Endogenous dendritic cells mediate the effects of intravenously injected therapeutic immunosuppressive dendritic cells in transplantation

Divito, Sherrie J.; Wang, Zhiliang; Shufesky, William J.; Liu, Quan; Tkacheva, Olga; Montecalvo, Angela; Erdö́s, G.; Larregina, Adriana T.; Morelli, Adrián E.

doi:10.1182/blood-2009-10-251058

Cited by 74 publications

(79 citation statements)

References 49 publications

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“…47 Beyond technical problems with the methods of administration of cellular vaccines, recent evidence indicates that the biology of therapeutic DCs is far more complex than originally expected, and that the exogenous DCs mediate their stimulatory or regulatory effects on T cells indirectly, via interaction with endogenous DCs in secondary lymphoid organs. 23,28,29 Our findings indicate that contrary to the accepted paradigm, elicitation of type 1-biased immunity following vaccination with Ag-loaded NK1R-signaled BMDCs depends on IL-12p70 produced by endogenous DCs. These DCs include LN-resident conventional and inflammatory DCs, the latter recruited from circulating CCR2 1 precursors.…”

Section: Discussioncontrasting

confidence: 49%

“…Intracellular cytokines were analyzed by flow cytometry as detailed. 23 Briefly, cells were surface-labeled with PE-Cy7-CD11c (BD PharMingen), Pacific Blue-CD11b (Biolegend), Alexa Fluor 700-CD8a, and PerCP-Cy5.5-Ly6C Ab (eBioscience). After fixation/permeabilization, cells were labeled with PE-IL-12p40/70, tumor necrosis factor-a (TNF-a) ( 20 In vitro Ag-presentation assays Splenic OT-I-CD8 T cells were purified by negative selection (R&D Systems).…”

Section: Analysis Of Bmdc Phenotype and Cytokinesmentioning

confidence: 99%

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Neurokinin-1 receptor agonists bias therapeutic dendritic cells to induce type 1 immunity by licensing host dendritic cells to produce IL-12

Janelsins¹,

Sumpter²,

Tkacheva³

et al. 2013

Blood

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Section: Discussioncontrasting

confidence: 49%

Section: Analysis Of Bmdc Phenotype and Cytokinesmentioning

confidence: 99%

Neurokinin-1 receptor agonists bias therapeutic dendritic cells to induce type 1 immunity by licensing host dendritic cells to produce IL-12

Janelsins¹,

Sumpter²,

Tkacheva³

et al. 2013

Blood

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“…12 All mouse studies were approved by the University of Pittsburgh Institutional Animal Care and Use Committee. The online version of this article contains a data supplement.…”

Section: Generation Of Dcsmentioning

confidence: 99%

Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes

Montecalvo¹,

Larregina

Shufesky³

et al. 2012

Blood

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1,156

996

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Dendritic cells (DCs) are the most potent APCs. Whereas immature DCs downregulate T-cell responses to induce/ maintain immunologic tolerance, mature DCs promote immunity. To amplify their functions, DCs communicate with neighboring DCs through soluble mediators, cell-to-cell contact, and vesicle exchange. Transfer of nanovesicles (< 100 nm) derived from the endocytic pathway (termed exosomes) represents a novel mechanism of DC-to-DC communication. The facts that exosomes contain exosomeshuttle miRNAs and DC functions can be regulated by exogenous miRNAs, suggest that DC-to-DC interactions could be mediated through exosome-shuttle miRNAs, a hypothesis that remains to be tested. Importantly, the mechanism of transfer of exosome-shuttle miRNAs from the exosome lumen to the cytosol of target cells is unknown. Here, we demonstrate that DCs release exosomes with different miRNAs depending on the maturation of the DCs. By visualizing spontaneous transfer of exosomes between DCs, we demonstrate that exosomes fused with the target DCs, the latter followed by release of the exosome content into the DC cytosol. Importantly, exosome-shuttle miRNAs are functional, because they repress target mRNAs of acceptor DCs. IntroductionCellular miRNAs are released membrane free 1 or packaged inside microvesicles (0.1-1 m) shed by the plasma membrane 2,3 or within nanovesicles (Ͻ 100nm) derived from the endocytic pathway known as exosomes. 4,5 Exosomes are generated as intraluminal vesicles by reverse budding of the membrane of multivesicular bodies (MVBs). Release of exosomes occurs when MVBs fuse their limiting membrane with the plasma membrane. [6][7][8][9] Dendritic cells (DCs) are APCs with the ability to regulate adaptive immunity. Whereas immature DCs down-regulate T-cell responses, mature DCs promote activation, proliferation, and differentiation of effector T cells. 10 Communication between DCs is essential to amplify their tolerogenic and immunogenic functions. 11,12 This DC-to-DC interaction is mediated through cell-tocell contact, soluble mediators, exchange of plasma membrane patches, 13,14 nanotubules, 15 and interaction with apoptotic cellderived vesicles 16 and exosomes. 17,18 Although the mechanisms have not been elucidated, it has been reported that DCs acquire proteins/peptides from other cells via exosomes. [17][18][19] Recently, it has been suggested that transfer of exosome-shuttle miRNAs might constitute a mechanism of cell-tocell communication that regulates mRNA translation 20 or, alternatively, a way to dispose of "unwanted" miRNAs. 21 An important unanswered question in the field is how exosome-shuttle miRNAs, transported inside the vesicles, are delivered into the cytosol of the acceptor cells, a problem we have investigated in this study with the use of DCs. Addressing this point has been challenging because (1) the composition of DC exosomes depends on the maturation of the DC of origin 22,23 ; (2) there is limited information on intercellular communication via "endogenous" (instead of exogenously added...

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“…We have further shown that recipient DC are necessary for DC therapy prolongation of allograft survival using CD11c-DTR bone marrow chimeric mice to selectively deplete recipient but not donor DC (Wang et al, 2012). Finally, we showed that apoptotic cell therapy, DST and DC therapy all act via the same mechanism of action, that is, they serve as a source of donor alloAg for recipient DC, rather than through direct interaction with anti-donor T cells (Divito et al, 2010).…”

Section: Therapies In Transplantation Of Solid Organ Allograftsmentioning

confidence: 84%

“…We demonstrated that donor-derived DC rapidly die once transfused into the prospective graft recipient and that apoptotic cell fragments derived from the injected therapeutic DC are taken up by the recipient's DC and processed into donor alloAg for presentation via recipient MHC molecules to indirect pathway CD4 + T cells (Divito et al, 2010). If the recipient DC are quiescent, then this process induces defective activation of indirect pathway CD4 + T cells with preferential survival of Treg (Divito et al, 2010).…”

Section: Therapies In Transplantation Of Solid Organ Allograftsmentioning

confidence: 99%

Cell-Based Therapies in the Prevention of Solid Organ Transplant Rejection

Morelli¹,

Divito²

2012

American Journal of Immunology

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Problem statement:Organ transplantation is a life-saving and increasingly common procedure, as it often serves as the only treatment available for end-stage organ disease. Although the constant development of new and more effective immunosuppressive drugs has revolutionized the prevention and treatment of acute graft rejection, these drugs have significant toxicity, greatly increase patient susceptibility to neoplasms and infection and exert little impact on chronic rejection. Approach: The literature was reviewed to illuminate the mechanisms by which the anti-donor immune response is initiated and how cellular therapies impact this response. Results: Data show that Donor Specific Transfusion, Apoptotic Cell therapies and Dendritic Cell therapies all function as a source of alloantigen to suppress the anti-donor T cell response. Conclusion: Cellular therapies hold promise in the prevention of solid organ allograft rejection, but require optimization and study in large animal models before clinical implementation.

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Endogenous dendritic cells mediate the effects of intravenously injected therapeutic immunosuppressive dendritic cells in transplantation

Cited by 74 publications

References 49 publications

Neurokinin-1 receptor agonists bias therapeutic dendritic cells to induce type 1 immunity by licensing host dendritic cells to produce IL-12

Neurokinin-1 receptor agonists bias therapeutic dendritic cells to induce type 1 immunity by licensing host dendritic cells to produce IL-12

Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes

Cell-Based Therapies in the Prevention of Solid Organ Transplant Rejection

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