Extent Of Immune Activation Research Articles

Exploring Symptom Overlaps: Post-COVID-19 Neurological Syndrome and Post-Concussion Syndrome in Athletes.

The COVID-19 pandemic has introduced new challenges in managing neurological conditions, particularly among athletes. This paper explores the intersection of post-COVID-19 neurological syndrome (PCNS/PASC) and post-concussion syndrome (PCS), focusing on their implications in sports medicine. Our analysis covers the symptomatology, pathophysiology, and management strategies for PCNS/PASC and PPCS, with special attention paid to the unique challenges faced by athletes recovering from these conditions, including the risk of symptom exacerbation and prolonged recovery. Key findings reveal that both PCNS/PASC and PPCS present with overlapping symptoms such as cognitive difficulties, exercise intolerance, and mental health issues, but differ in specific manifestations like anosmia and ageusia, unique to COVID-19. Pathophysiological analysis reveals similarities in blood-brain barrier disruption (BBB) but differences in the extent of immune activation. Management strategies emphasize a gradual increase in physical activity, close symptom monitoring, and psychological support, with a tailored approach for athletes. Specific interventions include progressive aerobic exercises, resistance training, and cognitive rehabilitation. Furthermore, our study highlights the importance of integrating neurology, psychiatry, physical therapy, and sports medicine to develop comprehensive care strategies. Our findings underscore the dual challenge of COVID-19 and concussion in athletes, necessitating a nuanced, interdisciplinary approach to effective management. Future research should focus on the long-term neurological effects of both conditions and optimizing treatment protocols to improve patient outcomes. This comprehensive understanding is crucial for advancing the management of athletes affected by these overlapping conditions and ensuring their safe return to sports.

P06.07.B DEVELOPMENT OF A NOVEL CO-CULTURE MODEL OF GLIOBLASTOMA NEUROSPHERES WITH AUTOLOGOUS PERIPHERAL BLOOD MONONUCLEAR CELLS TO INVESTIGATE THE EFFICACY OF ONCOLYTIC ADENOVIRUS THERAPY

Abstract BACKGROUND The dismal prognosis of glioblastoma (GBM) patients, with a median survival of less than 15 months despite maximal therapy urgently warrants new therapeutic approaches. Cancer immunotherapies such as oncolytic virotherapy have shown encouraging results against GBM, but a large fraction of patients fails to respond to treatment. As the mechanisms that malignant cells employ to avoid elimination by the immune system are diverse, we hypothesized that development of an ex vivo co-culture model that would capture the complex interactions between different immune cell types, would allow us to explore the nature and degree of immune response induced by oncolytic viruses. To this end, we established a co-culture model of primary GBM neurospheres with autologous patient peripheral blood mononuclear cells (PBMCs). MATERIAL AND METHODS Different culture parameters such as co-culture media and cell ratios were explored to select the optimal co-culture setting. Furthermore, we developed a 20-color flow cytometry panel to evaluate the phenotype of the PBMCs; markers such as CD69, HLA-DR, TIGIT on T cells, as well as M1 and M2-related signatures on monocyte-derived macrophages were assessed. Co-culture supernatants were evaluated for the presence of pro-inflammatory cytokines and chemokines. RESULTS We established that viability and effector functions of PBMCs were retained in our co-culture conditions. Co-culture of GBM cells with PBMCs induced a pro-tumoral microenvironment. However, treatment with oncolytic adenovirus led to downregulation of M2-related signatures on monocyte-derived macrophages as well as upregulation of activation markers on CD8+ T cells. We also observed increase in a number of pro-inflammatory cytokines and chemokines such as IFNγ, TNFα, CCL4 as well as granzyme b. The extent of immune activation upon treatment, however, was distinct per patient, indicating that our system may offer a tool to assess patient-specific responses to oncolytic virus treatment. Importantly, we showed that patient exposure to dexamethasone prior to PBMC isolation did not preclude the IFNγ production in our system. CONCLUSION We established an autologous GBM/PBMCs co-culture model which reflects inter-tumoral heterogeneity in response to oncolytic virotherapy. This may allow the establishment of an ex vivo assay to assess and predict individual patient response to oncolytic virotherapy and possibly in the future also to other immunotherapies.

IMMU-09. IMMUNOLOGICAL CHARACTERIZATION OF PEDIATRIC BRAIN TUMORS HAS CLINICAL IMPLICATIONS FOR PATIENT MANAGEMENT AND PROGNOSIS

Abstract The tumor immune microenvironment (TIME) is a growing area of interest, however, the extent of immune activation in childhood CNS tumors is unknown. Although immunotherapy has not gained success in most CNS cancers, our group described gliomas with MMRD which exhibit hypermutation and favorable responses to immune checkpoint inhibition (ICI). Therefore, detailed characterization of the CNS TIME is key for the development of novel immunotherapeutic strategies and application of existing ones in childhood brain tumors. We developed a clinical NanoString immune-oncology panel that includes markers reflecting cell types, therapeutic targets, and cellular pathways, as well as the 18-gene tumor inflammation signature (TIS), a biomarker for ICI response. We tested over 500 brain tumors, including 266 low-grade gliomas (LGG), 170 high-grade gliomas (HGG), 91 MMRD tumors, 16 ependymomas, 46 medulloblastomas, and 36 non-tumor brain samples. Overall, ependymomas and medulloblastomas had low levels of inflammation, although SHH medulloblastomas had higher inflammation than other subtypes. IDH-mutant LGG were immunologically cold, while many gliomas with pediatric-LGG mutations had high levels of inflammation, including upregulation of immune checkpoints – indicating that ICI may be an effective strategy. Interestingly, in pediatric-LGG inflammation impacted outcome in tumors with the same genetic alterations. BRAF V600E-mutant LGG exhibiting high TIS had inferior prognosis (p = 0.02), while no such relationship was observed in BRAF-fused tumors. Diffuse midline gliomas had higher inflammation than hemispheric HGG, indicating that these tumors are not immunologically cold, as has been previously reported. In MMRD tumors treated with ICI, high TIS correlated with improved survival and was independent from hypermutation and mutational burden. Furthermore, MMRD gliomas had high expression of several other immune checkpoints including LAG3, suggesting its value as an additional therapeutic target. In summary, characterization of the TIME across pediatric brain tumors provides potential prognostic clues and suggest treatment strategies for further investigation.

Inflammation, iron and vitamin D metabolism in different cardiomyopathy aetiologies

Abstract Immune activation coincides with disturbances in iron and vitamin D metabolism in patients with cardiomyopathy. In this study, we investigated whether there are differences regarding immune activation, iron and vitamin D metabolism between the different cardiomyopathy aetiologies. Patients and methods: Parameters of iron metabolism (haemoglobin, iron, transferrin, transferrin saturation, ferritin, hepcidin), vitamin D metabolism (Ct-FGF23, parathormone, phosphate, vitamin D) and immune activation (C-reactive protein and neopterin) were determined in 149 patients (98 men, 51 women) with non-ischaemic cardiomyopathy. Results: Patients with amyloid cardiomyopathy presented with higher neopterin, ferritin and hepcidin levels than other cardiomyopathy aetiologies. Furthermore, they showed the highest rate of cardiovascular events. C-reactive protein levels were significantly higher in patients with inflammatory cardiomyopathy. Patients with virus positive cardiomyopathy presented with significantly higher ferritin and Ct-FGF23 levels compared to patients with virus negative inflammatory cardiomyopathy. Conclusion: This study indicates that there are some differences regarding the extent of immune activation and inflammation as well as alterations in iron metabolism disorders between different cardiomyopathy aetiologies. Further studies with larger patient cohorts are needed to investigate these findings more precisely.

Quasispecies tropism and compartmentalization in gut and peripheral blood during early and chronic phases of HIV-1 infection: possible correlation with immune activation markers

HIV quasispecies was analysed in plasma and proviral genomes hosted by duodenal mucosa and peripheral blood cells (PBMC) from patients with early or chronic infection, with respect to viral heterogeneity, tropism compartmentalization and extent of immune activation. Seventeen HIV-1-infected combined antiretroviral therapy naive patients were enrolled (11 early infection and six chronic infection). V3 and nef genomic regions were analysed by ultra-deep pyrosequencing. Sequences were used to infer co-receptor usage and to construct phylogenetic trees. As markers of immune activation, plasma sCD14 and soluble tumour necrosis factor receptor II (sTNFRII) levels were measured. Median diversity of HIV RNA was lower in patients with early infection versus chronic infection patients. Overall, direct correlation was observed between V3 diversity and X4 frequency; V3 diversity of HIV RNA was inversely correlated with CD4 T-cell count; median sCD14 and sTNFRII values were similar in early and chronic patients, but X4 frequency of HIV RNA was directly correlated with plasma sCD14. The proportion of patients harbouring X4 variants and median intra-patient X4 frequency of proviral genomes tended to be higher in chronic infection than early infection patients. More pronounced compartmentalization of proviral quasispecies in gut compared with PBMC samples was observed in patients with early infection compared with chronic patients. The loss of gut/PBMC compartmentalization in more advanced stages of HIV infection was confirmed by longitudinal observation. More studies are needed to understand the pathogenetic significance of early HIV quasispecies compartmentalization and progressive intermixing of viral variants in subsequent phases of the infection, as well as the role of immune activation in tropism switch.

Abstract 1553: Key determinants of immunotherapy success in frequently-used murine tumor models

Abstract Cancer immunotherapy uses a patient's own immune system to recognize and eliminate malignant cells. The potential advantages of this approach over conventional treatments include the systemic trafficking of immune cells to treat primary and metastatic disease, inherent antigen-specificity of adaptive immunity to minimize collateral damage, and the induction of immunological memory to prevent recurrent disease. While many acknowledge the promise of immunotherapy, its translation to the clinic has been slow and only occasionally successful. In the more than 3 decades of experience of our laboratory in developing and testing immunotherapy reagents for cancer, we observed that a given set of reagents can produce complete regressions in some but not all tumor models. We hypothesized that a major contributor to this variability was underlying differences in the immune escape strategies utilized by different tumors. Our hypothesis was supported with data from a series of immunotherapy experiments on a panel of experimental murine solid tumor models. Comprehensive immune profiles were generated for each by measuring tumor infiltrating leukocytes (TIL), immune activation, and immune suppression present in the tumor microenvironment using qRT-PCR, immunohistochemistry staining, and flow cytometry techniques. Key differences emerged amongst models in the extent of immune activation that correlated directly with TIL and immunosuppression. From these data, it appears that some tumors are more “visible” to the immune system and have active countermeasures to survive, while others use immune evasion strategies to persist in the host. To classify tumor models along this spectrum, ten immune-related genes and cell markers showing significant change across the models were selected to generate an immunogenicity score for each model: CD40, 41BBL, OX40L, CD80, CD86, CD11c, CD45, BM-2 (PMN marker), Granzyme B, and CD8. Importantly, we observed that MHC class I mouse equivalent H2-D correlated with this immunogenicity level for each tumor. Secondly, Treg and MDSC were measured in the tumor microenvironment and draining lymphoid tissues using immunohistochemical and flow cytometry techniques to determine the dominant suppressor cell population(s) present. Immunotherapy regimens were then developed to match each tumor model using immunogenicity to indicate the level of immune stimulation needed and suppressor cell component to indicate targets for reversing tumor tolerance. These regimens were used to treat established solid tumors in mice and demonstrated that two features of a tumor's immune profile, namely immunogenicity level and dominant suppressor cell component, are the key determinants of immunotherapy success in vivo. Viewed in this way, the tumor/host relationship becomes the overriding feature for determining optimal treatment for patients based upon immune profiling data obtained at the time of biopsy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1553. doi:1538-7445.AM2012-1553

Imaging the immune response to monitor tumor immunotherapy

The goal of cancer immunotherapy is to promote antitumor immunity, and novel approaches include vaccination, adoptive transfer of tumor-reactive T cells, and administration of monoclonal antibodies and small molecules that target immune regulatory pathways. The molecular and cellular events responsible for tumor rejection are not completely defined and correlative studies have been used to help understand the mechanisms and extent of immune activation and tumor regression with these approaches. The real-time monitoring of immune responses to immunotherapy has been challenging as specific cell subsets may be difficult to define, and molecular pathways have evolved functionally diverse outcomes in different cells and in different tissues. Recently, improvements in optics and digital imaging have led to novel imaging techniques that make it possible to track the migration of individual immune cells ex vivo and in vivo, and to detect the dynamic interactions between T cells and antigen-presenting cells or tumor cells within complex microenvironments, including lymphoid tissue and established tumors. This review will explain some of the more established imaging techniques and discuss their role in monitoring the immune response in patients treated with various tumor immunotherapy approaches.

Monitoring of immune activation using biochemical changes in a porcine model of cardiac arrest.

In animal models, immune activation is often difficult to assess because of the limited availability of specific assays to detect cytokine activities. In human monocytes/macrophages, interferon-gamma induces increased production of neopterin and an enhanced activity of indoleamine 2,3-dioxygenase, which degrades tryptophan via the kynurenine pathway. Therefore, monitoring of neopterin concentrations and of tryptophan degradation can serve to detect the extent of T helper cell 1-type immune activation during cellular immune response in humans. In a porcine model of cardiac arrest, we examined the potential use of neopterin measurements and determination of the tryptophan degradation rate as a means of estimating the extent of immune activation. Urinary neopterin concentrations were measured with high-performance liquid chromatography (HPLC) and radioimmunoassay (RIA) (BRAHMS Diagnostica, Berlin, Germany). Serum and plasma tryptophan and kynurenine concentrations were also determined using HPLC. Serum and urine neopterin concentrations were not detectable with HPLC in these specimens, whereas RIA gave weakly (presumably false) positive results. The mean serum tryptophan concentration was 39.0 +/- 6.2 micromol/l, and the mean kynurenine concentration was 0.85 +/- 0.33 micromol/l. The average kynurenine-per-tryptophan quotient in serum was 21.7 +/- 8.4 nmol/micromol, and that in plasma was 20.7 +/- 9.5 nmol/micromol (n = 7), which corresponds well to normal values in humans. This study provides preliminary data to support the monitoring of tryptophan degradation but not neopterin concentrations as a potential means of detecting immune activation in a porcine model. The kynurenine-per-tryptophan quotient may serve as a short-term measurement of immune activation and hence permit an estimate of the extent of immune activation.