Conditioning therapies before transplantation induce the release of uric acid, which triggers the NLRP3 inflammasome and IL-1β production contributing to graft-versus-host disease.

In order to identify cellular genes which interfere with HIV-1 replication in monocyte-derived macrophages (MAC), cells were stimulated with interferon (IFN) or lipopolysaccharide (LPS) leading to a pronounced inhibition of HIV-1 infection in these cells, and the resulting gene expression was analyzed. Using the microarray technology we identified a gene named Stimulated Trans-Acting Factor of 50 kDa (Staf50), which is known to repress the activity of the HIV-1 LTR. Analysis of the Staf50 expression by real-time PCR showed an overexpression in IFNalpha (up to 20-fold) and LPS (up to 10-fold)-stimulated MAC as well as in infected cells (up to 3-fold). For stable overexpression, 293 T cells and primary macrophages were transduced with Staf50-IRES-GFP bicistronic pseudotype viruses. After transduction, 293 T CD4/CCR5 and MAC were infected with HIV-1, and virus replication was monitored by p24 ELISA. Overexpression of Staf50 inhibited the HIV-1 infection between 50% and 90% in 293 T CD4/CCR5 as well as in MAC. Our findings suggest that host genetic effects in combination with viral properties determine the susceptibility of an appropriate target cell for HIV-1 infection as well as the replication potential of the virus in the cell resulting in an overall productive infection.

Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic bone marrow transplantation (allo-BMT), and infiltration of donor leukocytes into aGVHD target organs is partially orchestrated by chemokines. Using a murine BMT model, the expression of 30 chemokines or chemokine receptors in the lung, liver, gut and tongue was analyzed using real-time PCR at 1, 2, 3 and 6 weeks after BMT during the development of clinical aGVHD and target organ histopathology. CXCL9-11 expression was linked to elevated expression of CXCR3 in the gut, lung and tongue. In contrast, hepatic CXCR3 expression was not changed, whereas a clear association was seen for CXCL16 and CXCR6 expression. An elevated intestinal CCL3 expression 1 week after allo-BMT was associated with an increased expression of CCR5 but not CCR1 or CCR3, and in the lung and liver CCL3-CCL5 expression was associated with increases in CCR1 and CCR5. Overexpression of CCL2, CCL8, CCL12 and their receptor CCR2 was found in the liver and lung, but not in the gut and tongue. On the basis of the differences in kinetics and organ distribution, more studies are required to better characterize specific targets within this network, as this will allow the development of novel preventive and therapeutic approaches by using single or multiple targeting reagents.

A putative involvement of the vasculature seems to play a critical role in the pathophysiology of graft-versus-host disease (GVHD). We aimed to characterize alterations of mesenteric resistance arteries in GVHD in a fully MHC-mismatched model of BALB/c mice conditioned with total body irradiation that underwent transplantation with bone marrow cells and splenocytes from syngeneic (BALB/c) or allogeneic (C57BL/6) donors. After 4 weeks, animals were sacrificed and mesenteric resistance arteries were studied in a pressurized myograph. The expression of endothelial (eNOS) and inducible nitric oxide (NO)-synthase (iNOS) was quantified and vessel wall ultrastructure was investigated with electron microscopy. The myograph study revealed an endothelial dysfunction in allogeneic-transplant recipients, whereas endothelium-independent vasodilation was similar to syngeneic-transplant recipients or untreated controls. The expression of eNOS was decreased and iNOS increased, possibly contributing to endothelial dysfunction. Additionally, arteries of allogeneic transplant recipients exhibited a geometry-independent increase in vessels strain. For both findings, electron microscopy provided a structural correlate by showing severe damage of the whole vessel wall in allogeneic-transplant recipient animals. Our study provides further data to prove, and is the first to characterize, functional and structural vascular alterations in the early course after allogeneic transplantation directly in an ex vivo setting and, therefore, strongly supports the hypothesis of a vascular form of GVHD.

The current COVID-19 pandemic, caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), has raised significant economic, social, and psychological concerns. The rapid spread of the virus, coupled with the absence of vaccines and antiviral treatments for SARS-CoV-2, has galvanized a major global endeavor to develop effective vaccines. Within a matter of just a few months of the initial outbreak, research teams worldwide, adopting a range of different strategies, embarked on a quest to develop effective vaccine that could be effectively used to suppress this virulent pathogen. In this review, we describe conventional approaches to vaccine development, including strategies employing proteins, peptides, and attenuated or inactivated pathogens in combination with adjuvants (including genetic adjuvants). We also present details of the novel strategies that were adopted by different research groups to successfully transfer recombinantly expressed antigens while using viral vectors (adenoviral and retroviral) and non-viral delivery systems, and how recently developed methods have been applied in order to produce vaccines that are based on mRNA, self-amplifying RNA (saRNA), and trans-amplifying RNA (taRNA). Moreover, we discuss the methods that are being used to enhance mRNA stability and protein production, the advantages and disadvantages of different methods, and the challenges that are encountered during the development of effective vaccines.

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