The autoimmune hepatitis AIH is liver diseases which characterized by impaired immunity Essay

The autoimmune hepatitis (AIH) is liver diseases which characterized by impaired immunity. The exact mechanism and developing of the AIH is not fully investigated and it can be suggested that genetic, environmental and dietary factors can be involved. AIH in patients can be completely asymptomatic or can display acute or fulminant hepatic failure (Than, Jeffery & Oo, 2016). Some of the symptoms of the AIH are general ill health, weight loss, malaise, anorexia.The biochemical markers of the disease are elevated serum transaminase level, serologically elevated levels of immunoglobulin G (IgG) with increased levels of anti-smooth muscle antibodies (ASMA) or with increased anti-nuclear antibodies (ANA), soluble liver antigen (SLA) and anti-liver-kidney-microsomal antibodies (anti-LKM) (Wies et al.

, 2000).Type 1 AIH is characterized by the presence in serum of ASMA or ANA with increased level of IgG. Type 1 present in about 65% of patients with AIH. Type 2 AIH is usually observed among children and characterized by the elevated anti-LKM antibodies with increased IgG levels (Mieli-Vergani & Vergani, 2014). Acute onset of AIH and its treatment is mediated through innate immune responselike innate lymphoid cells and natural killer cells (Oo & Adams, 2014).

On the other side, chronic AIH disease is mediated through CD8 T and effector CD4 cell immune response in liver cells (Oo, Hubscher & Adams, 2010). The T regulatory cells (Treg) derived from the thymus are characterized by the surface markers CD4+CD25highCD127low and by the transcription factor FOXP3+, playing important role in pathogenesis of AIH (Liu et al., 2006). In the peripheral blood of AIH patients was observed the decrease in frequency and impairment in function of CD4+CD25high Treg cells (Longhi et al., 2006). On the other side there were observed the parallel increase in Treg cells frequency with the increase of effector cells in the inflamed liver (Oo et al., 2010). The balance of Th1, Th17, cytotoxic and Treg cells may influence the duration and severity of the hepatitis. Sudden onset of AIH was characterized by increase of the effector T cell (Teff) with increase of Tref and B cells in liver tissue (Taubert et al., 2014). Patients with untreated AIH have parallel ration of Treg and Teff, while patients with biochemical remission have higher ratio of Treg/Teff and Treg/B cell ratios (Taubert et al., 2014). Conventional treatment consists of the prescription of immunosuppressive glucocorticoids drugs like prednisone, which can be used with or without azathioprine like Imuran. The remission is achieved in 60 or 80 percent of cases and many of patients (Than, Jeffery & Oo, 2016). In serious case where patient do not respond to immunosuppressive drugs usually suggested liver transplantation.Those patient with chronic AIH disease who do not respond to immunosuppressive drugs could be suggested alternative therapy based on the usage of the chimeric antigen receptor Treg (CAR-Treg) cells. Tregs cells can inhibit autoimmunity in animal models. Polyclonal Treg cells used on to attenuate type 1 diabetes shown the preservation of beta cells function and increasing the survival of pancreatic islet survival (Bluestone et al., 2015). While the usage of polyclonal Treg cells had some success their drawbacks still limits their usage. Those limitation are the need for the large amount of cells for infusion and the risk of non-specific immunosuppression. There was reported a case with viral reactivation after the polyclonal Treg infusion (Brunstein et al., 2013). On the other hand, these limitations can be overcome by the usage antigen-specific Tregs. Antigen specific Treg cells need less cells and can have more localized and targeted effect than polyclonal Treg cells (Boardman, Maher, Lechler, Smyth & Lombardi, 2016).Production of antigen specific Treg cells through presenting of APCs is not efficient, due to there are only few antigen-specific Treg cells in polyclonal cells. The usage of the engineered Treg cells with TCR (TCR-Treg) looks encouraging, but it still has MHC-restriction limiting it usage in patients (Brusko et al., 2010). MHC-independent strategy to produce antigen specificity will be usage of the Tregs transduced to express chimeric antigen receptor (CARs). CARs have single-chain variable fragment (scFv), which is binding part of monoclonal antibody, transmembrane region and intracellular signal domain. Initial usage of CAR technology is for cancer immunotherapies, and the usage CAR technology in Treg cells is extension of it. CAR-Treg has great potential to treat autoimmune disease. Skuljec et al. used CEA-CAR-Treg cells, since CEA is mostly present on the surface of adenoepithelia in the lung, towards the lung epithelia of a mouse model with induced allergic asthma (Skuljec et al., 2017). CEA-CAR-Treg cells in mice were activated and accumulated in the lungs tissue, reducing airway hyperactivness and eosinophilic airway inflammation. These results were more efficient than in polyclonal Treg cells (Skuljec et al., 2017).Based on the results from these studies it could be suggested that usage of the CAR-Treg with hepatocyte specific antigen should produce anti-inflammatory results better that using polyclonal cells and cause life-long remission. The problem of the Treg cells in the AIH is that due to the microenvironment in liver cells is deficient in IL-2 cytokine leading to impaired function.The advantage of the CAR-Treg cells is that they can migrate specifically to the organ of interest which has specific antigen, this generated less side effects. Also using CAR-Treg cells in AIH deiseal is better due to the being non-MHC-restricted and being less IL-2 dependent than TCR-Tregs. The disadvantages of using this therapy is a risk of having cytokine storm and the need for the tissue particular antigen to target by CAR-Tregs. 2nd problem to overcome is the problem of the exhaustion of the CAR-Tregs. It can be solved by using 3rd generation CAR where included both CD 28 and CD 137 co-stimulatory domains, which were reported to reducing T cell exhaustion and therefore improving persistence (Long et al., 2015).The initial target of CAR-Tregs with hepatocyte specific antigen will be murine model which resembles human AIH (Hardtke-Wolenski et al., 2013). In case of success CAR-Tregs cells will be used in clinical trials with humans.

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