Summary
Mesenchymal stromal cell (MSC) infusions have been reported to be effective in patients with steroid‐refractory, acute graft‐versus‐host disease (aGvHD) but comprehensive data on paediatric ...patients are limited. We retrospectively analysed a cohort of 37 children (aged 3 months‐17 years) treated with MSCs for steroid‐refractory grade III–IV aGvHD. All patients but three received multiple MSC infusions. Complete response (CR) was observed in 24 children (65%), while 13 children had either partial (n = 8) or no response (n = 5). Cumulative incidence of transplantation‐related mortality (TRM) in patients who did or did not achieve CR was 17% and 69%, respectively (P = 0·001). After a median follow‐up of 2·9 years, overall survival (OS) was 37%; it was 65% vs. 0% in patients who did or did not achieve CR, respectively (P = 0·001). The median time from starting steroids for GvHD treatment to first MSC infusion was 13 d (range 5–85). Children treated between 5 and 12 d after steroid initiation showed a trend for better OS (56%) and lower TRM (17%) as compared with patients receiving MSCs 13–85 d after steroids (25% and 53%, respectively; P = 0·22 and 0·06, respectively). Multiple MSC infusions are safe and effective for children with steroid‐refractory aGvHD, especially when employed early in the disease course.
There is increasing evidence that endothelial dysfunction is involved in refractoriness of acute GvHD (aGvHD). Here we investigated the hypothesis that another endothelial complication, ...transplant-associated thrombotic microangiopathy (TMA), contributes to the pathogenesis of aGvHD refractoriness. TMA was retrospectively assessed in 771 patients after allogeneic stem cell transplantation (alloSCT). Incidences of TMA and refractory aGvHD were correlated with biomarkers of endothelial damage obtained before alloSCT for patients receiving or not receiving statin-based endothelial prophylaxis (SEP). Diagnostic criteria for TMA and refractory aGvHD were met by 41 (5.3%) and 76 (10%) patients, respectively. TMA was overrepresented in patients with refractory aGvHD (45.0 vs 2.3% in all other patients, P<0.001). TMA independently increased mortality. Elevated pretransplant suppressor of tumorigenicity-2 and nitrates along with high-risk variants of the thrombomodulin gene were associated with increased risk of TMA. In contrast, SEP abolished the unfavorable outcome predicted by pretransplant biomarkers on TMA risk. Patients on SEP had a significantly lower risk of TMA (P=0.001) and refractory aGvHD (P=0.055) in a multivariate multistate model. Our data provide evidence that TMA contributes to the pathogenesis of aGvHD refractoriness. Patients with an increased TMA risk can be identified pretransplant and may benefit from pharmacological endothelium protection.
Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) ...occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype that potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and have implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.
Despite advances that have improved survival after allogeneic hematopoietic stem cell transplantation (HCT), chronic graft-versus-host disease (GVHD) remains a leading cause of late morbidity and ...mortality after transplant. Current treatment options show limited efficacy in steroid-refractory disease, and there exists a paucity of robust data to guide management decisions. Lack of United States Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-approved agents in GVHD underscore the importance of developing novel therapies. Better understanding of the biology of chronic GVHD has provided novel targets for treatment, and structured guidelines in diagnosis and in clinical trial design have provided a common language and pathways for research in this area. These, combined with the surge of drug development in Oncology and Immunology, are factors that have contributed to the accelerating field of drug development and clinical research in chronic GVHD. In these exciting times, it is possible to foresee long awaited advances in the treatment of this devastating complication of HCT. This review will summarize the ongoing clinical development for novel therapies in chronic GVHD.
Abstract
Many necrotrophic plant pathogenic fungi belonging to the class of Dothideomycetes produce phytotoxic metabolites and peptides that are usually required for pathogenicity. Phytotoxins that ...affect a broad range of plant species are known as non-host-specific toxins (non-HSTs), whereas HSTs affect only a particular plant species or more often genotypes of that species. For pathogens producing HSTs, pathogenicity and host specificity are largely defined by the ability to produce the toxin, while plant susceptibility is dependent on the presence of the toxin target. Non-HSTs are not the main determinants of pathogenicity but contribute to virulence of the producing pathogen. Dothideomycetes are remarkable for the production of toxins, particularly HSTs because they are the only fungal species known so far to produce them. The synthesis, regulation, and mechanisms of action of the most important HSTs and non-HSTs will be discussed. Studies on the mode of action of HSTs have highlighted the induction of programed cell death (PCD) as an important mechanism. We discuss HST-induced PCD and the plant hypersensitive response upon recognition of avirulence factors that share common pathways. In this respect, although nucleotide-binding-site-leucine-rich repeat types of resistance proteins mediate resistance against biotrophs, they can also contribute to susceptibility toward necrotrophs.
This review paper describes host-specific toxins (HSTs) and non-HSTs produced by fungal species belonging to the class of Dothideomycetes.
Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ...ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD.
We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56.
A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% 96 patients vs. 39% 61; odds ratio, 2.64; 95% confidence interval CI, 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% 61 patients vs. 22% 34; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients 33% in the ruxolitinib group and 27 of 150 18% in the control group), anemia (in 46 30% and 42 28%, respectively), and cytomegalovirus infection (in 39 26% and 31 21%).
Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy. (Funded by Novartis; REACH2 ClinicalTrials.gov number, NCT02913261.).
Update on ocular graft-versus-host disease Nair, Sridevi; Vanathi, Murugesan; Mukhija, Ritika ...
Indian journal of ophthalmology,
05/2021, Letnik:
69, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Ocular graft-versus-host disease (oGVHD) occurs as a complication following hematopoietic stem cell transplantation and is associated with significant ocular morbidity resulting in a marked reduction ...in the quality of life. With no current consensus on treatment protocols, management becomes challenging as recurrent oGVHD often refractory to conventional treatment. Most authors now diagnose and grade the disease based on criteria provided by the National Institutes of Health Consensus Conference (NIH CC) or the International Chronic oGVHD (ICCGVHD) consensus group. This article will provide an insight into the diagnostic criteria of oGVHD, its classification, and clinical severity grading scales. The inflammatory process in oGVHD can involve the entire ocular surface including the eyelids, meibomian gland, corneal, conjunctiva, and lacrimal system. The varied clinical presentations and treatment strategies employed to manage them have been discussed in the present study. The recent advances in ocular surface imaging in oGVHD patients such as the use of meibography and in vivo confocal microscopy may help in early diagnosis and prognostication of the disease. Researching tear proteomics and identification of novel potential tear biomarkers in oGVHD patients is an exciting field as they may help in objectively diagnosing the disease and monitoring the response to treatment.
Virtually all plants and animals, including humans, are home to symbiotic microorganisms. Symbiotic interactions can be neutral, harmful or have beneficial effects on the host organism. However, ...growing evidence suggests that microbial symbionts can evolve rapidly, resulting in drastic transitions along the parasite-mutualist continuum. In this Review, we integrate theoretical and empirical findings to discuss the mechanisms underpinning these evolutionary shifts, as well as the ecological drivers and why some host-microorganism interactions may be stuck at the end of the continuum. In addition to having biomedical consequences, understanding the dynamic life of microorganisms reveals how symbioses can shape an organism's biology and the entire community, particularly in a changing world.
Development of graft‐versus‐host disease (GvHD) is a rare complication after transfusions or solid organ transplantation. Patients typically present with a skin rash, diarrhea, liver failure, and ...bone marrow aplasia. A diagnosis of transfusion/transplantation associated‐GvHD is made based on the clinical and histologic evidence, yet it is often delayed due to the nonspecific symptoms attributed to the patient's underlying illness. Several therapeutic approaches are being used including both increasing and withdrawing immunosuppression, and the use of cellular therapies. Unfortunately, the success rate of these approaches is low and the mortality of this complication is very high. New approaches are needed. We report on three cases of GvHD developing after solid organ transplantation treated with ruxolitinib.
The authors report on three cases of graft‐versus‐host disease that developed after solid organ transplantation and were treated with ruxolitinib.
The Coronaviridae are a family of viruses that cause disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors common ...to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics. Here, we conducted genome-wide CRISPR screens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (for SARS-CoV-2), aminopeptidase N (for 229E), and glycosaminoglycans (for OC43). Additionally, we identified phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses. By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol kinases and cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle and the development of host-directed therapies.
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•Genome-wide CRISPR screens for SARS-CoV-2, HCoV-229E, and HCoV-OC43 host factors•Screens correctly identified divergent entry factors for the three coronaviruses•Cholesterol and phosphatidylinositol pathways are shared host dependency factors•Pharmacological inhibition of host factors reduces coronavirus replication
To identify host factors required for the infection with SARS-CoV-2 and the common cold coronaviruses OC43 and 229E, Wang et al. conduct genome-wide CRISPR knockout screens. In addition to virus-specific entry factors, they uncover shared host pathways, including cholesterol homeostasis and phosphatidylinositol kinases, required for the infection with all three viruses and demonstrate that pharmacological inhibition of these pathways exhibits pan-coronavirus antiviral activity.
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