Role of intra-islet endothelial cells in islet allo-immunity

Ankit Bharat, Deepti Saini, Nicholas Benshoff, Jeremy Goodman, Niraj M. Desai, William C. Chapman, Thalachallour Mohanakumar*

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

BACKGROUND. Intra-islet endothelial cells (IECs) express high levels of major histocompatibility complex (MHC) and are pivotal for posttransplant islet revascularization. We postulated that donor-specific sensitization would result in hyperacute rejection of IECs and prevent islet engraftment. Furthermore, ligation of endothelial cells with subsaturating concentrations of anti-MHC class I antibody (Ab) results in "accommodation" conferring protection against Ab/complement-mediated lysis. Therefore, we investigated whether accommodation of IECs would prevent hyperacute rejection of islets in sensitized recipients. METHODS. Islets were transplanted beneath the kidney capsule and allograft survival monitored using daily blood glucose (diabetes >300 mg/dL, normoglycemia <150 mg/dL). Recipients were presensitized with donor islets, splenocytes, or skin. Accommodation was induced by incubating human or murine islets with varying concentrations of anti-MHC class I Ab ex vivo. RESULTS. Isografts remained functional for >100 days, whereas allografts were rejected by day 14. Islet allo-transplantation induced donor-specific but not third-party anti-MHC Abs. Donor-specific, but not third-party, sensitization induced hyperacute rejection of subsequent islet allografts (median survival 1 day) associated with complement deposition. Preincubation of islets with subsaturating concentrations of anti-MHC-I Abs (1-100 ng/mL) up-regulated Bcl-2, Bcl-xl, and HO-1 within CD31 IEC. These accommodated islets were resistant against hyperacute rejection when transplanted into donor-(splenocyte) sensitized recipients without any immunosuppression (median survival 6 days). CONCLUSIONS. Pretransplant sensitization against donor antigens results in hyperacute rejection of murine islets. IECs may play a crucial role in development of donor-specific immunity after islet transplantation. Significantly, accommodation of IEC may confer resistance to hyperacute rejection in sensitized recipients.

Original languageEnglish (US)
Pages (from-to)1316-1323
Number of pages8
JournalTransplantation
Volume84
Issue number10
DOIs
StatePublished - Nov 1 2007

Fingerprint

Islets of Langerhans
Immunity
Endothelial Cells
Major Histocompatibility Complex
Allografts
Islets of Langerhans Transplantation
Immunoglobulin Isotypes
Immunosuppression
Capsules
Ligation
Blood Glucose
Kidney
Antigens
Antibodies

Keywords

  • Alloantibodies
  • Complement
  • Donor MHC
  • Islet transplantation
  • Sensitization

ASJC Scopus subject areas

  • Transplantation

Cite this

Bharat, A., Saini, D., Benshoff, N., Goodman, J., Desai, N. M., Chapman, W. C., & Mohanakumar, T. (2007). Role of intra-islet endothelial cells in islet allo-immunity. Transplantation, 84(10), 1316-1323. https://doi.org/10.1097/01.tp.0000288192.11396.70
Bharat, Ankit ; Saini, Deepti ; Benshoff, Nicholas ; Goodman, Jeremy ; Desai, Niraj M. ; Chapman, William C. ; Mohanakumar, Thalachallour. / Role of intra-islet endothelial cells in islet allo-immunity. In: Transplantation. 2007 ; Vol. 84, No. 10. pp. 1316-1323.
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Bharat, A, Saini, D, Benshoff, N, Goodman, J, Desai, NM, Chapman, WC & Mohanakumar, T 2007, 'Role of intra-islet endothelial cells in islet allo-immunity', Transplantation, vol. 84, no. 10, pp. 1316-1323. https://doi.org/10.1097/01.tp.0000288192.11396.70

Role of intra-islet endothelial cells in islet allo-immunity. / Bharat, Ankit; Saini, Deepti; Benshoff, Nicholas; Goodman, Jeremy; Desai, Niraj M.; Chapman, William C.; Mohanakumar, Thalachallour.

In: Transplantation, Vol. 84, No. 10, 01.11.2007, p. 1316-1323.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Role of intra-islet endothelial cells in islet allo-immunity

AU - Bharat, Ankit

AU - Saini, Deepti

AU - Benshoff, Nicholas

AU - Goodman, Jeremy

AU - Desai, Niraj M.

AU - Chapman, William C.

AU - Mohanakumar, Thalachallour

PY - 2007/11/1

Y1 - 2007/11/1

N2 - BACKGROUND. Intra-islet endothelial cells (IECs) express high levels of major histocompatibility complex (MHC) and are pivotal for posttransplant islet revascularization. We postulated that donor-specific sensitization would result in hyperacute rejection of IECs and prevent islet engraftment. Furthermore, ligation of endothelial cells with subsaturating concentrations of anti-MHC class I antibody (Ab) results in "accommodation" conferring protection against Ab/complement-mediated lysis. Therefore, we investigated whether accommodation of IECs would prevent hyperacute rejection of islets in sensitized recipients. METHODS. Islets were transplanted beneath the kidney capsule and allograft survival monitored using daily blood glucose (diabetes >300 mg/dL, normoglycemia <150 mg/dL). Recipients were presensitized with donor islets, splenocytes, or skin. Accommodation was induced by incubating human or murine islets with varying concentrations of anti-MHC class I Ab ex vivo. RESULTS. Isografts remained functional for >100 days, whereas allografts were rejected by day 14. Islet allo-transplantation induced donor-specific but not third-party anti-MHC Abs. Donor-specific, but not third-party, sensitization induced hyperacute rejection of subsequent islet allografts (median survival 1 day) associated with complement deposition. Preincubation of islets with subsaturating concentrations of anti-MHC-I Abs (1-100 ng/mL) up-regulated Bcl-2, Bcl-xl, and HO-1 within CD31 IEC. These accommodated islets were resistant against hyperacute rejection when transplanted into donor-(splenocyte) sensitized recipients without any immunosuppression (median survival 6 days). CONCLUSIONS. Pretransplant sensitization against donor antigens results in hyperacute rejection of murine islets. IECs may play a crucial role in development of donor-specific immunity after islet transplantation. Significantly, accommodation of IEC may confer resistance to hyperacute rejection in sensitized recipients.

AB - BACKGROUND. Intra-islet endothelial cells (IECs) express high levels of major histocompatibility complex (MHC) and are pivotal for posttransplant islet revascularization. We postulated that donor-specific sensitization would result in hyperacute rejection of IECs and prevent islet engraftment. Furthermore, ligation of endothelial cells with subsaturating concentrations of anti-MHC class I antibody (Ab) results in "accommodation" conferring protection against Ab/complement-mediated lysis. Therefore, we investigated whether accommodation of IECs would prevent hyperacute rejection of islets in sensitized recipients. METHODS. Islets were transplanted beneath the kidney capsule and allograft survival monitored using daily blood glucose (diabetes >300 mg/dL, normoglycemia <150 mg/dL). Recipients were presensitized with donor islets, splenocytes, or skin. Accommodation was induced by incubating human or murine islets with varying concentrations of anti-MHC class I Ab ex vivo. RESULTS. Isografts remained functional for >100 days, whereas allografts were rejected by day 14. Islet allo-transplantation induced donor-specific but not third-party anti-MHC Abs. Donor-specific, but not third-party, sensitization induced hyperacute rejection of subsequent islet allografts (median survival 1 day) associated with complement deposition. Preincubation of islets with subsaturating concentrations of anti-MHC-I Abs (1-100 ng/mL) up-regulated Bcl-2, Bcl-xl, and HO-1 within CD31 IEC. These accommodated islets were resistant against hyperacute rejection when transplanted into donor-(splenocyte) sensitized recipients without any immunosuppression (median survival 6 days). CONCLUSIONS. Pretransplant sensitization against donor antigens results in hyperacute rejection of murine islets. IECs may play a crucial role in development of donor-specific immunity after islet transplantation. Significantly, accommodation of IEC may confer resistance to hyperacute rejection in sensitized recipients.

KW - Alloantibodies

KW - Complement

KW - Donor MHC

KW - Islet transplantation

KW - Sensitization

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Bharat A, Saini D, Benshoff N, Goodman J, Desai NM, Chapman WC et al. Role of intra-islet endothelial cells in islet allo-immunity. Transplantation. 2007 Nov 1;84(10):1316-1323. https://doi.org/10.1097/01.tp.0000288192.11396.70