Introduction
Autoimmune hepatitis (AIH) is a chronic, progressive inflammatory liver disease driven by autoimmune mechanisms. It is characterized by elevated serum aminotransferase levels, hypergammaglobulinemia with increased immunoglobulin G (IgG), the presence of positive serum autoantibodies, and moderate to severe interface hepatitis observed in liver histology.1 AIH has a global annual incidence of 1.37 per 100,000 population (1.11 for females and 0.22 for males) and a prevalence of 17.44 per 100,000 population (12.77 for females and 2.91 for males). The pooled annual incidence rate in Asia (1.31/100,000) is similar to that in Europe (1.37/100,000) and the Americas (1.00/100,000); however, the pooled prevalence rate in Asia (12.99/100,000) is lower than that in Europe (19.44/100,000) and the Americas (22.80/100,000).2 AIH may manifest as either asymptomatic or acute hepatitis, and it can progress to more severe conditions such as severe hepatitis, liver fibrosis, or cirrhosis. In extreme cases, it may lead to acute liver failure or end-stage liver disease.3
Currently, immunosuppressive therapy remains the predominant treatment modality for AIH. Without treatment, patients with moderate to severe AIH have a significantly poor prognosis. Immunosuppressive therapy has been demonstrated to improve liver function test results, alleviate clinical symptoms, and enhance patient survival rates.4 Corticosteroids and azathioprine are first-line drugs for the treatment of AIH and are often used in combination. The short-term use of corticosteroids may be safe, with minimal adverse reactions, and is highly effective in mitigating hepatic inflammation.2 However, prolonged utilization of corticosteroids is associated with a range of side effects, including an increased risk of gastrointestinal bleeding, endocrine disorders, osteoporosis, diabetes mellitus, and weight gain.5 Furthermore, some patients fail to achieve biochemical remission despite standard therapy, which significantly impacts the prognosis of AIH.2 The pathogenesis of AIH is associated with an imbalance among genetic susceptibility, molecular mimicry, and the interplay between effector and regulatory immune responses.6 In AIH, the intricate network of immune cells, signaling pathways, and their interactions plays a critical role in disease pathogenesis. Research has demonstrated that factors such as the loss of self-tolerance in regulatory T (Treg) cells, accelerated activation of effector T cells, increased proliferation of autoreactive B cells, and heightened activity of natural killer cells are all implicated in the progression of AIH.7 Consequently, several researchers have proposed innovative immunomodulatory agents for the treatment of AIH, and their efficacy has been validated through various studies (Table 1).8–13 This section provides an overview of the novel immunomodulators that are currently primarily utilized in the treatment of AIH, along with their mechanisms of action.
Table 1Characteristics of major immunomodulators
| Classes | Suggested dosages (cannot be universally administered, but levels should be monitored) | Potential side effects |
|---|
| Immune cell nucleic acid inhibitor | MMF: 1.5–2 g/day | Infections, diseases of the blood and immune system, gastrointestinal reactions, etc. |
| Calmodulin phosphate inhibitors | Cyclosporin: 2–3 mg/kg/day; Tacrolimus: 1–6 mg/day | Renal insufficiency, tremor, hirsutism, hypertension, diarrhea, anorexia, nausea, vomiting, etc. |
| mTOR inhibitor | Sirolimus: 1–2 mg/ day | Hyperlipidemia, proteinuria and edema, etc. |
| TNF-α inhibitor | Infliximab: 5 mg/kg at day 0, weeks two and six, and thereafter every four to eight weeks depending on laboratory and clinical course | Infection, gastrointestinal reactions, headache, fatigue, allergic reactions, hepatitis, or liver function impairment, etc. |
| Anti-CD20 monoclonal antibody | Rituximab: 1,000 mg, two weeks apart | Delayed neutropenia, immune reconstitution deficiency with associated immune dysfunction, infection, progressive multifocal leukoencephalopathy, hepatitis reactivation, intestinal perforation and interstitial pneumonia, induced AIH, etc. |
| BAFF inhibitor | Belimumab (At present, it has not been formally approved by major global regulatory bodies, and the standard dose has not been clarified, refer to the dose standard for treating SLE):10mg/kg, once every two weeks (first three times) and once every four weeks thereafter | Infections, allergic reactions, neurological symptoms (headache, depression, anxiety, etc.), gastrointestinal discomfort, blood abnormalities (affecting platelets, white blood cell counts), etc. |
| IL-2 | IL-2 (At present, it has not been formally approved by major global regulatory bodies, and the standard dose has not been clarified, refer to the dose standard for treating SLE): 500,000, one million IU/day, once every other day, subcutaneous injection, two weeks for one course of treatment | Infection, gastrointestinal reaction, capillary leakage, abnormal liver and kidney function, abnormal blood system (such as leukopenia, anemia, thrombocytopenia), etc. |
Immune cell nucleic acid inhibitor
Nucleic acid inhibitors primarily target the metabolic pathways of nucleic acids in pathogens, inhibiting their proliferation by suppressing DNA and RNA synthesis. The main representative medication is mycophenolate mofetil (MMF), an immunosuppressive agent that functions as a nucleoside analog inhibitor. It specifically targets inosine monophosphate dehydrogenase (IMPDH), thereby inhibiting the de novo synthesis of guanosine monophosphate, which ultimately suppresses DNA synthesis. IMPDH is a rate-limiting enzyme in purine synthesis, and the proliferation of T cells and B cells critically depends on this metabolic pathway.14 MMF inhibits the proliferation of T and B cells by suppressing IMPDH and is utilized in the treatment of AIH.15 In animal experiment, MMF was observed to significantly increase the proportion of apoptotic T and B cells in colitis mice, particularly CD19+ B cells. Additionally, MMF pretreatment led to a downregulation of Th1 cytokines (tumor necrosis factor (TNF)-α, interferon (IFN)-γ) and an increase in CD4+CD45RB (low) Treg cells. These findings suggest that MMF pretreatment can reduce the expanded B cell population through enhanced apoptosis and increased Treg cell activity.16
A randomized controlled trial examined the efficacy of MMF in combination with prednisolone versus azathioprine combined with prednisolone in a cohort of 70 patients newly diagnosed with AIH. At six months, the MMF group exhibited a higher rate of complete biochemical response. Notably, no severe adverse reactions were observed in patients receiving MMF. In contrast, four patients in the azathioprine group experienced severe adverse reactions. Additionally, treatment discontinuation due to adverse events was reported in two patients in the MMF group and eight patients in the azathioprine group.8 A single-center retrospective study collected data from 160 patients diagnosed with AIH and screened 144 patients who met the inclusion criteria, of whom 58 received MMF treatment. The study specifically examined the treatment response and baseline characteristics of 50 patients receiving MMF as a second-line therapy. The findings indicated that MMF demonstrated favorable efficacy and tolerability in AIH patients. Notably, among those intolerant to first-line treatments, 81% achieved remission with MMF monotherapy.17 Furthermore, a meta-analysis revealed that the remission rate achieved with the combination of MMF and prednisone was significantly higher than that observed with the standard treatment.18 In a retrospective analysis of 292 AIH cases, 183 patients received MMF therapy. The MMF cohort exhibited a significantly lower non-response rate and achieved a higher complete biochemical response rate at the 12-month follow-up.19 In a propensity-matched study involving 64 adult AIH patients, 32 received MMF treatment. At the end of the follow-up period, the overall efficacy in the MMF group was significantly higher compared to the azathioprine group.20 A retrospective analysis involving 131 AIH patients, 109 of whom received either MMF or prednisolone, followed up over an extended period to assess outcomes following drug discontinuation. This study demonstrated the high efficacy and favorable safety profile of MMF as a first-line treatment for AIH. Notably, for the first time, it was observed that under strict remission criteria, the rate of maintaining complete remission after MMF withdrawal reached up to 75%.21 In a prospective study, 59 well-defined, treatment-naive patients with AIH were administered combination therapy consisting of prednisone and MMF, with MMF treatment lasting for 26 months. Eighty-eight percent (88%) of the patients exhibited initial clinical and biochemical responses, marked by the normalization of aminotransferase and γ-globulin levels, with the majority achieving this response within three months. The remaining 12% of patients achieved partial remission.22
Based on these findings, the Hellenic Association for the Study of the Liver recommends MMF as a primary treatment option, particularly in specialized centers dedicated to AIH.23 These studies suggest that MMF not only exhibits superior safety compared to traditional immunomodulatory agents but may also demonstrate enhanced efficacy. However, the existing clinical research data are limited, necessitating further evidence-based studies to substantiate these findings.
Calmodulin phosphate inhibitors
Calcium/calmodulin-dependent protein phosphatase is a serine/threonine-specific phosphatase that functions in a calcium and calmodulin-dependent manner. This enzyme dephosphorylates the transcription factor nuclear factor of activated T (NFAT) cells within the cytoplasm of activated T cells, leading to its translocation to the nucleus. The activated NFAT cells then upregulate the expression of interleukin (IL)-2, stimulating T-cell proliferation and differentiation.24 Calcineurin inhibitors selectively bind with high affinity to specific cytoplasmic receptors of immunophilins, such as cyclophilin and FK-binding protein. By inhibiting calcineurin, calcineurin inhibitors effectively block the transcription of IL-2 and other cytokines in T lymphocytes, thereby suppressing T cell activation, proliferation, and differentiation.25 The primary representative drug is tacrolimus, which, upon entering the cytoplasm, binds to FKBP12. This interaction inhibits calcineurin activity and prevents the nuclear translocation of the NFAT transcription factor, which is crucial for IL-2 gene transcription. Consequently, T cell activation is suppressed, resulting in reduced cytokine production. Additionally, this suppression also diminishes B cell activation, class switching, and immunoglobulin production (Fig. 1).26 In animal experiment, it has been demonstrated that tacrolimus can effectively reduce the populations of Th2 and Th17 cells in lupus-prone mice, as well as suppress the production of IFN-γ and IL-17A.27 The plasma concentrations of IFN-γ and IL-12p70 in tacrolimus-treated mice with immune thrombocytopenia were significantly decreased.28 These findings suggest that tacrolimus exerts its effects in AIH through the inhibition of T cell activation and cytokine production.
A multicenter study reported on 23 patients with AIH who were treated with tacrolimus. Among these patients, 18 demonstrated a sustained biochemical response, and only one patient discontinued tacrolimus due to severe adverse reactions.29 A retrospective analysis of data from 13 centers across Europe, the United States, and Canada revealed that among 38 pediatric AIH patients under 18 years of age who received second-line treatment (18 with MMF and 20 with tacrolimus), 71.1% achieved biochemical remission through the use of either tacrolimus or MMF. The study findings suggest that pediatric AIH patients generally tolerate long-term treatment with either MMF or tacrolimus well.30 Furthermore, cyclosporine has been shown to play a significant role in the management of pediatric AIH. A retrospective study assessed the efficacy and tolerability of cyclosporine treatment in 15 pediatric and adolescent patients with type 2 AIH. Eight patients received cyclosporine as the primary immunosuppressant, while the remaining five patients, who experienced recurrent AIH and were unwilling to resume steroid therapy, were treated with cyclosporine. Within six months, alanine aminotransferase (ALT) levels normalized in both groups.31 Another systematic review also demonstrated comparable therapeutic outcomes. Data were collected from 2,260 AIH patients across 19 centers in Europe, the United States, Canada, and China. Among these, 201 AIH patients received second-line treatment, with 121 treated with MMF and 80 treated with tacrolimus. The final analysis revealed no statistically significant difference in the proportion of patients achieving complete remission between MMF (69.4%) and tacrolimus (72.5%).32 Clinical research has demonstrated that patients with AIH undergoing tacrolimus treatment can achieve both biochemical remission and histological improvement. A meta-analysis of 162 adult AIH patients treated with tacrolimus revealed that 121 patients achieved complete biochemical remission. Furthermore, among the 30 patients who underwent liver biopsy post-treatment, 25 exhibited histological improvement as assessed by inflammation grade or fibrosis stage.33 It is evident that calmodulin phosphate inhibitors represent a viable second-line therapeutic option for AIH patients who are either intolerant or unresponsive to standard therapy, with these patients showing good tolerability to the treatment. However, several studies have demonstrated that patients treated with calcineurin inhibitors tend to undergo a longer treatment duration compared to those receiving other second-line therapies.34 Additionally, patients receiving tacrolimus may experience adverse effects such as tremors, nausea, diarrhea, and vertigo.34 Furthermore, the use of tacrolimus is associated with potential risks of nephrotoxicity, neurotoxicity, and metabolic abnormalities.35 Therefore, the selection of tacrolimus as a second-line treatment should be individualized based on patient-specific factors.
Mammalian target of rapamycin (mTOR) inhibitor
The mTOR pathway regulates cellular metabolism, growth, and proliferation through the formation and signaling of two protein complexes, mTORC1 and mTORC2. Additionally, it modulates the proliferation and survival of activated lymphocytes.36 mTOR inhibitors effectively block the aberrant signal transduction of multiple growth factors, thereby inhibiting disease progression by suppressing the mTOR signaling pathway. A primary representative drug is sirolimus, which works by inhibiting the mTOR and modulating proteins involved in the proliferation and survival of activated lymphocytes.37 Sirolimus forms an immunosuppressive complex with the intracellular protein FKBP12, which inhibits the activation of the cell cycle-specific kinase mTOR. This inhibition results in the arrest of cell cycle progression at the G1/S phase boundary due to mTOR inactivation.38 In animal experiment, it has been demonstrated that sirolimus effectively inhibits the production of high levels of autoantibodies in lupus mice. Compared to untreated controls, all IgG subclasses were significantly reduced in the treated group.39 These findings suggest that sirolimus may have potential as a treatment for AIH.
In a study examining the incidence of AIH following liver transplantation, patients who exhibited no response to treatment with prednisone and azathioprine/MMF were effectively managed by escalating the prednisone dosage and incorporating sirolimus into their maintenance immunosuppressive regimen.40 MMF and sirolimus constitute a safe and effective immunosuppressive therapy for autoimmune cytopenias and immune dysregulation syndromes. An experiment have demonstrated that in patients treated with MMF or sirolimus, the incidence of severe infection events is relatively low, with only 13% of patients experiencing events that required hospitalization or intravenous antimicrobial therapy.41 The research suggests that sirolimus could serve as a potential therapeutic option for patients with refractory AIH, with a relatively low incidence of adverse events. However, given the limited scope of current research, further prospective studies are needed to comprehensively evaluate the efficacy and safety of sirolimus as a viable treatment modality for refractory AIH.
TNF-α inhibitor
TNF is a pro-inflammatory cytokine primarily synthesized by lymphocytes and activated monocytes/macrophages. It is also produced in smaller quantities by other immune cells, including dendritic cells, neutrophils, and mast cells, as well as by non-immune cells such as keratinocytes and fibroblasts.42 In the liver, TNF mediates hepatocyte death by inducing liver damage through the activation of JNK2-dependent caspase-8 and mitochondrial apoptosis pathways (Fig. 2).43 Research has demonstrated that reduced levels of TNF-α may contribute to the development of systemic lupus erythematosus (SLE) in genetically susceptible mice.44 An experiment shows that anti-TNF-α therapy effectively decreases the frequencies of splenic TNF-α+CD4+ and TNF-α+CD8+ T cells, as well as effector memory T cells in peripheral blood, lymph nodes, and lungs.45 In patients with autoimmune liver disease, serum levels of pro-inflammatory cytokines, including IL-6, IL-8, and TNF-α, are significantly elevated.46 Therefore, TNF-α inhibitors are considered a promising therapeutic option for AIH, potentially offering significant clinical benefits.
Currently, the TNF-α inhibitors used to treat autoimmune diseases primarily include etanercept, adalimumab, and infliximab.47 The primary representative drug, infliximab, is a recombinant chimeric monoclonal antibody (75% human and 25% murine) targeting TNF-α. It consists of the human IgG1κ constant region and the Fv region from a high-affinity neutralizing mouse anti-human TNF-α antibody. Infliximab has a half-life of eight to ten days and exhibits high affinity for both soluble and membrane-bound forms of TNF-α, effectively inhibiting the binding of the ligand to its receptor. Additionally, infliximab exerts its therapeutic effects by inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, thereby destroying cells that express TNF-α.48 Infliximab has demonstrated efficacy in treating a range of inflammatory conditions, such as rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and Crohn’s disease. Additionally, infliximab has been investigated in several clinical studies for the treatment of AIH.49 In a clinical study, 11 AIH patients who were intolerant to azathioprine or experienced severe adverse effects from standard therapy were treated with infliximab, leading to biochemical remission in 60% of the cases.50 A retrospective study across 21 liver centers in 12 countries involving 42 AIH patients treated with infliximab demonstrated that 65% of patients with active AIH achieved complete biochemical remission during the course of infliximab therapy.9 These studies suggest that infliximab may serve as a potential salvage therapy for refractory autoimmune hepatitis. However, anti-TNF-α therapy may have dual effects. Infliximab treatment could increase patients’ susceptibility to severe infections. Specifically, in patients with cirrhotic autoimmune hepatitis, who already experience immune system dysregulation, infliximab treatment may exacerbate the risk of severe infections, thus increasing the likelihood of serious infection-related complications.51 In a separate study, the administration of anti-TNF drugs to patients with compensated cirrhosis was found to have no significant impact on the risk of decompensation, severe infection, transplant-free survival, or malignancy development.52 Furthermore, a case reports have highlighted the potential risk of infliximab inducing autoimmune hepatitis, a condition that may necessitate liver transplantation.53 Hence, when contemplating the utilization of infliximab, it is imperative to thoroughly assess its potential adverse effects.
Anti-CD20 monoclonal antibody
CD20 is a membrane antigen that does not bind to any specific physiological ligands.54 While its precise functional role remains undefined, it has been demonstrated to play a significant role in regulating B cell differentiation and proliferation.55 CD20 is an integral component of a cell surface complex that regulates calcium transport. Specifically, CD20 modulates calcium influx, thereby initiating intracellular signaling cascades.56 Autoreactive B cells can contribute to autoimmunity through multiple mechanisms upon binding to self-antigens. These mechanisms include presenting antigens to autoreactive T cells, producing autoantibodies that activate complement or promote phagocytosis, secreting cytokines that drive Th1/Th2/Th17 differentiation pathways, and inhibiting the function of regulatory T and B cells.57–61 Recent evidence increasingly underscores the pivotal role of B cells in AIH. Animal experiment have demonstrated that, B cells secrete pro-inflammatory cytokines and contribute to regulating T cell activation and proliferation. Depletion of B cells has been shown to reduce the presentation of autoantigens, thereby diminishing T cell activation and proliferation, which subsequently alleviates the progression of AIH (Fig. 3).62 These findings suggest that B cells are critically involved in the pathogenesis and perpetuation of AIH, and that B cell depletion may represent a promising therapeutic strategy for managing AIH.
The primary anti-CD20 therapeutic agents include rituximab, Ofatumumab, Obinutuzumab, and Ocrelizumab.63 Among these, rituximab is the most widely utilized. It is a genetically engineered chimeric (mouse/human) monoclonal antibody that specifically targets the CD20 antigen present on both normal and malignant B cells.64 By binding to CD20 molecules on the cell membrane, rituximab initiates the C1q complement cascade, thereby promoting cell death via complement-dependent cytotoxicity and apoptosis. Activation of the C1q cascade results in the deposition of complement components on the cell surface, further enhancing the cytotoxic effect.65 Rituximab was first approved in 1997 for the treatment of non-Hodgkin lymphoma and has since been approved for the management of rheumatoid arthritis. Extensive clinical studies have confirmed its efficacy in treating refractory diseases, such as autoimmune hematologic disorders, dermatological conditions, primary biliary cholangitis, and autoimmune hepatitis.66–69 In a preliminary open-label, single-center study, six patients with biopsy-confirmed AIH, who had previously failed to respond to treatment with prednisone and azathioprine, were administered two infusions of rituximab. This resulted in a significant reduction in aspartate aminotransferase (AST) levels, a decrease in average IgG levels, and no serious adverse events were observed.69 In a multicenter, international retrospective cohort study, clinical data from 22 AIH patients treated with rituximab at centers in the United Kingdom, Germany, and Canada between 2007 and 2017 were collected. Following rituximab therapy, there was a significant reduction in ALT, AST, and globulin levels.70 These studies suggest that rituximab demonstrates efficacy in the treatment of AIH; however, the current body of clinical research is limited, and additional clinical data are required to substantiate these findings. Despite its therapeutic benefits, rituximab administration may be associated with a spectrum of adverse reactions, such as delayed neutropenia, immune reconstitution inflammatory syndrome leading to immune dysfunction, heightened susceptibility to infections, progressive multifocal leukoencephalopathy, hepatitis reactivation, intestinal perforation, and interstitial pneumonia.71 Hence, when considering rituximab for treatment, it is imperative to thoroughly assess all potential adverse reactions.
B cell-activating factor (BAFF) inhibitor
B cells are pivotal in the pathogenesis of autoimmune diseases through the production of autoantibodies, secretion of cytokines, and presentation of self-antigens. BAFF, primarily synthesized by stromal and myeloid cells, serves as a critical survival factor that supports B cell maturation and homeostasis across different stages of B cell differentiation(Fig. 4).72 B cell survival is enhanced through the downregulation of pro-apoptotic molecules such as Bak, Blk, and Bim, while simultaneously upregulating anti-apoptotic molecules including Bcl-2, Bcl-xL, and Mcl-1. BAFF also promotes the survival of high-affinity B cell clones and stimulates immunoglobulin class switch recombination.73 Research demonstrates that the overexpression of BAFF in mice leads to a substantial expansion of activated B cells and marginal zone B cells, as well as elevated hypergammaglobulinemia and increased autoantibody production.74,75 The blockade of BAFF has been shown to significantly alter the immune microenvironment within the spleens of lupus mice, modulating the B cell receptor repertoire and concurrently decreasing serum immunoglobulin levels, splenic IL-10 mRNA levels, and serum IL-10 protein levels.76 Based on these findings, inhibiting BAFF may represent a promising therapeutic strategy for AIH.
BAFF inhibitors include a range of agents, such as belimumab, tarextumab, blisibimod, and ianalumab. Notably, belimumab is a human monoclonal antibody of the immunoglobulin G1λ subclass that specifically binds to soluble BAFF, thereby inhibiting its interaction with receptors.77 It is currently the only approved biologic agent for the treatment of non-renal SLE.78 A randomized, double-blind, placebo-controlled phase III clinical trial has demonstrated the safety and efficacy of belimumab in managing SLE across a diverse patient population. Belimumab specifically inhibits soluble B lymphocyte stimulator, providing novel therapeutic avenues for this significant autoimmune disorder. Furthermore, belimumab has been shown to improve serological activity, reduce disease flares, enhance quality of life, and decrease steroid usage. Serious adverse reactions are rare and generally reversible.79 In a retrospective study, the treatment responses of six patients with AIH or primary biliary cholangitis who received anti-BAFF therapy at the University Hospital of Bern, Switzerland, were evaluated. Among these patients, belimumab was administered to three AIH patients, alleviating disease symptoms and mitigating the adverse effects associated with corticosteroids and calcineurin inhibitors.80 Another study described two AIH patients treated with belimumab; both achieved complete remission, and no adverse events attributable to belimumab were observed during the treatment period.12 These studies suggest that anti-BAFF therapy may serve as a potential adjunctive treatment for autoimmune diseases, with belimumab possibly representing a promising therapeutic option for patients with AIH. However, additional studies are warranted due to the current paucity of case data.
IL-2
Human IL-2 is a cytokine encoded by a gene located on chromosome 4q27. IL-2 was the first cytokine to be molecularly cloned and serves as a crucial growth factor for T cells, facilitating their proliferation and the development of effector and memory T cell populations.81 Low-dose IL-2 can selectively expand the Treg population, a critical subset of T cells that plays an essential role in maintaining immune homeostasis.82 Low-dose IL-2 treatment not only augments the number of Tregs but also potentiates their immunosuppressive function. Peripheral blood mononuclear cells are exposed to nanogram-per-milliliter concentrations of IL-2, activating the Janus kinase/signal transducer and activator of transcription pathway. This activation ultimately results in the upregulation of FoxP3 expression. The increase in FoxP3 levels enhances the suppressive capacity of Tregs and modulates the immune response through the regulation of multiple downstream pathways (Fig. 5).83 Studies by Diestelhorst et al. suggest that AIH patients who fail to achieve biochemical remission following corticosteroid therapy often exhibit a deficiency in IL-2 and impaired Treg function.84 Based on the high affinity of Tregs for IL-2, Buitrago-Molina et al. administered IL-2/anti-IL-2 complexes to mice with AIH. Following treatment, a significant increase was observed in the frequency of Tregs and the ratio of Tregs to CD4+ T cells in peripheral blood, spleen, and liver. Concurrently, ALT levels were markedly reduced.85 Low-dose IL-2 therapy enhances the frequency and sensitivity of Tregs to IL-2 in patients with refractory AIH, whereas other immune cell populations show no significant changes.86
In a multicenter, interventional, open-label study, the efficacy of low-dose IL-2 therapy was evaluated in patients with 11 autoimmune diseases, including AIH. The findings indicated that low-dose IL-2 treatment significantly increased the proportion of Tregs and modified the Treg-to-effector T cell ratio. Additionally, this therapeutic approach demonstrated improvements in disease activity and severity, suggesting that low-dose IL-2 may represent a promising therapeutic strategy for autoimmune diseases.87 A preliminary clinical trial demonstrated that low-dose IL-2 therapy significantly enhances liver function and immune regulation in patients. The study revealed that low-dose IL-2 administration effectively lowered serum AST levels, increased the proportion of Tregs, and augmented Treg sensitivity to IL-2.88 These findings suggest that low-dose IL-2 represents a promising novel therapeutic strategy for refractory AIH.
Conclusions
Emerging immunoregulatory agents currently under investigation have demonstrated promising effects in the management of AIH by modulating T-cell activity, inhibiting cytokine production, promoting anti-inflammatory responses, and regulating B-cell function (Fig. 6). Preliminary clinical studies have also indicated that some of these compounds exhibit favorable efficacy and safety profiles. Compared to traditional immunosuppressants, novel immunomodulators offer superior target specificity and a reduced incidence of adverse effects, presenting promising new directions for both research and clinical management of AIH. However, it is important to note that clinical data on these new immunomodulators in the context of AIH treatment remain limited. Key challenges, such as accurately selecting suitable candidates for treatment, minimizing post-treatment complications, and optimizing combination therapy to maximize patient outcomes, require further investigation.
Declarations
Funding
This work was supported by the Yunnan Revitalization Talent Support Program; Priority Union Foundation of Yunnan Provincial Science and Technology Department and Kunming Medical University (202401AY070001-245); The “535” High-level Talent Disciplinary Leader Project of the First Affiliated Hospital of Kunming Medical University (2023535D14).
Conflict of interest
The authors have no conflicts of interest related to this publication.
Authors’ contributions
Conception and design (HL, JLi), provision of study materials (all authors), figure drawing (JLi, HW), manuscript writing (JLi), and revisions and final approval of the manuscript (HL). All authors proved the final version and publication of the manuscript.