A model of acute antibody-mediated renal allograft rejection in the sensitized rat

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Objectives: Antibody-mediated rejection in transplant recipients with preexisting donor-specific antibodies is a challenging clinical situation. However, we lack suitable animal models to study this scenario. The aim of this study was to develop an animal model of acute antibody-mediated rejection of renal allografts in sensitized recipients. Materials and Methods: We used major histocompatibility complex class I and II incompatible rat strains (Dark Agouti RT1av1 and Lewis RT1l), which develop aggressive rejection. Recipient Lewis rats were immunized with donor strain spleen cells 5 days before surgery to induce donor-specific antibodies. Rats underwent bilateral nephrectomy and orthotopic transplant of the donor kidney. To minimize T-cellmediated rejection while allowing the development of donor-specific antibodies, recipient animals were given tacrolimus starting the day before surgery. Results: Hyperacute rejection was not seen, but acute graft dysfunction was evident on day 1 with a rapid deterioration of graft function by day 3. Histologic damage featured glomerulopathy, capillaritis, capillary thrombosis, and acute tubular injury. Recipients exhibited high serum levels of donorspecific antibodies and deposition of immunoglobulin G and C4d on graft endothelium. Immunostaining showed substantial endothelial damage, fibrin deposition in glomerular and peritubular capillaries, and infiltrates of macrophages, neutrophils, and natural killer cells. T-cell activation was efficiently suppressed by tacrolimus. Conclusions: We have developed a clinically relevant model of acute antibody-mediated rejection in recipients with preexisting donor-specific antibodies, which is suitable for testing novel therapies.

Original languageEnglish
Pages (from-to)294-300
Number of pages7
JournalExperimental and Clinical Transplantation
Volume16
Issue number3
DOIs
Publication statusPublished - 1 Jun 2018

Keywords

  • Donor-specific antibody
  • Macrophage
  • Thrombosis

Cite this

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title = "A model of acute antibody-mediated renal allograft rejection in the sensitized rat",
abstract = "Objectives: Antibody-mediated rejection in transplant recipients with preexisting donor-specific antibodies is a challenging clinical situation. However, we lack suitable animal models to study this scenario. The aim of this study was to develop an animal model of acute antibody-mediated rejection of renal allografts in sensitized recipients. Materials and Methods: We used major histocompatibility complex class I and II incompatible rat strains (Dark Agouti RT1av1 and Lewis RT1l), which develop aggressive rejection. Recipient Lewis rats were immunized with donor strain spleen cells 5 days before surgery to induce donor-specific antibodies. Rats underwent bilateral nephrectomy and orthotopic transplant of the donor kidney. To minimize T-cellmediated rejection while allowing the development of donor-specific antibodies, recipient animals were given tacrolimus starting the day before surgery. Results: Hyperacute rejection was not seen, but acute graft dysfunction was evident on day 1 with a rapid deterioration of graft function by day 3. Histologic damage featured glomerulopathy, capillaritis, capillary thrombosis, and acute tubular injury. Recipients exhibited high serum levels of donorspecific antibodies and deposition of immunoglobulin G and C4d on graft endothelium. Immunostaining showed substantial endothelial damage, fibrin deposition in glomerular and peritubular capillaries, and infiltrates of macrophages, neutrophils, and natural killer cells. T-cell activation was efficiently suppressed by tacrolimus. Conclusions: We have developed a clinically relevant model of acute antibody-mediated rejection in recipients with preexisting donor-specific antibodies, which is suitable for testing novel therapies.",
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A model of acute antibody-mediated renal allograft rejection in the sensitized rat. / Chandran, Sharmila Ramessur; Mulley, William R.; Kanellis, John; Nikolic-Paterson, David J.; Ma, Frank Y.

In: Experimental and Clinical Transplantation, Vol. 16, No. 3, 01.06.2018, p. 294-300.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - A model of acute antibody-mediated renal allograft rejection in the sensitized rat

AU - Chandran, Sharmila Ramessur

AU - Mulley, William R.

AU - Kanellis, John

AU - Nikolic-Paterson, David J.

AU - Ma, Frank Y.

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N2 - Objectives: Antibody-mediated rejection in transplant recipients with preexisting donor-specific antibodies is a challenging clinical situation. However, we lack suitable animal models to study this scenario. The aim of this study was to develop an animal model of acute antibody-mediated rejection of renal allografts in sensitized recipients. Materials and Methods: We used major histocompatibility complex class I and II incompatible rat strains (Dark Agouti RT1av1 and Lewis RT1l), which develop aggressive rejection. Recipient Lewis rats were immunized with donor strain spleen cells 5 days before surgery to induce donor-specific antibodies. Rats underwent bilateral nephrectomy and orthotopic transplant of the donor kidney. To minimize T-cellmediated rejection while allowing the development of donor-specific antibodies, recipient animals were given tacrolimus starting the day before surgery. Results: Hyperacute rejection was not seen, but acute graft dysfunction was evident on day 1 with a rapid deterioration of graft function by day 3. Histologic damage featured glomerulopathy, capillaritis, capillary thrombosis, and acute tubular injury. Recipients exhibited high serum levels of donorspecific antibodies and deposition of immunoglobulin G and C4d on graft endothelium. Immunostaining showed substantial endothelial damage, fibrin deposition in glomerular and peritubular capillaries, and infiltrates of macrophages, neutrophils, and natural killer cells. T-cell activation was efficiently suppressed by tacrolimus. Conclusions: We have developed a clinically relevant model of acute antibody-mediated rejection in recipients with preexisting donor-specific antibodies, which is suitable for testing novel therapies.

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