Neutralization of Extracellular HMGB1 Suppresses Xeno-Immune Response and Delays Xenograft Rejection in a Rat-to Mouse Cardiac Xenotransplant Model
Institue of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Meeting: 2013 American Transplant Congress
Abstract number: B1151
Background: Extracellular HMGB1 has been found to be a potent stimulator for adaptive immune responses. It has been reported that blockade of extracellular HMGB1 significantly prolonged murine cardiac allograft survival. However, the role of HMGB1 in xenotransplantation is still unknown.
Methods: Sprague Dawley rat hearts were transplanted heterotopically into BALB/c mice. Rabbit anti-mouse HMGB1 neutralizing antibody (Ab) was given intraperitoneally every other day from day -1 (600Μg each time). Mice treated with PBS or control IgG were used as controls. Blood samples were collected for the evaluation of anti-rat lymphocyte IgG and IgM by FACS, cardiac xenografts were harvested for pathologic and immunopathologic analysis. Deposition of xenoantibodies and expression of HMGB1, JG12 and MPO in xenografts were detected by either immunohistochemistry or immunofluorescence. Cell apoptosis in xenografts was assessed by TUNEL assay. Additionally, the expression of CD19 and MHC-II on splenic cells and PBMCs were measured by FACS.
Results: Treatment with anti-HMGB1 Ab significantly delayed xenograft rejection (median survival time: 9 days vs. 5 days in control groups, P<0.01). At the time of rejection (4-6 days), control mice had a marked increase of both serum anti-rat IgG and IgM levels and massive IgG and IgM deposition was shown in xenografts. However, recipient mice treated with anti-HMGB1 Ab only had a slight increase of serum anti-rat IgG and IgM levels and much less xenoantibody deposition was shown in xenografts at day 6. Pathological examination demonstrated that both acute vascular rejection and cellular rejection (at day 6) was markedly reduced as a result of neutralizing Ab treatment. Additionally, immunopathology showed a significant attenuation of HMGB1, MPO expression and much higher JG12 expression in xenografts treated with anti-HMGB1 Ab. Furthermore, CD19+ B cells in both spleen and PBMCs showed much lower MHC-II expression in anti-HMGB1 Ab-treated group at day 6.
Conclusion: HMGB1 plays an important role in mediating xenograft rejection. Neutralization of extracellular HMGB1 can significantly inhibit xeno-immune responses and prolong xenograft survival in a concordant rat-to-mouse cardiac transplant model.
To cite this abstract in AMA style:
Chen G, Li J, Ruan Y, Wang L, Huang X, Guo H, Gong F. Neutralization of Extracellular HMGB1 Suppresses Xeno-Immune Response and Delays Xenograft Rejection in a Rat-to Mouse Cardiac Xenotransplant Model [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/neutralization-of-extracellular-hmgb1-suppresses-xeno-immune-response-and-delays-xenograft-rejection-in-a-rat-to-mouse-cardiac-xenotransplant-model/. Accessed May 14, 2025.« Back to 2013 American Transplant Congress