Exosomes expressing the self-antigens myosin and vimentin play an important role in syngeneic cardiac transplant rejection induced by antibodies to cardiac myosin

Sharma, Monal; Liu, Wei; Perincheri, Sudhir; Gunasekaran, Muthukumar; Mohanakumar, Thalachallour

doi:10.1111/ajt.14650

Cited by 41 publications

(44 citation statements)

References 37 publications

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“…Tregs suppress humoral responses either indirectly by reducing CD4 + T cell help, or directly by cell‐to‐cell interactions with B cells . Because a significant proportion of recipient‐derived APCs can acquire intact donor MHC molecules through the uptake of donor exosomes and/or trogocytosis, this may be a mechanism by which dsCAR‐Tregs could directly suppress recipient‐derived B cells. Moreover, our data suggest that the dsCAR‐Tregs themselves can also acquire donor MHC molecules.…”

Section: Discussionmentioning

confidence: 99%

Donor-specific chimeric antigen receptor Tregs limit rejection in naive but not sensitized allograft recipients

Sicard

Lamarche

Speck

et al. 2020

American Journal of Transplantation

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Cell therapy with autologous donor-specific regulatory T cells (Tregs) is a promising strategy to minimize immunosuppression in transplant recipients. Chimeric antigen receptor (CAR) technology has recently been used successfully to generate donor-specific Tregs and overcome the limitations of enrichment protocols based on repetitive stimulations with alloantigens. However, the ability of CAR-Treg therapy to control alloreactivity in immunocompetent recipients is unknown. We first analyzed the effect of donor-specific CAR Tregs on alloreactivity in naive, immunocompetent mice receiving skin allografts. Tregs expressing an irrelevant or anti-HLA-A2-specific CAR were administered to Bl/6 mice at the time of transplanting an HLA-A2 + Bl/6 skin graft.Donor-specific CAR-Tregs, but not irrelevant-CAR Tregs, significantly delayed skin rejection and diminished donor-specific antibodies (DSAs) and frequencies of DSAsecreting B cells. Donor-specific CAR-Treg-treated mice also had a weaker recall DSA response, but normal responses to an irrelevant antigen, demonstrating antigen-specific suppression. When donor-specific CAR Tregs were tested in HLA-A2-sensitized mice, they were unable to delay allograft rejection or diminish DSAs. The finding that donor-specific CAR-Tregs restrain de novo but not memory alloreactivity has important implications for their use as an adoptive cell therapy in transplantation. K E Y W O R D S alloantigen, B cell biology, basic (laboratory) research/science, cellular biology, cellular transplantation (non-islet), immunosuppression/immune modulation, T cell biology, tolerance, translational research/science | 1563 SICARD et Al.

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Section: Discussionmentioning

confidence: 99%

Donor-specific chimeric antigen receptor Tregs limit rejection in naive but not sensitized allograft recipients

Sicard

Lamarche

Speck

et al. 2020

American Journal of Transplantation

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“…A proteome analysis of extracellular vesicles also identified vimentin in EVs released from microglia (Drago et al, 2017). Noteworthy, a very recent finding demonstrated serum exosomes to contain vimentin in a murine cardiac explant model system (Sharma, Liu, Perincheri, Gunasekaran, & Mohanakumar, 2018).…”

Section: Exosomal Release Of Vimentinmentioning

confidence: 91%

Release of astroglial vimentin by extracellular vesicles: Modulation of binding and internalization of C3 transferase in astrocytes and neurons

Adolf

Rohrbeck

Münster-Wandowski

et al. 2018

Glia

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Clostridium botulinum C3 transferase (C3bot) ADP‐ribosylates rho proteins to change cellular functions in a variety of cell types including astrocytes and neurons. The intermediate filament protein vimentin as well as transmembrane integrins are involved in internalization of C3bot into cells. The exact contribution, however, of these proteins to binding of C3bot to the cell surface and subsequent cellular uptake remains to be unraveled. By comparing primary astrocyte cultures derived from wild‐type with Vim−/− mice, we demonstrate that astrocytes lacking vimentin exhibited a delayed ADP‐ribosylation of rhoA concurrent with a blunted morphological response. This functional impairment was rescued by the extracellular excess of recombinant vimentin. Binding assays using C3bot harboring a mutated integrin‐binding RGD motif (C3bot‐G89I) revealed the involvement of integrins in astrocyte binding of C3bot. Axonotrophic effects of C3bot are vimentin dependent and postulate an underlying mechanism entertaining a molecular cross‐talk between astrocytes and neurons. We present functional evidence for astrocytic release of vimentin by exosomes using an in vitro scratch wound model. Exosomal vimentin+ particles released from wild‐type astrocytes promote the interaction of C3bot with neuronal membranes. This effect vanished when culturing Vim−/− astrocytes. Specificity of these findings was confirmed by recombinant vimentin propagating enhanced binding of C3bot to synaptosomes from rat spinal cord and mouse brain. We hypothesize that vimentin+ exosomes released by reactive astrocytes provide a novel molecular mechanism constituting axonotrophic (neuroprotective) and plasticity augmenting effects of C3bot after spinal cord injury.

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“…Exosomes were isolated from serum samples of LTxRs with RVI and from stable controls by ultracentrifugation as previously described. 21,24,25 Exosome purity was validated using the sucrose cushion method. 21,26 The presence of the exosome-specific markers CD9 (312102, BioLegend, San Diego, CA) and Alix (634502, BioLegend) was assessed using immunoblot.…”

Section: Exosome Isolation and Validationmentioning

confidence: 99%

“…Immunization of C57BL/6 mice with exosomes from LTxRs diagnosed with RVI and stable controls Exosomes (10 mg/100 ml) isolated from LTxRs with RVI or from stable controls were used for immunization of C57BL/6 mice ( Days 1,7,18,and 25). Prior experiments have demonstrated that injury to the native lungs is required for Abs to lung SAgs to cause lesions.…”

Section: Determination Of Lung Sags 20s Proteasome and Viral Antigementioning

confidence: 99%

Respiratory viral infection in lung transplantation induces exosomes that trigger chronic rejection

Gunasekaran

Bansal

Ranjithkumar

et al. 2020

The Journal of Heart and Lung Transplantation

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BACKGROUND: Respiratory viral infections can increase the risk of chronic lung allograft dysfunction after lung transplantation, but the mechanisms are unknown. In this study, we determined whether symptomatic respiratory viral infections after lung transplantation induce circulating exosomes that contain lung-associated self-antigens and assessed whether these exosomes activate immune responses to self-antigens. METHODS: Serum samples were collected from lung transplant recipients with symptomatic lower-and upper-tract respiratory viral infections and from non-symptomatic stable recipients. Exosomes were isolated via ultracentrifugation; purity was determined using sucrose cushion; and presence of lung self-antigens, 20S proteasome, and viral antigens for rhinovirus, coronavirus, and respiratory syncytial virus were determined using immunoblot. Mice were immunized with circulating exosomes from each group and resulting differential immune responses and lung histology were analyzed. RESULTS: Exosomes containing self-antigens, 20S proteasome, and viral antigens were detected at significantly higher levels (p < 0.05) in serum of recipients with symptomatic respiratory viral infections (n = 35) as compared with stable controls (n = 32). Mice immunized with exosomes from recipients with respiratory viral infections developed immune responses to self-antigens, fibrosis, small airway occlusion, and significant cellular infiltration; mice immunized with exosomes from controls did not (p < 0.05). CONCLUSIONS: Circulating exosomes isolated from lung transplant recipients diagnosed with respiratory viral infections contained lung self-antigens, viral antigens, and 20S proteasome and elicited immune responses to lung self-antigens that resulted in development of chronic lung allograft dysfunction in immunized mice.

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Exosomes expressing the self-antigens myosin and vimentin play an important role in syngeneic cardiac transplant rejection induced by antibodies to cardiac myosin

Cited by 41 publications

References 37 publications

Donor-specific chimeric antigen receptor Tregs limit rejection in naive but not sensitized allograft recipients

Donor-specific chimeric antigen receptor Tregs limit rejection in naive but not sensitized allograft recipients

Release of astroglial vimentin by extracellular vesicles: Modulation of binding and internalization of C3 transferase in astrocytes and neurons

Respiratory viral infection in lung transplantation induces exosomes that trigger chronic rejection

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