Blockade of Extracellular HMGB1 Suppresses Xenoreactive B Cell Responses and Delays Acute Vascular Xenogeneic Rejection

Abstract

Blockade of extracellular high mobility group box 1 (HMGB1) can significantly prolong murine cardiac allograft survival. Here, we determined the role of HMGB1 in xenotransplantation. Sprague‐Dawley rat hearts were transplanted heterotopically into BALB/c mice. Xenografts without any treatment developed predominant acute vascular rejection within 6 days. Both passively released HMGB1 from xenografts and actively secreted HMGB1 from infiltrated immune cells were significantly increased after xenotransplantation. HMGB1‐neutralizing antibody treatment significantly prolonged xenograft survival and attenuated pathologic damage, immune cell infiltration, and HMGB1 expression and release in the xenografts. Compared to control IgG treatment evaluated at study endpoint, treatment with HMGB1‐neutralizing antibody markedly suppressed xenoreactive B cell responses, as evidenced by the significant inhibition of anti‐rat antibody production and deposition in xenografts at Day 6 posttransplant. Furthermore, treatment with anti‐HMGB1 antibody suppressed B cell activation and reduced IFN‐γ and IL‐17A production after xenotransplantation. These results demonstrate for the first time that HMGB1 plays an important role in mediating acute xenograft rejection. Thus, we have shown that neutralization of extracellular HMGB1 can significantly inhibit xenoreactive B cell responses and delay xenograft rejection in a rat‐to‐mouse model of xenotransplantation, uncovering new insights in the role of HMGB1 in transplantation.

Porcine IL‐6, IL‐1β, and TNF‐α regulate the expression of pro‐inflammatory‐related genes and tissue factor in human umbilical vein endothelial cells

“…[1][2][3][4][5] These cytokines play important roles in inflammation in human diseases. Various pro-inflammatory cytokines are also produced and cross-react with donor or recipient cells in xenotransplantation, [6][7][8][9][10][11][12] and we predict that they will play important roles in the immune and coagulation responses. Many pro-inflammatory cytokines increase the expression of tissue factor (TF), which promotes activation of coagulation.…”

Transgenic Expression of Human Thrombomodulin Inhibits HMGB1-Induced Porcine Aortic Endothelial Cell Activation

“…12 Anti-HMGB1 treatment can significantly prolong cardiac xenograft survival in a rat-to-mouse model. 13 However, HMGB1-mediated activation of porcine endothelial cells has not been explored, and the protective effect of hTBM against HMGB1's actions in this setting has not been examined. We therefore aimed to test HMGB1-mediated proinflammatory and procoagulant effects on PAEC and to assess the capacity of transgenic expression of hTBM on PAEC to neutralize HMGB1.…”

Alarmins and Their Receptors as Modulators and Indicators of Alloimmune Responses

“…Similar to IL-1a, HMGB1 also turns myeloid APCs into potent T cell stimulators by upregulating APC costimulatory molecules and inducing proinflammatory cytokine secretion by APCs, particularly IL-12p70 (20). As expected from these properties, released HMGB1 supports IRI (32,33) and the alloimmune response leading to GVHD (34) and transplant rejection (35)(36)(37)(38). Zou et al delivered anti-HMGB1 antibody to C57BL/6 recipients for 4 weeks after heterotopic transplantation of MHC class II disparate bm12 hearts and demonstrated that HMGB1 release supports chronic cardiac rejection (38).…”

“…Mechanistic studies indicated that decreases in systemic HMGB1 result in less activated DCs and thus reduced Th1 and Th17 responses (38). Li et al established that anti-HMGB1 antibodies suppressed B cell activation and reduced IFN-c and IL-17A production after xenotransplantation of rat hearts into BALB/c mice (36). Anti-HMGB1 antibody delivery promoted allogeneic islet survival (39,40).…”