflammation[126], perhaps due to changes in the subset of antigen presenting cells that phagocytose RBCs[127]. In fact, these mice demonstrated evidence of true immunologic tolerance in that later challenge with hGPA in the context of inflammation still did not result in an immune response.…”

Section: Effects Of Drugs On Rbcsmentioning

confidence: 99%

Erythrocytes as Carriers for Drug Delivery in Blood Transfusion and Beyond

Villa

Cines

Siegel

et al. 2017

Transfusion Medicine Reviews

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Red blood cells (RBCs) are innate carriers that can also be engineered to improve the pharmacokinetics and pharmacodynamics of many drugs, particularly bio-therapeutics. Successful loading of drugs, both internally and on the external surface of RBCs, has been demonstrated for many drugs including anti-inflammatory, anti-microbial, and anti-thrombotic agents. Methods for internal loading of drugs within RBCs are now entering clinical use. While internal loading can result in membrane disruption that may compromise biocompatibility, surface loading using either affinity or chemical ligands offers a diverse set of approaches for the production of RBC drug carriers. A wide range of surface determinants is potentially available for this approach, although there remains a need to characterize the effects of coupling agents to these surface proteins. Somewhat surprisingly, recent data also suggest that red cell mediated delivery may confer tolerogenic immune effects. Questions remaining before widespread application of these technologies include determining the optimal loading protocol, source of RBCs, and production logistics, as well as addressing regulatory hurdles. RBC drug carriers, after many decades of progress, are now poised to enter the clinic and broaden the potential application of RBCs in blood transfusion.

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“…This is likely attributed to the significant changes in PRBC that occur during routine storage which result in expression of DAMP [287]. It has been reported that inflammation enhances erythrophagocytosis [91,92] and the modulation of mDC and BDCA3 + DC phenotype observed in this study, particularly in the models associated with infection processes, may be the result of increased erythrophagocytosis.…”

Section: Prbc Storage Was Associated With Increased Erythrophagocytosismentioning

confidence: 49%

“…In addition, a murine transfusion model using non-leukodepleted PRBC demonstrated CD200 + (tolerising) DC may play a role in modulating transfusion-associated tumour growth [90]. Erythrophagocytosis by murine plasmacytoid (p)DC particularly in costimulation with TLR3 agonist, polyinosinic-polycytidylic acid (polyI:C)-driven inflammation has been reported [91]. Murine studies have also demonstrated that splenic DC are important for outcomes in terms of alloimmunisation [92,93].…”

Section: In-vitro and In-vivo Models Of Prbc Transfusion (Related To mentioning

confidence: 99%

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Characterisation of dendritic cell immune profile in models of transfusion

Ki¹

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Blood transfusion modulates recipients' immune responses sometimes resulting in poor clinical outcomes. Further, transfusion with blood products at date-of-expiry has been associated with exacerbation of this concerning problem. In-vitro studies have demonstrated exposure to packed red blood cell (PRBC) and platelet products modulate the responses of leukocytes, however, there are limited studies on the impact of transfusion on dendritic cells (DC). Despite DC being central to the immune response, their role in transfusion-related immune modulation remains largely undefined. I hypothesised that exposure to blood components changes DC phenotype and function, which could be one mechanism underpinning transfusion-related immune modulation. The potential for blood components (PRBC, buffy-coat-derived platelet concentrates (PC) and cryopreserved platelets (cryo-PLT)) to modulate responses of myeloid dendritic cells ii whether blood components exposing F-actin for Clec9A ligation were present within the blood product. rhClec9A did not bind fresh or stored PRBC, and this outcome was supported by the lack of detection of F-actin. Although, no binding of rhClec9A to PC or cryo-PLT was demonstrated, F-actin was detected on both types of platelet products. As binding of rhClec9A to PRBC, PC or cryo-PLT was not detected, EDTA blood collection tubes were used for the remainder of the study under the premise that lack of expression of this receptor would not impact on outcomes in my transfusion models.I assessed the impact of fresh and/or stored blood products on mDC and BDCA3 + DC surface antigen and inflammatory profile using a human in-vitro whole blood model of transfusion. In parallel, to model the processes associated with viral or bacterial infection, polyinosinic:polycytidylic acid (polyI:C) or lipopolysaccharide (LPS) was added respectively. Exposure to PRBC and PC predominately suppressed surface antigen expression (CD40, CD80, CD83 and CD86) and inflammatory mediator production (interleukin (IL)-6, IL-8, IL-12, tumour necrosis factor-α and interferon-gamma inducible protein-10 or IL-10) on both DC subsets. These changes were often more evident in the presence of polyI:C and LPS, and when DC were exposed to stored PRBC. Similar modulation was evident for BDCA3 + DC when exposed to cryo-PLT alone and cryo-PLT in the presence of polyI:C and LPS. The impact of blood transfusion on the overall inflammatory response by leukocytes was also examined. The immunomodulatory effect of transfusion in-vitro was more pronounced in the presence of polyI:C and LPS. For PRBC, an additional erythrophagocytosis assay was conducted where the uptake of stored PRBC by mDC and BDCA3 + DC was significantly increased in comparison to fresher PRBC.This study provided the first evidence that exposure of PRBC, PC and cryo-PLT modulates mDC and/or BDCA3 + DC maturation and activation. The changes were more pronounced when modelling processes associated with concurrent viral or bacterial infection.Experimental evidence suggested that mod...

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Erythrophagocytosis by plasmacytoid dendritic cells and monocytes is enhanced during inflammation

Abstract: The nature of APCs that consume transfused RBCs is changed by inflammation. Given that APCs initiate humoral immune responses, these findings provide potential mechanistic insight into how inflammation regulates RBC alloimmunization.

Cited by 33 publications

References 44 publications

Engineered erythrocytes covalently linked to antigenic peptides can protect against autoimmune disease

Engineered erythrocytes covalently linked to antigenic peptides can protect against autoimmune disease

Erythrocytes as Carriers for Drug Delivery in Blood Transfusion and Beyond

Characterisation of dendritic cell immune profile in models of transfusion

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