Heart failure (HF) is a highly lethal condition affecting an estimated 26 million people worldwide and heart transplantation represents the main treatment for HF end-stage. In this context, the treatment of acute rejection remains a significant challenge. Acute allograft rejection includes Acute cellular rejection (ACR), mediated by cytotoxic T-cell response, and Antibody-mediated rejection (AMR), that causes activation of the complement cascade, resulting in myocardial injury and microvascular damage. The gold standard for the definitive diagnosis of AMR is the endomyocardial biopsy (EMB), evaluated in compliance with the criteria established by the International Society for Heart and Lung Transplantation (ISHLT).

The latter requires the presence of characteristic morphological and immunopathological findings, in particular immunohistochemical positivity for C4d may lack specificity, being correlated to other nonimmunologic conditions, and, on the other hand, AMR can occur without complement activation (C4d-negative AMR). Therefore, AMR continues to pose significant diagnostic challenges, highlighting the need for more specific, less invasive biomarkers to improve its diagnosis and treatment. In the last decades AMR’s pathogenesis has been widely studied, uncovering the key role of BAFF (B cell activating factor) and BAFFR (B cell activating factor receptor) activation in the inflammatory response against the allograft. BAFF is expressed by different cells including antigen presenting cells (APCs) like macrophages, B lymphocytes, dendritic cells, and neutrophils. By interacting with its receptors (BAFFR, TACI, BCMA), BAFF stimulates survival, differentiation and proliferation of B cell and plasma cells, representing a promising biomarker for acute transplant rejection and a possible therapeutic target. Indeed, it has been shown that BAFF immunohistochemical expression is increased in kidney transplant induced rejection and that increasing of its serum levels in the pretransplant setting is related to a higher risk of AMR. Based on that, we investigated the role of BAFF in the setting of heart transplantation and its influence in macrophage polarization to better understand the significance of macrophages in the local immune microenvironment of allogeneic transplantation after heart transplantation.

The case cohort comprised 8 patients with clinically evident antibody-mediated rejection (AMR) and 8 patients without clinically or histopathological antibody-mediated rejection (AMR0), as a negative control. Our results showed a statistically significant difference in the number of intermyocyte M2- macrophages (CD68 +, CD163 +, CD206 +/-) in both groups, while intravascular macrophages were more M1- enriched (CD68+, CD163-, CD206-). Together these results suggest that the role of intermyocite macrophages is not critical in the immune pathogenesis of rejection. Conversely, as previously described, the presence of intravascular M1-macrophages suggested their active role in rejection. Additionally, we’ve evaluated immunohistochemical expression for BAFFR in both AMR and AMR0 patients. Our results showed the presence of cytoplasmic BAFFR- positivity in intermyocyte small vessel endothelia in AMR patients compared with AMR0 patients which showed BAFFR-negativity. These preliminary results suggest that BAFFR may participate in acute humoral rejection in cardiac transplantation, similar to what is already known in renal transplantation rejection. Considering the small number of patients enrolled, further studies are needed to better understand the potential role of BAFFR to improve patient outcome, possibly opening up alternative prognostic and therapeutics strategies.

To be Updated