Antiinflammatory strategies in intrahepatic islet transplantation: a comparative study in preclinical models

A Citro, E Cantarelli, S Pellegrini, E Dugnani, L Piemonti

Research output: Contribution to journalArticle

Abstract

BACKGROUND: The identification of pathway(s) playing a pivotal role in peritransplant detrimental inflammatory events represents the crucial step towards a better management and outcome of pancreatic islet transplanted patients. Recently, we candidate the CXCR1/2 inhibition as a relevant strategy in enhancing pancreatic islet survival after transplantation. METHODS: Here, the most clinically used antiinflammatory compounds (IL1-receptor antagonist, steroids and TNF-α inhibitor) alone or in combination with a CXCR1/2 inhibitor were evaluated in their ability to improve engraftment or delay graft rejection. To rule out bias related to transplantation site, we used well-established preclinical syngeneic (250 C57BL/6 equivalent islets in C57BL/6) and allogeneic (400 Balb/c equivalent islets in C57BL6) intrahepatic islet transplantation platforms. RESULTS: In mice, we confirmed that targeting the CXCR1/2 pathway is crucial in preserving islet function and improving engraftment. In the allogeneic setting, CXCR1/2 inhibitor alone could reduce the overall recruitment of transplant-induced leukocytes and significantly prolong the time to graft rejection both as single agent and in combination with immunosuppression. No other antiinflammatory compounds tested (IL1-receptor antagonist, steroids and TNF-α inhibitor) alone or in combination with CXCR1/2 inhibitor, improve islet engraftment and significantly delay graft rejection in the presence of MMF+FK-506 immunosuppressive treatment. CONCLUSIONS: These findings indicate that only the CXCR1/2-mediated axis plays a crucial role in controlling the islet damage and should be a target for intervention to improve the efficiency of islet transplantation.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.
Original languageEnglish
Pages (from-to)240-248
Number of pages9
JournalTransplantation
Volume102
Issue number2
DOIs
Publication statusPublished - 2018

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Islets of Langerhans Transplantation
Graft Rejection
Anti-Inflammatory Agents
Interleukin-1 Receptors
Islets of Langerhans
Transplantation
Steroids
Tacrolimus
Licensure
Immunosuppressive Agents
Immunosuppression
Leukocytes
Transplants
Therapeutics

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Antiinflammatory strategies in intrahepatic islet transplantation: a comparative study in preclinical models. / Citro, A; Cantarelli, E; Pellegrini, S; Dugnani, E; Piemonti, L.

In: Transplantation, Vol. 102, No. 2, 2018, p. 240-248.

Research output: Contribution to journalArticle

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abstract = "BACKGROUND: The identification of pathway(s) playing a pivotal role in peritransplant detrimental inflammatory events represents the crucial step towards a better management and outcome of pancreatic islet transplanted patients. Recently, we candidate the CXCR1/2 inhibition as a relevant strategy in enhancing pancreatic islet survival after transplantation. METHODS: Here, the most clinically used antiinflammatory compounds (IL1-receptor antagonist, steroids and TNF-α inhibitor) alone or in combination with a CXCR1/2 inhibitor were evaluated in their ability to improve engraftment or delay graft rejection. To rule out bias related to transplantation site, we used well-established preclinical syngeneic (250 C57BL/6 equivalent islets in C57BL/6) and allogeneic (400 Balb/c equivalent islets in C57BL6) intrahepatic islet transplantation platforms. RESULTS: In mice, we confirmed that targeting the CXCR1/2 pathway is crucial in preserving islet function and improving engraftment. In the allogeneic setting, CXCR1/2 inhibitor alone could reduce the overall recruitment of transplant-induced leukocytes and significantly prolong the time to graft rejection both as single agent and in combination with immunosuppression. No other antiinflammatory compounds tested (IL1-receptor antagonist, steroids and TNF-α inhibitor) alone or in combination with CXCR1/2 inhibitor, improve islet engraftment and significantly delay graft rejection in the presence of MMF+FK-506 immunosuppressive treatment. CONCLUSIONS: These findings indicate that only the CXCR1/2-mediated axis plays a crucial role in controlling the islet damage and should be a target for intervention to improve the efficiency of islet transplantation.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.",
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