| 1. |
- Zufferey, Anne, et al.
(författare)
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Mature murine megakaryocytes present antigen-MHC class I molecules to T cells and transfer them to platelets
- 2017
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:20, s. 1773-1785
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Tidskriftsartikel (refereegranskat)abstract
- Megakaryocytes (MKs) are bone marrow-derived cells that are primarily responsible for generating platelets for the maintenance of hemostasis. Although MK can variably express major histocompatibility complex (MHC) class I and II molecules during their differentiation, little is known whether they can elicit nonhemostatic immune functions such as T-cell activation. Here, we demonstrate that mature CD342 MHC class II2 CD411 MKs can endocytose exogenous ovalbumin (OVA) and proteolytically generate its immunogenic peptide ligand, which is crosspresented on their surface in association with MHC class I molecules. This crosspresentation triggered in vitro and in vivo OVA-specific CD81 T-cell activation and proliferation. In addition, the OVA-MHC class I complexes were transferred from MK to pro-platelets upon thrombopoiesis in vitro. MK could also present endogenous MK-associated (CD61) peptides to activate CD61-specific CD81 T cells and mediate immune thrombocytopenia in vivo. These results suggest that, in addition to their hemostatic role, mature MKs can significantly affect antigen-specific CD81 T-cell responses via antigen presentation and are able to spread this immunogenic information through platelets.
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| 2. |
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| 3. |
- Kapur, Rick, et al.
(författare)
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Gastrointestinal microbiota contributes to the development of murine transfusion-related acute lung injury
- 2018
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 2:13, s. 1651-1663
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Tidskriftsartikel (refereegranskat)abstract
- Transfusion-related acute lung injury (TRALI) is a syndrome of respiratory distress upon blood transfusion and is the leading cause of transfusion-related fatalities. Whether the gut microbiota plays any role in the development of TRALI is currently unknown. We observed that untreated barrier-free (BF) mice suffered from severe antibody-mediated acute lung injury, whereas the more sterile housed specific pathogen-free (SPF) mice and gut flora-depleted BF mice were both protected from lung injury. The prevention of TRALI in the SPF mice and gut flora-depleted BF mice was associated with decreased plasma macrophage inflammatory protein-2 levels as well as decreased pulmonary neutrophil accumulation. DNA sequencing of amplicons of the 16S ribosomal RNA gene revealed a varying gastrointestinal bacterial composition between BF and SPF mice. BF fecal matter transferred into SPF mice significantly restored TRALI susceptibility in SPF mice. These data reveal a link between the gut flora composition and the development of antibody-mediated TRALI in mice. Assessment of gut microbial composition may help in TRALI risk assessment before transfusion.
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| 4. |
- Kapur, Rick, et al.
(författare)
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T regulatory cells and dendritic cells protect against transfusion-related acute lung injury via IL-10
- 2017
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 129:18, s. 2557-2569
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Tidskriftsartikel (refereegranskat)abstract
- Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related fatalities and is characterized by acute respiratory distress following blood transfusion. Donor antibodies are frequently involved; however, the pathogenesis and protective mechanisms in the recipient are poorly understood, and specific therapies are lacking. Using newly developed murine TRALI models based on injection of anti-major histocompatibility complex class I antibodies, we found CD4+CD25+FoxP3+ T regulatory cells (Tregs) and CD11c+ dendritic cells (DCs) to be critical effectors that protect against TRALI. Treg or DC depletion in vivo resulted in aggravated antibody-mediated acute lung injury within 90 minutes with 60% mortality upon DC depletion. In addition, resistance to antibody-mediated TRALI was associated with increased interleukin-10 (IL-10) levels, and IL-10 levels were found to be decreased in mice suffering from TRALI. Importantly, IL-10 injection completely prevented and rescued the development of TRALI in mice and may prove to be a promising new therapeutic approach for alleviating lung injury in this serious complication of transfusion.
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| 5. |
- Kapur, Rick, et al.
(författare)
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Thrombopoietin receptor agonist (TPO-RA) treatment raises platelet counts and reduces anti-platelet antibody levels in mice with immune thrombocytopenia (ITP)
- 2020
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Ingår i: Platelets. - : Informa UK Limited. - 0953-7104 .- 1369-1635. ; 31:3, s. 399-402
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Tidskriftsartikel (refereegranskat)abstract
- Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder in which autoantibodies and/or autoreactive T cells destroy platelets and megakaryocytes in the spleen and bone marrow, respectively. Thrombopoietin receptor agonists (TPO-RA e.g. Romiplostim and Eltrombopag) have made a substantial contribution to the treatment of patients with ITP, which are refractory to first-line treatments and approximately 30% demonstrate sustained elevated platelet counts after drug tapering. How TPO-RA induce these sustained responses is not known. We analyzed the efficacy of a murine TPO-RA in a well-established murine model of active ITP. Treatment with TPO-RA (10 ug/kg, based on pilot dose escalation experiments) significantly raised the platelet counts in ITP-mice. Immunomodulation was assessed by measuring serum IgG anti-platelet antibody levels; TPO-RA-treated mice had significantly reduced IgG anti-platelet antibodies despite the increasing platelet counts. These results suggest that TPO-RA is not only an efficacious therapy but also reduces anti-platelet humoral immunity in ITP.
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