In this review, we have focused on immune restoration after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and solid organ transplantations (SOT). We discuss the kinetics of cytokine secretion during immune reconstitution phases that play a unique role in the connection between innate and adaptive immunity, therefore essential in normal and pathological immune reconstitution. We overview the importance of T cell immunity for antigen-specific immune reconstitution and the production of cytokines. We briefly touch upon a graft versus host disease and other immunopathology that accompany poor immune restoration after transplantation and discuss therapeutic interventions.
Background Cryptococcal meningitis (CM) is a major cause of death in HIV-infected patients in sub-Saharan Africa. Many CM patients experience cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), which is often fatal. We sought to identify transcriptomic biomarker pathways in peripheral blood that are associated with or predict the development of death or fatal C-IRIS among patients with CM who were enrolled in the Cryptococcal Optimal ART Timing Trial. Methods We assessed peripheral blood gene expression using next-generation RNA sequencing in 4 groups of patients with CM: (1) no C-IRIS or Death; (2) C-IRIS survivors; (3) fatal C-IRIS; (4) Death without C-IRIS. Gene expression was assessed at the time of ART initiation, at 1, 4, and 8 weeks on ART, and at the time of C-IRIS events. Results We identified 12 inflammatory and stress response pathways, including interferon type 1 signaling, that were upregulated at the time of ART initiation in patients with future fatal C-IRIS, as compared with survivors. The upregulation of transcripts involved in innate immunity (inflammasome, Toll-like receptor signaling), was observed at the time of fatal or nonfatal C-IRIS events. At the time of fatal C-IRIS events, numerous transcripts within fMLP, Rho family GTPases, HMGB1, and other acute phase response signaling pathways were upregulated, which reflects the severity of inflammation and systemic oxidative stress. Patients who died without recognized C-IRIS also had increased expression of pathways associated with oxidative stress and tissue damage. Conclusions Our results showed that overactivated innate immunity, involving Toll-like receptor/inflammasome pathways, and inflammation-induced oxidative stress, are associated with fatal outcomes. The results of this study provide insight into the molecular drivers of death and fatal C-IRIS to inform future diagnostic test development or guide targeted treatments.
Three decades of research in hematopoietic stem cell transplantation and HIV/AIDS fields have shaped a picture of immune restoration disorders. This manuscript overviews the molecular biology of interferon networks, the molecular pathogenesis of immune reconstitution inflammatory syndrome, and post-hematopoietic stem cell transplantation immune restoration disorders (IRD). It also summarizes the effects of thymic involution on T cell diversity, and the results of the assessment of diagnostic biomarkers of IRD, and tested targeted immunomodulatory treatments
Background: Cryptococcal meningitis (CM) is a major cause of death in HIV-infected patients in sub-Saharan Africa. Many CM patients experience cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), which is often fatal. We sought to identify transcriptomic biomarker pathways in peripheral blood that are associated with, or, predict the development of death or fatal C-IRIS among patients with CM who were enrolled in the Cryptococcal Optimal ART Timing (COAT) Trial. Methods: We assessed peripheral blood gene expression using next-generation RNA sequencing in 4 groups of patients with CM: 1) no C-IRIS or Death; 2) C-IRIS survivors; 3) fatal C-IRIS; 4) Death without C-IRIS. Gene expression was assessed at the time of ART initiation, at 1, 4, and 8 weeks on ART, and at the time of C-IRIS events. Results: We identified 12 inflammatory and stress response pathways, including interferon type 1 signaling, that were upregulated at the time of ART initiation in patients with future fatal C-IRIS, as compared with survivors. The upregulation of transcripts involved in innate immunity (inflammasome, Toll-like receptor signaling), was observed at the time of fatal or nonfatal C-IRIS events. At the time of fatal C-IRIS events, numerous transcripts within fMLP, Rho family GTPases, HMGB1, and other acute phase response signaling pathways were upregulated, which reflect the severity of inflammation and systemic oxidative stress. Those who died without recognized C-IRIS also had increased expression of pathways associated with oxidative stress and tissue damage. The Partial Least Squares model estimated above mentioned pathways as predictors of fatal outcome.Conclusions: Our results showed that overactivated innate immunity, involving Toll-like receptor/inflammasome, and inflammation-induced oxidative stress, are associated with fatal outcomes. The results of this study provide insight into the molecular drivers of death and fatal C-IRIS to inform future diagnostic test development or guide targeted treatments.
To examine the frequency and predictive factors for bowel incarceration following transjugular intrahepatic portosystemic shunts (TIPS) placement to treat refractory cirrhosisinduced ascites.MATERIALS AND METHODS: Ninety-nine patients with known hernias at the time of TIPS placement were identified. Their electronic medical records were reviewed and pertinent preprocedural, procedural, and outcome variables were recorded. Patients were divided between those that suffered incarceration (study group) and a control group of those with a hernia who did not suffer incarceration.RESULTS: Twelve of the 99 patients (12.1%) suffered hernia incarceration, of which seven (7.1%) suffered incarceration in the first 90 days. One patient who suffered incarceration ultimately died from complications of the incarceration. When comparing all patients who suffered incarceration to controls, incarceration patients were found to have significantly higher albumin levels (mean 3.13 versus 2.73, p¼0.02). When just considering those who had incarcerations in the first 90 days to controls, incarceration patients were less likely to have improvement in their ascites (p¼0.04).CONCLUSIONS: Incarcerated hernias occur frequently after TIPS placement and can lead to significant morbidity and mortality. Clinicians should be aware of this complication and counsel patients on presenting symptoms prior to placement.
A growing body of evidence supports the role of Parkin as a tumor suppressor involved in a number of cellular processes, including the downregulation of cell cycle and proliferation, migration, invasion, metastasis, mitophagy, and energy metabolic reprogramming. Indeed, epidemiological, genetic, and bioinformatic studies have shown multiple degrees of defects in the PARK2 gene, localized in human chromosome 6q25-27, a region frequently lost in cancers. In the present study, we show a novel role of Parkin in tumor immune surveillance through dysregulation of the PTEN/PI3k/AKT pathway, involving the modulation of antigen presentation machinery and antitumor-specific CD8+ T cell reactivity. We generated murine and human models that resemble the advanced-stage tumors where Parkin deficiencies are mostly found. In the mouse models, we observed a striking increase of tumor aggressiveness in the absence of Parkin that was associated with loss of antigen presentation and a significant decrease in the infiltration of antitumor CD8+ T cells. Importantly, loss of PARK2 also affected the efficacy of a Tumor-Associated Mitochondria Antigens (TAMAs) based vaccine showing the crucial role of Parkin in tumor development and in the context of antitumor cellular therapeutic strategies. Moreover, we also found that the lack of Parkin in the B16-OVA melanoma model also negatively impacts cytosol-derived antigen presentation and CD8+ T cell immunity. Finally, the analysis of TCGA tumor atlas validates the relevance of PARK2 loss on cancer immunotherapy effectiveness. Thus, during the progression and immunotherapy of cancer, the presence of Parkin mutations that result in loss of its functionality impact antigen presentation and facilitate tumor evasion. Citation Format: Renzo Perales Linares, Hesham Mohei, Nektaria M. Leli, Silvia Beghi, Nektarios Kostopoulos, Amit Maity, Costantinos Koumenis, Andrea Facciabene. Parkin regulates tumor evasion by controlling antigen processing and presentation through the PTEN/AKT network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3846.
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