Alloantigen specific t cell depletion from haematopoietic stem cell grafts for the prevention of graft versus host disease

Graft versus host disease (GvHD) is a multi-step immune process involving lymphocyte activation and proliferation. We have devised a novel method of selectively depleting alloreactive cells from haematopoietic stem cell grafts while retaining a pool of immunocompetent non alloreactive lymphocytes possessing antiviral and possibly anti-leukaemic activity and capable of hastening immune reconstitution. This method involved identifying the alloreactive cells thought to initiate GvHD by means of an activation marker, CD69 in an in-vitro system and depleting these cells by paramagnetic bead sorting. The temporal dynamics of CD69 expression as well as other activation markers in an allogeneic setting was first initially determined to determine the optimal marker and time for depletion. Using flow cytometric analysis and cell proliferation data, the engineered graft was shown to retain only 12% of its original alloreactivity but preserving 78% of its 3rd party reactivity. This system has been tested on mismatched and histocompatibility matched donor/patient pairs. A modified mixed lymphocyte culture system using cytokines has also been studied and this has proved to be of clinical significance in predicting GvHD. Cytokines, in particular, ?-interferon was shown to upregulate various cell surface molecules important in antigen presentation and may explain in part the crucial role of cytokines in GvHD. This depletion strategy was then tested in a NOD/SCID murine GvHD model. This involved comparing the intraperitoneal injection of 5-10x106 unmanipulated T cells from a CBA (H-2k) mouse into a non-lethally irradiated (250 cGy) NOD/SCID (H-2g7) recipient (positive control), with that of mice who received allo-depleted cells. This allodepletion strategy protected against death from lethal GvHD in a complete MHC mismatched setting (survival 12.5% in positive control versus 71.4% in allo-depleted group). In parallel, by using tetrameric HLA-peptide complexes and looking at CMV+, HLA-A2 individuals, it has been demonstrated that the non-alloreactive fraction using this strategy retained 90% of the specific anti-CMV activity, suggesting that these grafts would protect from CMV reactivation. Moreover, the alloreactive cells are easily recoverable in this selective T-cell depletion strategy for cryopreservation and ready for immediate access as therapeutic donor lymphocyte infusions in cases of frank relapse post-transplant

Antiviral immunity and T-regulatory cell function are retained after selective alloreactive T-cell depletion in both the HLA-identical and HLA-mismatched settings

AbstractNonselective T-cell depletion reduces the incidence of severe graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, but the cost is delayed and disordered antigen-specific immune reconstitution and increased infection. We use a method of selective depletion of alloreactive T cells expressing the activation marker CD69 after coculture with stimulator cells in a modified or standard mixed lymphocyte reaction. The technique has been shown to reduce alloreactivity while retaining third-party responses in vitro and, in a mismatched murine model, led to donor T-cell engraftment with a virtual absence of graft-versus-host disease and increased survival. We show in a human HLA-mismatched and unrelated HLA-identical setting that this technique retains >80% of specific cellular antiviral activity by cytomegalovirus-tetramer analysis and cytomegalovirus/Epstein-Barr virus peptide-stimulated interferon-γ ELISpot assay. Furthermore, CD4+ CD25+ T-regulatory cells are not removed by this method of selective allodepletion and retain their function in suppressing allogeneic proliferative responses. Preservation of antiviral cytotoxic T lymphocytes in selectively allodepleted stem cell grafts would lead to improved antiviral immunity after transplantation. The retention of immunosuppressive CD4+ CD25+ T-regulatory cells could lead to more ordered immune reconstitution and further suppress alloreactive responses after transplantation

BRIDGE DEVICES FOR WIRELESS PROJECTION OF VEHICLE OPERATING SYSTEMS

Vehicles may provide an infotainment experience that is hosted by a head unit or other computing device. The head unit may execute a native operating system that provides an execution environment in which an operating system client may execute to support execution of a different operating system hosted by another computing device (e.g., a smartphone, laptop computer, tablet computer, etc.). The head unit may require that the computing device physically interconnect with the head unit as the head unit may not support wireless connections (or only support limited wireless connections in the form of bandwidth limited connection – e.g., personal area network connections, such as Bluetooth® connections). Techniques described in this disclosure provide a bridge device for enabling wireless connections between the head unit and the computing devices for wireless projection of the different operating system, where the bridge device provides the physical interconnection required by the head unit while maintaining the wireless connection with the computing device to support wireless projection of the different operating system

RNA-seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature.

Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.Wellcome Trust, Bloodwise, Cancer Research UK

Dengue Virus Activates Polyreactive, Natural IgG B Cells after Primary and Secondary Infection

BACKGROUND: Dengue virus is transmitted by mosquitoes and has four serotypes. Cross-protection to other serotypes lasting for a few months is observed following infection with one serotype. There is evidence that low-affinity T and/or B cells from primary infections contribute to the severe syndromes often associated with secondary dengue infections. such pronounced immune-mediated enhancement suggests a dengue-specific pattern of immune cell activation. This study investigates the acute and early convalescent B cell response leading to the generation of cross-reactive and neutralizing antibodies following dengue infection. METHODOLOGY/PRINCIPAL FINDINGS: We assayed blood samples taken from dengue patients with primary or secondary infection during acute disease and convalescence and compared them to samples from patients presenting with non-dengue related fever. Dengue induced massive early plasmablast formation, which correlated with the appearance of polyclonal, cross-reactive IgG for both primary and secondary infection. Surprisingly, the contribution of IgG to the neutralizing titer 4-7 days after fever onset was more than 50% even after primary infection. CONCLUSIONS/SIGNIFICANCE: Poly-reactive and virus serotype cross-reactive IgG are an important component of the innate response in humans during both primary and secondary dengue infection, and "innate specificities" seem to constitute part of the adaptive response in dengue. While of potential importance for protection during secondary infection, cross-reactive B cells will also compete with highly neutralizing B cells and possibly interfere with their development

Sex differences modulating serotonergic polymorphisms implicated in the mechanistic pathways of risk for depression and related disorders:

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137310/1/jnr23877.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137310/2/jnr23877_am.pd

SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (<380 AU ml−1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies