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Background: Soluble major histocompatibility complex class Ⅱ(sMHCII) molecules have been described to maintain tolerance through the suppression of autoreactive T lymphocytes. In order to evaluate their ability to rescue autoimmune hepatitis (AIH) symptoms, the present work attempted to administer sMHCⅡ molecules to an in vitro as well as in vivo concanavalin A (ConA)-induced AIH model.Methods: The in vitro AIH model consisted of splenocyte stimulation with ConA in the presence or absence of serum-isolated sMHCⅡ molecules. An in vivo ConA-modified model with or without sMHCⅡ treatment was developed. The cytokine profile in culture supatants and serum was tested by ELISA. Cell markers were evaluated by immunofluorescence, while cell proliferation by tritiated thymidine up-take. AIH symptoms were assessed by daily observations for the establishment of a disease severity scoring system and liver histology was evaluated using a biomolecu-lar imager. Results: The presence of sMHCⅡ molecules in the ConA-stimulated cell cultures leads to a significant reduction of cell proliferation. The administration of sMHCⅡ molecules to the ConA-treated animals showed a significant reduction in the levels of IL-2, IL-4, and IL-10, as well as a decrease in the number of spleen CD4+ and CD8+ cells. Upon development of a scoring system, it was shown that the sMHCⅡ treat-ment was accompanied by a slower progression of the disease, while rescuing fibrotic liver morphology. Conclusion: The results presented in this study confirm the ability of sMHCⅡ proteins to alleviate autoimmune hepatitis, possibly highlighting new therapeutic approaches for autoimmune diseases.