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Liver transplantation is associated with significant blood loss, often requiring massive blood product transfusion. Transfusion-related acute lung injury (TRALI) is a devastating cause of transfusion-related deaths. While reports have investigated the general incidence of TRALI, the incidence of TRALI specifically following transfusion during liver transplant remains unclear. This scoping review summarizes existing literature regarding TRALI during the liver transplantation perioperative period. Databases were searched for all articles and abstracts reporting on TRALI after liver transplantation. Data collected included number of patients studied, patient characteristics, incidences of TRALI, TRALI characteristics, and patient outcomes. The primary outcome investigated was the incidence of TRALI in the setting of liver transplantation. Thirteen full-text citations were included in this review. The incidence of TRALI post-liver transplant was 0.68% (65 of 9,554). Based on reported transfusion data, patients diagnosed with TRALI received an average of 10.92 ± 10.81 units of packed red blood cells (pRBC), 20.05 ± 15.72 units of fresh frozen plasma, and 5.75 ± 10.00 units of platelets. Common interventions following TRALI diagnosis included mechanical ventilation with positive end-expiratory pressure, inhaled high-flow oxygen, inhaled pulmonary vasodilator, and pharmacologic treatment using pressors or inotropes, corticosteroids, or diuretics. Based on reported mortality data, 26.67% of patients (12 of 45) diagnosed with TRALI died during the postoperative period. This scoping review underscores the importance of better understanding the incidence and presentation of TRALI after liver transplant surgery. The clinical implications of these results warrant the development of identification and management strategies for liver transplant patients at increased risk for developing TRALI.

Natural killer (NK) cells are an emerging immunotherapy approach to acute myeloid leukemia (AML); however, the optimal approach to activate NK cells before adoptive transfer remains unclear. Human NK cells that are primed with the CTV-1 leukemia cell line lysate CNDO-109 exhibit enhanced cytotoxicity against NK-cell-resistant cell lines. To translate this finding to the clinic, CNDO-109-activated NK cells (CNDO-109-NK cells) isolated from related human leukocyte antigen complex (HLA)-haploidentical donors were evaluated in a phase 1 dose-escalation trial at doses of 3×10^5 (n=3), 1×10^6 (n=3), and 3×10^6 (n=6) cells/kg in patients with AML in first complete remission (CR1) at high risk for recurrence. Before CNDO-109-NK cell administration, patients were treated with lymphodepleting fludarabine/cyclophosphamide. CNDO-109-NK cells were well tolerated, and no dose-limiting toxicities were observed at the highest tested dose. The median relapse free (RFS) survival by dose level was 105 (3×10^5), 156 (1×10^6), and 337 (3×10^6) days. Two patients remain relapse-free in post-trial follow-up, with RFS durations exceeding 42.5 months. Donor NK cell micro-chimerism was detected on Day 7 in 10 of 12 patients, with 3 patients having evidence of donor cells on day 14 or later. This trial establishes that CNDO-109-NK cells generated from related HLA-haploidentical donors, cryopreserved, and then safely administered to AML patients with transient persistence without exogenous cytokine support. Three durable complete remissions of 32.6 to 47.6+ months were observed, suggesting additional clinical investigation of CNDO-109-NK cells for patients with myeloid malignancies, alone or in combination with additional immunotherapy strategies, is warranted.

Background JC virus (JCV) infection is a prerequisite for development of progressive multifocal leukoencephalopathy (PML). We previously described the development of a novel, two-step enzyme-linked immunosorbent assay (ELISA) that detects anti-JCV antibodies in human serum or plasma, and the potential clinical utility of anti-JCV antibody status for PML risk stratification. Objectives To validate the anti-JCV antibody ELISA at multiple clinical laboratories in order to demonstrate the robustness of the method. Study design Analytical validation of the ELISA was performed at four laboratories by evaluation of intra- and inter-assay precision, analytical specificity and sensitivity, matrix interference, robustness, sample and reagent stability. Results Analytical validation demonstrated that the assay is sensitive, specific, and precise. The assay sensitivity was estimated at 1.7 ng/mL using a humanized anti-JCV monoclonal antibody control. The sensitivity to detect JCV infection was estimated to be 97.5%. The specificity of the assay to discriminate JCV-specific antibodies from antibodies directed to BK virus, a related polyomavirus, was also demonstrated. The inter- and intra-assay precision was ≤6.0% and 9.8% for the screening step and 2.6% and 11.3% for the confirmation step. Results obtained for plasma and serum were highly congruent, and assay robustness was demonstrated by the highly concordant results generated by four laboratories testing a common panel of 100 blinded samples. Conclusions The novel, two-step ELISA to detect anti-JCV antibodies in human serum and plasma is robust, and assay performance is consistent and reproducible in multiple laboratories, making it suitable to support testing for global clinical studies.

BAFF is considered a therapeutic target because dysregulated production of BAFF can induce systemic lupus erythematosus-like phenotype in mice, and elevated levels of BAFF are associated with disease severity in systemic lupus erythematosus and rheumatoid arthritis patients. Fc fusion decoy receptors, BCMA-Fc and BAFF-R-Fc, are therapeutic candidates for blocking BAFF. While studying their interactions with BAFF, we found that BAFF-R-Fc is more effective than BCMA-Fc for blocking BAFF binding to its receptors. We also found that a trimeric BAFF can bind more than one BAFF-R-Fc but only one BCMA-Fc. Moreover, we show that, in contrast to monovalent BAFF-R-Fc, monovalent BCMA does not form stable complexes with BAFF. Differences in their interaction with BAFF predict BAFF-R-Fc would be a better inhibitor. Indeed, we show BAFF-R-Fc is 10-fold more efficacious than BCMA-Fc for blocking BAFF-induced B cell proliferation in vitro and for blocking BAFF-mediated survival of mouse splenic B lymphocytes in vivo.

We have previously demonstrated the importance of endogenous GM-CSF production for the B7-2-dependent potentiating effect of exogenous TNF for CTL generation by stimulation cultures of splenic cells from mice bearing a large MOPC-315 tumor. Here we show that addition of GM-CSF to stimulation cultures of such tumor-bearer splenic cells also leads to the generation of enhanced anti-MOPC-315 CTL activity via a B7-dependent mechanism. However, while the potentiating effect of TNF was previously shown to be IL-2-independent, the potentiating effect of GM-CSF is shown here to be completely IL-2-dependent. Still, the potentiating activity of exogenous GM-CSF for the in vitro generation of CTL activity is shown to depend completely on endogenous TNF production. Finally, TNF and GM-CSF may cooperate in enhancing the in vivo generation of CTL activity in MOPC-315 tumor bearers because low-dose melphalan ( l -phenylalanine mustard) therapy, which was previously shown to lead to the rapid up-regulation of TNF production at the tumor site and the subsequent TNF-dependent in vivo acquisition of potent CTL activity, is shown here to lead to the rapid up-regulation of GM-CSF production at the tumor site.

Background Atopic dermatitis and allergic contact dermatitis are skin disorders triggered by epicutaneous sensitization with protein antigens and contact sensitization with haptens, respectively. Skin is colonized with bacteria, which are a source of Toll-like receptor (TLR) 2 ligands. Objective We sought to examine the role of TLR2 in murine models of atopic dermatitis and allergic contact dermatitis. Methods TLR2 −/− mice and wild-type littermates were epicutaneously sensitized with ovalbumin (OVA) or contact sensitized with oxazolone (OX). Skin histology was assessed by means of hematoxylin and eosin staining and immunohistochemistry. Ear swelling was measured with a micrometer. Cytokine mRNA expression was examined by means of quantitative RT-PCR. Antibody levels and splenocyte secretion of cytokines in response to OVA stimulation were measured by means of ELISA. Dendritic cells were examined for their ability to polarize T-cell receptor/OVA transgenic naive T cells to T H 1 and T H 2. Results In response to OVA sensitization, TLR2 −/− mice experienced skin infiltration with eosinophils and CD4 + cells, as well as upregulation of T H 2 cytokine mRNAs that was comparable with that seen in wild-type littermates. In contrast, epidermal thickening, IFN-γ expression in the skin, IFN-γ production by splenocytes, and IgG2a anti-OVA antibody levels were impaired in TLR2 −/− mice. After OX ear challenge, contact sensitized TLR2 −/− mice exhibited defective ear swelling with impaired cellular infiltration, decreased epidermal thickening and local IFN-γ expression, and impaired OX-specific IgG2a responses. Dendritic cells from TLR2 −/− mice induced significantly lower production of IFN-γ but normal IL-4 and IL-13 production in naive T cells. Conclusions These results indicate that TLR2 promotes the IFN-γ response to cutaneously introduced antigens.