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Communication

RANTES, IP-10 and MCP-1 Profiles in Patients with Autoimmune Hepatitis (AIH) at Baseline and During Immunosuppressive Treatment

by
Giuseppe Colucci
1,*,
Enrico Sguazzini
1,
Sara Uceda Renteria
2,
Riccardo Perbellini
1,
Ferruccio Ceriotti
2,
Clara Dibenedetto
1,
Maria Francesca Donato
1 and
Pietro Lampertico
1,3
1
Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
2
Microbiology and Virology Unit and Clinical Pathology Laboratory, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
3
CRC “A. M. and A. Migliavacca” Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
*
Author to whom correspondence should be addressed.
Livers 2025, 5(2), 19; https://doi.org/10.3390/livers5020019
Submission received: 29 January 2025 / Revised: 10 March 2025 / Accepted: 1 April 2025 / Published: 23 April 2025
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Abstract

:
Background and aims: The CC5, CXC3, and CC2 chemokines (CK) are known to play a role in the pathogenesis of autoimmune hepatitis (AIH). However, no data are available on their potential utility as markers of disease progression or response to treatment. Material and methods: We analyzed their role as markers of remission in a population of patients with AIH. We retrospectively investigated the kinetics of RANTES (CCL5), IP-10 (CXCL10), and MCP-1 (CCL2) in 48 patients with AIH at the time of treatment initiation and also in 32 at biochemical, clinical and histological remission. Forty-nine healthy donors (HDs) served as controls. Results: At baseline, IP-10 and MCP-1 levels were higher in AIH patients than in HDs (261 vs. 101 pg/mL and 689 vs. 330 pg/mL, p < 0.01), and RANTES levels showed no differences. Correlations were observed between RANTES and IgG concentrations (r = 0.36 p = 0.04) and between IP-10 and Ishak’s grade (r = 0.52 p = 0.02). At remission, in 32 patients, while IP-10 and MCP-1 values showed a significant decrease from baseline reaching HD levels (261 vs. 106 pg/mL and 689 vs. 387 pg/mL, p < 0.01), RANTES did not. However, two kinetics patterns emerged, with 20 patients showing lower and 12 higher baseline RANTES values compared to HDs (29,450 pg/mL and 70,960 pg/mL vs. 52,010 pg/mL, p < 0.01). The former required longer treatment to reach remission and had higher Ishak’s grades than the latter (p < 0.01). Conclusions: RANTES, IP-10, and MCP-1 may help in predicting response to treatment and stable remission and in supporting the decision if and when to discontinue immune suppressive therapy.

1. Introduction

Chemokines (CKs) are small proteins produced and released by a variety of cell types, including endothelial cells, hepatocytes, immunological effector cells, lymphocytes and monocyte–macrophages. CKs are classified in two major groups, CC and CXC, depending on the position of the two cysteine (C) residues at their amino terminus, either adjacent (CC) or separated by one or more amino acid (CXC) [1,2]. CKs recognize and bind a variety of cellular transmembrane G protein-coupled receptors; some highly specific, others promiscuous [3]. By interacting with their cognate cell-surface receptors, CKs induce several distinct effects, including the recruitment and activation of different lymphocyte subpopulations both in physiological and pathological conditions [4,5]. They are also known to induce phenotypic changes on certain cell types, including hepatic stellate cells (HSCs) during liver inflammation, causing their conversion to myofibroblasts with an increase in matrix deposition [5,6]. The main inflammatory CKs, including RANTES, IP-10, and MCP-1, have been found to regulate the trafficking of immune cells into the liver with the recruitment of monocytes, macrophages, T lymphocytes, natural killer cells, and dendritic cells to the site of the lesion [7,8]. Several CK pathways are involved in causing liver diseases of different etiologies, including alcoholic and metabolic-associated steatosis, where MCP-1 and RANTES are known to induce necrosis and fibrogenesis [9]. In immune-mediated and autoimmune acute and chronic diseases, CKs play an important role as mediators of tissue injuries. This has been shown in several studies carried out in rheumatoid arthritis, LES, and a variety of endocrinological diseases, including autoimmune thyroiditis, Graves’ disease, type 1 diabetes, and Addison’s disease [10,11]. Autoimmune hepatitis (AIH) is a chronic liver disease with a worldwide prevalence of 10–24 in 105 cases and relevant direct (medical) and indirect (loss of productivity/quality of life) costs. AIH is characterized by immune-mediated liver injury and the presence of detectable anti-nuclear antibody (ANA), anti-smooth muscle antibodies (ASMAs), liver kidney microsomal type 1 antibodies (anti-LKM-1), and anti-soluble liver antigen–antibody (SLA). Severe inflammatory AIH infiltrates with a typical predominance of plasma cells, pathognomonic of the disease, is likely to be induced by the activation of several CK pathways, including RANTES and IP-10 [12,13,14]. In this respect, CKs could be useful as potential markers of disease activity, response to treatment, and predictors of relapse. They could potentially support the decision-making process for stopping immunosuppressive therapy in AIH, which is at the moment still an unmet need.
However, no consistent data are currently available on chemokines’ patterns, either during immunosuppressive treatment in patients with AIH or on their predictive role for stable remission.
In the present study, we investigated the pattern of circulating RANTES as well as IP 10 and MCP-1 in a representative group of patients with AIH at the beginning of immunosuppressive therapy and at the time of remission to analyze their association with response to treatment and confirmed remission.

2. Materials and Methods

2.1. Patients

In a retrospective, single-center study (conducted at the Gastroenterology and Hepatology Division, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan, Italy), 48 patients with AIH were enrolled. The diagnosis of AIH was based on serology, clinical chemistry, and liver histology findings, as recommended by current guidelines [15,16,17]. A liver biopsy was performed at baseline, before starting immunosuppressive treatment, and at clinical and biochemical remission in 15 patients. Remission is defined by the absence of symptoms related to hepatitis (clinical remission), the normalization of liver enzymes (biochemical remission), and the absence of significant inflammation or liver damage observed in liver biopsy samples (histological remission). A liver biopsy is indicated at remission when necessary to decide the dose of maintenance immunosuppression treatment and dose-tapering schedule. A total of 49 healthy blood donors (HDs) served as controls. Liver tissue sections were routinely processed and stained with hematoxylin-eosin (HE) and Masson’s trichrome staining. Fibrosis stage and activity were histologically defined according to Ishak’s score [18].

2.2. Chemokines Determination

Serum RANTES, IP 10, and MCP-1 levels were assessed in frozen serum samples collected at baseline and at the time of remission, using specific ELISA assays (Human CCL5/RANTES Quantikine ELISA Kit, Human CXCL10/IP-10 Quantikine ELISA Kit, and a Human CCL2/MCP-1 Quantikine ELISA Kit R&D System (Minneapolis, MN, USA)).
Stored frozen serial serum samples were available at the time of diagnosis and, in 32 patients, also at remission, defined by the absence of clinical signs and symptoms and the normalization of liver enzymes. Remission was induced by immunosuppressive treatment based on high doses of prednisone 1 mg/kg with subsequent serial dose reduction and the addiction of AZA. Non-responders and breakthrough patients, as well as those with low Thiopurine Methyltransferase (TPMT) concentrations, were treated with MMIF.
Patients gave their informed consent to data handling and sera use. The Institutional Review Board approved the study as compliant with the Good Clinical Practice Guidelines and the principles of the Declaration of Helsinki.

2.3. Statistical Analysis

Summary statistical analyses, including the unpaired and paired Student’s t-test for continuous variables, Mann–Whitney test, and Pearson correlation were calculated using the MedCalc™ program (MedCalc Software Ltd. (Ostend, Belgium)).

3. Results

3.1. Patients’ Characteristics

Forty-eight patients with AIH, whose epidemiological, biochemical, serological, and histological data are reported in Table 1, were included in the study. Most of the patients were females (60%) with a median age of 56 years. All patients presented with acute hepatitis and about 60% were hospitalized. Forty-nine HDs, 55% female, with median age of 43, served as controls.

3.2. At Diagnosis

As shown in Table 2, prior to treatment initiation (baseline), median IP-10 and MCP-1 levels were higher in AIH patients than in HDs (Figure 1a,b), while RANTES did not show any significant difference between groups (Figure 1c). Although most of these profiles did not correlate with other parameters, including liver enzymes, IgG, and histological staging scores, a significant correlation was observed between RANTES and IgG concentrations (r = 0.36, p = 0.04, Figure 2a) and between IP-10 and the Ishak’s grade score (r = 0.52, p = 0.02, Figure 2b).

3.3. On Therapy

Immunosuppressive treatment included primarily prednisone and azathioprine (AZT), with prednisone and mycophenolate mofetil in 10% of cases (Table 3). All patients achieved biochemical remission after 36 to 172 days of treatment (median 103 days).
In 32 patients, samples were available at clinical and biochemical remission for further analysis. Both IP-10 and MCP-1 levels showed a significant reduction compared to baseline and reached normal values in all patients (Table 4, Figure 3a,b).
While overall RANTES levels did not show any significant change compared to baseline, two different patients’ profiles were observed: 20 patients showed increasing and 12 decreasing values compared to baseline (Figure 4a–c). These patients’ levels, that at baseline were significantly higher or lower than in HDs (Figure 5a), reached normal values at remission (Figure 5b). The subpopulation of patients with baseline RANTES levels lower than HDs showed a significantly longer time to remission and higher Ishak’s grading score (Figure 6a,b).
We then analyzed patients who had CK levels in the upper distribution range (greater than the third quartile), and found no relevant associations with biochemical, clinical, and histological parameters for RANTES and MCP-1.
On the contrary, in the IP-10 values’ distribution, patients with higher than the 3° quartile levels (207 pg/mL) showed a significant longer treatment time to remission (Figure 6c) with frequent adjustments to the dose and duration of immunosuppressive therapy.

4. Discussion

Chemokines and their cognate receptors are known to be deeply involved in the pathogenesis of AIH [10]. In the present study, monitoring IP-10, MCP-1, and RANTES levels during immunosuppressive treatment showed their potential utility as markers of remission. IP-10 and MCP-1 baseline levels were significantly higher in patients with AIH than in HDs, suggesting their upregulation and role in the disease pathogenesis, consistent with previous observations in AIH and in HCV-related chronic hepatitis [19,20]. Increased levels of IP-10, a well-known pro-inflammatory CK, have been observed in acute and chronic liver diseases of different etiologies as well as in a variety of autoimmune diseases. In these conditions, IP-10 normalization is considered a marker of response to treatment and disease remission [21,22,23,24]. The significant correlation between IP-10 and Ishak’s grade further confirms its active pro-inflammatory role. A similar pattern of increased values, progressively returning to normal levels, was also seen in MCP-1, indicating its contribution in activating the immune/inflammatory response and its related liver damage that characterizes AIH [25,26,27]. MCP-1 is a potent recruiter of macrophages, the pro-inflammatory M1 subtype, and induces a cascade of events that, through the activation of other immunological effector cells and hepatic stellate cells (HSTs), lead to interface hepatitis and liver fibrosis [28].
The reduction in both IP-10 and MCP-1 levels during treatment to normal HD values at biochemical and histological remission support their prognostic/predictive role, as additional criteria to safely consider withdrawal of maintenance therapy. This is the most challenging aspect in the clinical management of AIH, as disease relapses are often observed while tapering immunosuppressive therapy and the decision on whether and when to discontinue maintenance treatment is still under debate [29,30,31,32]. Controversial observations have also been reported in other immune-mediated chronic diseases, including inflammatory bowel diseases and rheumatoid arthritis, indicating the need to develop panels with several serum cytokines and CK biomarkers as potential predictor of sustained remission [33,34,35]. In this respect, IP-10 levels higher than the 3° quartiles at biochemical remission, may suggest the need to prolong maintenance treatment, as they were associated with more frequent therapy breakthrough and longer time to remission.
As to RANTES, the significant correlation we found with IgG levels supports its involvement in inducing the autoimmune response. The different profiles we observed with baseline lower or higher values in AIH than in HD, with subsequent increasing or decreasing levels, may reflect an inhibition or induction of its release from different cell types. The apoptosis of liver resident cells, including hepatocytes, endothelial cells, Kupffer cells, may be responsible for the reduction in RANTES secretion and circulating levels. Of note, these patients tended to have a delayed remission, suggesting a more extended parenchymal damage with a slower rate of recovery. On the other hand, the recruitment of CCR5 positive immune effector cells that respond to RANTES stimulation may also produce and release RANTES [36,37]. In a recent study on patients with HCV-related decompensate cirrhosis and liver transplant recipients, we observed the same dynamics with increasing or decreasing RANTES values during the first 4 weeks of DAA-based antiviral treatment, approaching HD levels at virus eradication [38]. In this respect, normal or near-normal RANTES levels at remission could be considered useful to confirm response to treatment and stable disease remission. As also hypothesized in other autoimmune diseases, adjuvant treatment based on the agonist/antagonists of CK receptors may help in patients who are non-responders to immunosuppressive therapy [39,40,41,42].

5. Conclusions

The results of our study suggest that monitoring IP-10, MCP-1, and RANTES serum levels in patients with AIH may support the decision to discontinue immunosuppression following stable clinical and histological remission, as their normalization reflects the resolution of the immune-mediated pathogenic mechanisms. However, further research is required and we plan to validate these data on a prospective investigational study with a larger sample size and more frequent Ck monitoring at different time points during treatment and follow-up.

Author Contributions

Conceptualization, G.C.; Methodology, S.U.R.; Investigation, E.S.; Resources, R.P. and F.C.; Data curation, C.D. and M.F.D.; Supervision, P.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

We did not need a specific ethical committee approval and/or informed consent because we used retrospective, archived extra-aliquots of samples obtained during routine clinical follow-ups, with informed consent also containing the approval of any subsequent disease-related studies.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

Data are available upon request.

Acknowledgments

We thank Dario Consonni and Nancy Lowe for critically reviewing the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

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Livers 05 00019 g001
Figure 1. IP-10 (a), MCP-1 (b), and RANTES (c) values at baseline (Bas) in patients with AIH as compared to HDs. (* AIH Bas vs. HD1). Results are expressed as pg/mL.
Figure 1. IP-10 (a), MCP-1 (b), and RANTES (c) values at baseline (Bas) in patients with AIH as compared to HDs. (* AIH Bas vs. HD1). Results are expressed as pg/mL.
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Figure 2. Correlations between baseline RANTES values (pg/mL) and IgG (mg/L) (a) and between baseline IP-10 values (pg/mL) and Ishak’s grade (b). r = Pearson coefficient.
Figure 2. Correlations between baseline RANTES values (pg/mL) and IgG (mg/L) (a) and between baseline IP-10 values (pg/mL) and Ishak’s grade (b). r = Pearson coefficient.
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Figure 3. IP-10 (a) and MCP-1 (b) values at baseline (Bas) and at remission (Rem) in patients with AIH. (* AIH Bas vs. AIH Rem, p < 0.01) Results are expressed as pg/mL.
Figure 3. IP-10 (a) and MCP-1 (b) values at baseline (Bas) and at remission (Rem) in patients with AIH. (* AIH Bas vs. AIH Rem, p < 0.01) Results are expressed as pg/mL.
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Figure 4. Different profiles of RANTES values at baseline (Bas) and at remission (Rem) in 32 patients (a), of whom 20 and 12 with increasing (b) and decreasing (c) levels compared to baseline.
Figure 4. Different profiles of RANTES values at baseline (Bas) and at remission (Rem) in 32 patients (a), of whom 20 and 12 with increasing (b) and decreasing (c) levels compared to baseline.
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Figure 5. RANTES values at baseline (Bas) (a) and at baseline (Bas) and at remission (Rem) (b) in patients with AIH with decreasing (H) or increasing (L) levels at remission, compared to HDs. (* AIH H Bas vs. HD, p < 0.01, AIH L Bas vs. HD p < 0.01) (* AIH H Bas vs. AIH H Rem p < 0.01) (AIH L Bas vs. AIH L Rem, p < 0.01). Results are expressed as pg/mL.
Figure 5. RANTES values at baseline (Bas) (a) and at baseline (Bas) and at remission (Rem) (b) in patients with AIH with decreasing (H) or increasing (L) levels at remission, compared to HDs. (* AIH H Bas vs. HD, p < 0.01, AIH L Bas vs. HD p < 0.01) (* AIH H Bas vs. AIH H Rem p < 0.01) (AIH L Bas vs. AIH L Rem, p < 0.01). Results are expressed as pg/mL.
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Figure 6. Time to remission in days (a) and baseline Ishak’s grade score (b) in patients with RANTES decreasing (H) or increasing (L) baseline levels compared to HDs. (*AIH H vs. AIH L, p < 0.01). (c) Time to remission in patients with IP-10 levels at remission higher than the third quartile (>207 pg/mL) compared to those contained in the inter-quartiles’ range. (* IP-10 > 3°QR vs. IP-10 IQR, p < 0.01).
Figure 6. Time to remission in days (a) and baseline Ishak’s grade score (b) in patients with RANTES decreasing (H) or increasing (L) baseline levels compared to HDs. (*AIH H vs. AIH L, p < 0.01). (c) Time to remission in patients with IP-10 levels at remission higher than the third quartile (>207 pg/mL) compared to those contained in the inter-quartiles’ range. (* IP-10 > 3°QR vs. IP-10 IQR, p < 0.01).
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Table 1. Patients’ baseline parameters.
Table 1. Patients’ baseline parameters.
Baseline ParametersPatients (n. 48)
Age [years] *56.5 (20–83)
Males 20 (41.7%)
Histological grading [Ishak] *
    G4–G820 (42%)
    G9–G1224 (50%)
    G13–G184 (8%)
Histological staging [Ishak] *
    S1–S340 (83%)
    S4–S68 (17%)
Autoantibodies
    ANA- and SMA-positive26 (54%)
    ANA-positive18 (38%)
    SMA-positive 4 (8%)
Total bilirubin [mg/dL] *2.05 (0.4–29.8)
Direct bilirubin [mg/dL] *2.06 (0.1–20.9)
AST [U/L] *849 (112–3396)
ALT [U/L] *1107 (149–6059)
GGT [U/L] *254 (16–1470)
ALP [U/L] *135 (49–530)
IgG [mg/dL] *2033 (1169–5178)
Gamma-globulins [g/dL] *2.3 (1.11–4.54)
* median (range). AST: aspartate amino transaminase; ALT: alanine amino transaminase; GGT: gamma-glutamyl transpeptidase; ALP: alkaline phosphatase; ANA: anti-nuclear antibodies; SMA: smooth muscle antibodies.
Table 2. Median levels of IP-10, MCP-1 and RANTES at baseline compared to HD (healthy donor) controls.
Table 2. Median levels of IP-10, MCP-1 and RANTES at baseline compared to HD (healthy donor) controls.
BaselineAIH *
n. 48		HD *
n. 49		p Value
IP-10 pg/mL261 (50–1008)101 (60–374)<0.01 **
MCP-1 pg/mL689 (321–1612)330 (261–558)<0.01 **
RANTES pg/mL59,095 (5656–71,403)52,010 (26,410–73,200)NS **
* Median (range); ** Baseline vs. HD.
Table 3. Immunosuppressive treatment regimens. Pred: prednisone; AZT: azathioprine; MMF: mycophenolate mofetil.
Table 3. Immunosuppressive treatment regimens. Pred: prednisone; AZT: azathioprine; MMF: mycophenolate mofetil.
Treatment Patients
Induction therapy
Pred43 (90%)
AZT1 (2%)
Pred + AZT4 (8%)
Maintenance therapy
Pred15 (31%)
AZT13 (27%)
Pred + AZT15 (31%)
Pred + MMF5 (10%)
Table 4. Median levels of IP-10, MCP-1 and RANTES in samples available from 32 patients at baseline and remission compared to HD (healthy donor) controls. RANTES includes 2 distinct distributions based on their decreasing (H) or increasing levels (L).
Table 4. Median levels of IP-10, MCP-1 and RANTES in samples available from 32 patients at baseline and remission compared to HD (healthy donor) controls. RANTES includes 2 distinct distributions based on their decreasing (H) or increasing levels (L).
CkN.AIH BaselineAIH RemissionHD (49)p Value
IP-10 pg/mL32261 (50–1008)106 (28–791)101 (60–374)<0.01 *NS **
MCP-1 pg/mL32689 (321–1612)387 (138–710)330 (261–558)<0.01 *NS **
RANTES pg/mL3259,095 (5656–71,403)53,560 (3250–51,100)52,010 (26,410–73,200)NS *NS **
RANTES H pg/mL1270,960 (48,700–61,600)49,149 (24,810–53,700)<0.01 *NS **
RANTES L pg/mL2029,450 (5656–71,403)64,687 (31,200–51,100)<0.05 *NS **
* Baseline vs. Remission; ** Remission vs. HD.
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MDPI and ACS Style

Colucci, G.; Sguazzini, E.; Uceda Renteria, S.; Perbellini, R.; Ceriotti, F.; Dibenedetto, C.; Donato, M.F.; Lampertico, P. RANTES, IP-10 and MCP-1 Profiles in Patients with Autoimmune Hepatitis (AIH) at Baseline and During Immunosuppressive Treatment. Livers 2025, 5, 19. https://doi.org/10.3390/livers5020019

AMA Style

Colucci G, Sguazzini E, Uceda Renteria S, Perbellini R, Ceriotti F, Dibenedetto C, Donato MF, Lampertico P. RANTES, IP-10 and MCP-1 Profiles in Patients with Autoimmune Hepatitis (AIH) at Baseline and During Immunosuppressive Treatment. Livers. 2025; 5(2):19. https://doi.org/10.3390/livers5020019

Chicago/Turabian Style

Colucci, Giuseppe, Enrico Sguazzini, Sara Uceda Renteria, Riccardo Perbellini, Ferruccio Ceriotti, Clara Dibenedetto, Maria Francesca Donato, and Pietro Lampertico. 2025. "RANTES, IP-10 and MCP-1 Profiles in Patients with Autoimmune Hepatitis (AIH) at Baseline and During Immunosuppressive Treatment" Livers 5, no. 2: 19. https://doi.org/10.3390/livers5020019

APA Style

Colucci, G., Sguazzini, E., Uceda Renteria, S., Perbellini, R., Ceriotti, F., Dibenedetto, C., Donato, M. F., & Lampertico, P. (2025). RANTES, IP-10 and MCP-1 Profiles in Patients with Autoimmune Hepatitis (AIH) at Baseline and During Immunosuppressive Treatment. Livers, 5(2), 19. https://doi.org/10.3390/livers5020019

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