Summary Background Hepatitis B virus (HBV)‐specific CD8+ cell response restoration during nucleos(t)ide analogue (NUC) treatment could lead to off‐treatment HBV control in e‐antigen‐negative chronic hepatitis B (CHBe(−)). Aim To predict this response with variables involved in T‐cell exhaustion for use as a treatment stopping tool. Methods In NUC‐treated CHBe(−) patients, we considered a functional response in cases with HBV‐specific CD8+ cells against core and polymerase HBV epitopes able to proliferate and secrete type I cytokines after antigen encounter. We performed a logistic regression model (LRM) to predict the likelihood of developing this response, based on patient age (subrogate of infection length), HBsAg level, NUC therapy starting point and duration (antigenic pressure). We discontinued treatment and assessed HBV DNA dynamics, HBsAg decline and loss during off‐treatment follow‐up according to LRM likelihood. Results We developed an LRM that predicted the presence of a proliferative type I cytokine‐secreting CD8+ cell response, which correlated positively with treatment duration and negatively with treatment initiation after the age of 40 years and with age adjusted by HBsAg level. We observed a positive correlation between LRM probability and intensity of proliferation, number of epitopes with the functional proliferating response and type I cytokine secretion level. Off‐treatment, HBsAg loss, HBsAg decline >50% and HBV control were more frequent in the group with >90% LRM probability. Conclusions Short‐term low‐level antigen exposure and early long‐term NUC treatment influence the restoration of a functional HBV‐specific CD8+ cell response. Based on these predictors, a high likelihood of detecting this response at treatment withdrawal is associated with off‐treatment HBV control and HBsAg decline and loss.
Thirty to fifty percent of hepatocellular carcinomas (HCC) display an immune class genetic signature. In this type of tumor, HCC-specific CD8 T cells carry out a key role in HCC control. Those potential reactive HCC-specific CD8 T cells recognize either HCC immunogenic neoantigens or aberrantly expressed host’s antigens, but they become progressively exhausted or deleted. These cells express the negative immunoregulatory checkpoint programmed cell death protein 1 (PD-1) which impairs T cell receptor signaling by blocking the CD28 positive co-stimulatory signal. The pool of CD8 cells sensitive to anti-PD-1/PD-L1 treatment is the PD-1dim memory-like precursor pool that gives rise to the effector subset involved in HCC control. Due to the epigenetic imprints that are transmitted to the next generation, the effect of PD-1 blockade is transient, and repeated treatments lead to tumor resistance. During long-lasting disease, besides the TCR signaling impairment, T cells develop other failures that should be also set-up to increase T cell reactivity. Therefore, several PD-1 blockade-based combinatory therapies are currently under investigation such as adding antiangiogenics, anti-TGFβ1, blockade of other negative immune checkpoints, or increasing HCC antigen presentation. The effect of these combinations on CD8+ T cells is discussed in this review.
Hepatitis C virus (HCV)-specific CD8+ T cell response is essential in natural HCV infection control, but it becomes exhausted during persistent infection. Nowadays, chronic HCV infection can be resolved by direct acting anti-viral treatment, but there are still some non-responders that could benefit from CD8+ T cell response restoration. To become fully reactive, T cell needs the complete release of T cell receptor (TCR) signalling but, during exhaustion this is blocked by the PD-1 effect on CD28 triggering. The T cell pool sensitive to PD-1 modulation is the progenitor subset but not the terminally differentiated effector population. Nevertheless, the blockade of PD-1/PD-L1 checkpoint cannot be always enough to restore this pool. This is due to the HCV ability to impair other co-stimulatory mechanisms and metabolic pathways and to induce a pro-apoptotic state besides the TCR signalling impairment. In this sense, gamma-chain receptor cytokines involved in memory generation and maintenance, such as low-level IL-2, IL-7, IL-15, and IL-21, might carry out a positive effect on metabolic reprogramming, apoptosis blockade and restoration of co-stimulatory signalling. This review sheds light on the role of combinatory immunotherapeutic strategies to restore a reactive anti-HCV T cell response based on the mixture of PD-1 blocking plus IL-2/IL-7/IL-15/IL-21 treatment.
Background Autoimmune myocarditis is a cause of dilated cardiomyopathy and heart failure. Recent studies have indicated that leaky gut may allow environmental factors to enter the body and trigger the initiation/development of autoimmune disease. Moreover, there is a growing literature supporting that, beside myocardial fibrosis, a leaky intestinal barrier and gut dysbiosis are pathogenic factors linked to heart failure. The natural triterpene oleanolic acid (OA) has been shown to beneficially influence the severity of the experimental autoimmune myocarditis (EAM), a preclinical model of human myocarditis, via anti-oxidant and immunomodulatory mechanisms. Herein, we investigate gastrointestinal (GI) disturbances and the gut microbiota composition associated with EAM as potential therapeutic target of OA. Methods and results BALB/c mice were α-myosin-inmunized to induce EAM and treated with OA (25 mg/kg/day, i.p). On day 21, heart fibrosis and parameters related to gut damage such as oxidative stress (O2- ions, lipid peroxidation), gut permeability (D-lactate; I-FABP), inflammation and mucins were determined in serum and/or colon. Fecal microbial profiles were identified by 16S rRNA gene sequencing analysis. Firstly, histological analysis of hearts showed presence of fibrosis (Sirius Red stain) in EAM mice, whereas these effects were not detectable in myocardium from healthy or OA-treated EAM mice. In addition, OA preserved the mucin-containing goblet cells along the colon (Alcian Blue/PAS stain). Consistently, serum levels of the epithelial gut damage markers, including D-lactate and iFABP were significantly reduced in OA treated-EAM mice. The beneficial OA effects also included a decrease in the pro-inflammatory mediators sPLA2-IIA and IL-1β and a protection from the oxidative stress response (DHE stain and TBARS) in serum and colonic tissue of EAM-mice. Furthermore, gut microbiota composition showed a lower bacterial diversity and different relative abundance of certain bacterial taxa in EAM-mice compared to control mice. The families of Muribaculaceae, Lachnospiraceae, and Ruminococcaceae were significantly affected in EAM mice, and only Muribaculaceae recovered levels similar to the healthy-control group, after treatment with OA. Conclusion Our data show that in addition to the heart, the intestinal barrier and gut microbiota are altered in myocarditis, and that OA treatment could ameliorate this profile. Our data contribute to the idea that gut dysbiosis and GI dysfunction influences myocarditis pathogenesis, and provides new findings regarding the beneficial activity of OA in EAM, suggesting that it may be an interesting candidate to be explored for the treatment of human patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): MINECO, ISCIII, CIBERCV-ISCIII
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