Papel da anexina A1 na regulação da resposta inflamatória associada à doença do enxerto - versus - hospedeiro

Abstract

Allogeneic hematopoietic stem cell transplantation is a commonly used therapy for the treatment of hematologic and non-hematologic diseases. The main complication related to this therapy is the development of graft-versus-host disease (GVHD), which occurs when T lymphocytes in the transplant regularly present antigenic disparities between the donor and the recipient, resulting in activation, toxicity and recruitment of immune system cells to organs such as the skin, liver and intestine. Currently, only 50% of patients with GVHD respond to conventional treatments, highlighting the need for new therapeutic approaches. Annexin A1 (ANXA1) protein deficiency has been associated with greater severity of inflammation and increased mortality in several models of inflammatory diseases, such as colitis and sepsis. Therapeutic strategies based on the use of its mimetic peptide, Ac2-26, have shown promise in the treatment of severe inflammatory diseases resistant to conventional therapies. Therefore, this study aimed to evaluate the role of ANXA1 in the modulation of the inflammatory response associated with GVHD. For this purpose, an experimental model was used in which acute GVHD was caused by the transplantation of allogeneic bone marrow cells and splenocytes from C57BL/6J mice into BALB/c WT and BALB/c ANXA1-/- mice. Mice that received bone marrow cells and splenocytes from syngeneic BALB/c mice did not develop the disease, constituting the control group. In addition, a group of animals with GVHD were treated with the ANXA1 mimetic peptide (Ac2-26). Our results demonstrated that with the disease, the expression of the ANXA1 protein is altered, with greater cleavage in the target organs. ANXA1 deficiency led to exacerbation of the inflammatory response observed in the disease, with early mortality, increased clinical signs, greater tissue damage and production of inflammatory mediators. On the other hand, treatment with the annexin A1 mimetic peptide (Ac2-26) resulted in clinical improvement and increased survival of the animals. No humanized model has shown ANXA1 to be modulated by the disease in a manner similar to that observed in the murine model. Taken together, these data suggest that ANXA1 plays a crucial role in regulating the inflammatory response and severity of GVHD, highlighting a potential therapeutic target for new treatments of the disease.