Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats

Jesus Paez-Mayorga; Jocelyn Nikita Campa-Carranza; Simone Capuani; Nathanael Hernandez; Hsuan-Chen Liu; Corrine Ying Xuan Chua; Fernanda Paola Pons-Faudoa; Gulsah Malgir; Bella Alvarez; Jean A Niles; Lissenya B Argueta; Kathryn A Shelton; Sarah Kezar; Pramod N Nehete; Dora M Berman; Melissa A Willman; Xian C Li; Camillo Ricordi; Joan E Nichols; A Osama Gaber; Norma S Kenyon; Alessandro Grattoni

doi:10.1038/s41467-022-35629-z

Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats

Jesus Paez-Mayorga, Jocelyn Nikita Campa-Carranza, Simone Capuani, Nathanael Hernandez, Hsuan-Chen Liu, Corrine Ying Xuan Chua, Fernanda Paola Pons-Faudoa, Gulsah Malgir, Bella Alvarez, Jean A Niles, Lissenya B Argueta, Kathryn A Shelton, Sarah Kezar, Pramod N Nehete, Dora M Berman, Melissa A Willman, Xian C Li, Camillo Ricordi, Joan E Nichols, A Osama GaberNorma S Kenyon, Alessandro Grattoni

Research output: Contribution to journal › Article › peer-review

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Abstract

Pancreatic islet transplantation efficacy for type 1 diabetes (T1D) management is limited by hypoxia-related graft attrition and need for systemic immunosuppression. To overcome these challenges, we developed the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, which integrates direct vascularization for facile mass transfer and localized immunosuppressant delivery for islet rejection prophylaxis. Here, we investigated NICHE efficacy for allogeneic islet transplantation and long-term diabetes reversal in an immunocompetent, male rat model. We demonstrated that allogeneic islets transplanted within pre-vascularized NICHE were engrafted, revascularized, and functional, reverting diabetes in rats for over 150 days. Notably, we confirmed that localized immunosuppression prevented islet rejection without inducing toxicity or systemic immunosuppression. Moreover, for translatability efforts, we showed NICHE biocompatibility and feasibility of deployment as well as short-term allogeneic islet engraftment in an MHC-mismatched nonhuman primate model. In sum, the NICHE holds promise as a viable approach for safe and effective islet transplantation and long-term T1D management.

Original language	English (US)
Article number	7951
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-35629-z https://doi.org/10.1038/s41467-022-35629-z
State	Published - Dec 26 2022

Keywords

Rats
Animals
Male
Diabetes Mellitus, Type 1/therapy
Immunosuppression Therapy
Islets of Langerhans Transplantation
Immune Tolerance
Immunosuppressive Agents/pharmacology
Islets of Langerhans
Graft Survival

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Paez-Mayorga, J., Campa-Carranza, J. N., Capuani, S., Hernandez, N., Liu, H.-C., Chua, C. Y. X., Pons-Faudoa, F. P., Malgir, G., Alvarez, B., Niles, J. A., Argueta, L. B., Shelton, K. A., Kezar, S., Nehete, P. N., Berman, D. M., Willman, M. A., Li, X. C., Ricordi, C., Nichols, J. E., ... Grattoni, A. (2022). Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats. Nature Communications, 13(1), Article 7951. https://doi.org/10.1038/s41467-022-35629-z, https://doi.org/10.1038/s41467-022-35629-z

Paez-Mayorga, J, Campa-Carranza, JN, Capuani, S, Hernandez, N, Liu, H-C, Chua, CYX, Pons-Faudoa, FP, Malgir, G, Alvarez, B, Niles, JA, Argueta, LB, Shelton, KA, Kezar, S, Nehete, PN, Berman, DM, Willman, MA, Li, XC, Ricordi, C, Nichols, JE , Gaber, AO, Kenyon, NS & Grattoni, A 2022, 'Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats', Nature Communications, vol. 13, no. 1, 7951. https://doi.org/10.1038/s41467-022-35629-z, https://doi.org/10.1038/s41467-022-35629-z

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title = "Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats",

abstract = "Pancreatic islet transplantation efficacy for type 1 diabetes (T1D) management is limited by hypoxia-related graft attrition and need for systemic immunosuppression. To overcome these challenges, we developed the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, which integrates direct vascularization for facile mass transfer and localized immunosuppressant delivery for islet rejection prophylaxis. Here, we investigated NICHE efficacy for allogeneic islet transplantation and long-term diabetes reversal in an immunocompetent, male rat model. We demonstrated that allogeneic islets transplanted within pre-vascularized NICHE were engrafted, revascularized, and functional, reverting diabetes in rats for over 150 days. Notably, we confirmed that localized immunosuppression prevented islet rejection without inducing toxicity or systemic immunosuppression. Moreover, for translatability efforts, we showed NICHE biocompatibility and feasibility of deployment as well as short-term allogeneic islet engraftment in an MHC-mismatched nonhuman primate model. In sum, the NICHE holds promise as a viable approach for safe and effective islet transplantation and long-term T1D management.",

keywords = "Rats, Animals, Male, Diabetes Mellitus, Type 1/therapy, Immunosuppression Therapy, Islets of Langerhans Transplantation, Immune Tolerance, Immunosuppressive Agents/pharmacology, Islets of Langerhans, Graft Survival",

author = "Jesus Paez-Mayorga and Campa-Carranza, {Jocelyn Nikita} and Simone Capuani and Nathanael Hernandez and Hsuan-Chen Liu and Chua, {Corrine Ying Xuan} and Pons-Faudoa, {Fernanda Paola} and Gulsah Malgir and Bella Alvarez and Niles, {Jean A} and Argueta, {Lissenya B} and Shelton, {Kathryn A} and Sarah Kezar and Nehete, {Pramod N} and Berman, {Dora M} and Willman, {Melissa A} and Li, {Xian C} and Camillo Ricordi and Nichols, {Joan E} and Gaber, {A Osama} and Kenyon, {Norma S} and Alessandro Grattoni",

note = "Funding Information: The authors are grateful to Dr. Marco Farina for insightful discussion and information. The authors thank Dr. Jianhua (James) Gu from the electron microscopy core of Houston Methodist Research Institute; Dr. Andreana L. Rivera, Yuelan Ren, and Sandra Steptoe from the research pathology core of Houston Methodist Research Institute; Drs. Yitian Xu, Licheng Zhang, and Shu-Hsia Chen from the ImmunoMonitoring Core of Houston Methodist Research Institute; Dr. David L. Haviland and Nicole Vaughn from the flow cytometry core of Houston Methodist Research Institute; Alex Rabassa and Waldo L. Diaz from the Diabetes Research Institute at the University of Miami for pancreas procurement and islet isolation; and Luke Segura, Elizabeth Lindemann, Dana Salazar, Bharti Nehete, and Dr. Greg Wilkerson from the Michale E. Keeling Center for Comparative Medicine and Research at UTMDACC for support in NHP studies. Figure was partially created with biorender.org. The authors also thank graphic designer Virginia Facciotto (virginia.facciotto@gmail.com) for the preparation of schematics and illustrations. Funding support from Juvenile Diabetes Research Foundation 1-INO-2018-595-A-N (A.G.), Vivian L. Smith Foundation (A.G.), Houston Methodist Research Institute (A.G.), Diabetes Research Institute (N.K.), and in part by NIH NIDDK R01DK132104 (A.G., J.N.). Funding Information: The authors are grateful to Dr. Marco Farina for insightful discussion and information. The authors thank Dr. Jianhua (James) Gu from the electron microscopy core of Houston Methodist Research Institute; Dr. Andreana L. Rivera, Yuelan Ren, and Sandra Steptoe from the research pathology core of Houston Methodist Research Institute; Drs. Yitian Xu, Licheng Zhang, and Shu-Hsia Chen from the ImmunoMonitoring Core of Houston Methodist Research Institute; Dr. David L. Haviland and Nicole Vaughn from the flow cytometry core of Houston Methodist Research Institute; Alex Rabassa and Waldo L. Diaz from the Diabetes Research Institute at the University of Miami for pancreas procurement and islet isolation; and Luke Segura, Elizabeth Lindemann, Dana Salazar, Bharti Nehete, and Dr. Greg Wilkerson from the Michale E. Keeling Center for Comparative Medicine and Research at UTMDACC for support in NHP studies. Figure 3a was partially created with biorender.org. The authors also thank graphic designer Virginia Facciotto (virginia.facciotto@gmail.com) for the preparation of schematics and illustrations. Funding support from Juvenile Diabetes Research Foundation 1-INO-2018-595-A-N (A.G.), Vivian L. Smith Foundation (A.G.), Houston Methodist Research Institute (A.G.), Diabetes Research Institute (N.K.), and in part by NIH NIDDK R01DK132104 (A.G., J.N.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

day = "26",

doi = "10.1038/s41467-022-35629-z",

language = "English (US)",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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TY - JOUR

T1 - Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats

AU - Paez-Mayorga, Jesus

AU - Campa-Carranza, Jocelyn Nikita

AU - Capuani, Simone

AU - Hernandez, Nathanael

AU - Liu, Hsuan-Chen

AU - Chua, Corrine Ying Xuan

AU - Pons-Faudoa, Fernanda Paola

AU - Malgir, Gulsah

AU - Alvarez, Bella

AU - Niles, Jean A

AU - Argueta, Lissenya B

AU - Shelton, Kathryn A

AU - Kezar, Sarah

AU - Nehete, Pramod N

AU - Berman, Dora M

AU - Willman, Melissa A

AU - Li, Xian C

AU - Ricordi, Camillo

AU - Nichols, Joan E

AU - Gaber, A Osama

AU - Kenyon, Norma S

AU - Grattoni, Alessandro

N1 - Funding Information: The authors are grateful to Dr. Marco Farina for insightful discussion and information. The authors thank Dr. Jianhua (James) Gu from the electron microscopy core of Houston Methodist Research Institute; Dr. Andreana L. Rivera, Yuelan Ren, and Sandra Steptoe from the research pathology core of Houston Methodist Research Institute; Drs. Yitian Xu, Licheng Zhang, and Shu-Hsia Chen from the ImmunoMonitoring Core of Houston Methodist Research Institute; Dr. David L. Haviland and Nicole Vaughn from the flow cytometry core of Houston Methodist Research Institute; Alex Rabassa and Waldo L. Diaz from the Diabetes Research Institute at the University of Miami for pancreas procurement and islet isolation; and Luke Segura, Elizabeth Lindemann, Dana Salazar, Bharti Nehete, and Dr. Greg Wilkerson from the Michale E. Keeling Center for Comparative Medicine and Research at UTMDACC for support in NHP studies. Figure was partially created with biorender.org. The authors also thank graphic designer Virginia Facciotto (virginia.facciotto@gmail.com) for the preparation of schematics and illustrations. Funding support from Juvenile Diabetes Research Foundation 1-INO-2018-595-A-N (A.G.), Vivian L. Smith Foundation (A.G.), Houston Methodist Research Institute (A.G.), Diabetes Research Institute (N.K.), and in part by NIH NIDDK R01DK132104 (A.G., J.N.). Funding Information: The authors are grateful to Dr. Marco Farina for insightful discussion and information. The authors thank Dr. Jianhua (James) Gu from the electron microscopy core of Houston Methodist Research Institute; Dr. Andreana L. Rivera, Yuelan Ren, and Sandra Steptoe from the research pathology core of Houston Methodist Research Institute; Drs. Yitian Xu, Licheng Zhang, and Shu-Hsia Chen from the ImmunoMonitoring Core of Houston Methodist Research Institute; Dr. David L. Haviland and Nicole Vaughn from the flow cytometry core of Houston Methodist Research Institute; Alex Rabassa and Waldo L. Diaz from the Diabetes Research Institute at the University of Miami for pancreas procurement and islet isolation; and Luke Segura, Elizabeth Lindemann, Dana Salazar, Bharti Nehete, and Dr. Greg Wilkerson from the Michale E. Keeling Center for Comparative Medicine and Research at UTMDACC for support in NHP studies. Figure 3a was partially created with biorender.org. The authors also thank graphic designer Virginia Facciotto (virginia.facciotto@gmail.com) for the preparation of schematics and illustrations. Funding support from Juvenile Diabetes Research Foundation 1-INO-2018-595-A-N (A.G.), Vivian L. Smith Foundation (A.G.), Houston Methodist Research Institute (A.G.), Diabetes Research Institute (N.K.), and in part by NIH NIDDK R01DK132104 (A.G., J.N.). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12/26

Y1 - 2022/12/26

N2 - Pancreatic islet transplantation efficacy for type 1 diabetes (T1D) management is limited by hypoxia-related graft attrition and need for systemic immunosuppression. To overcome these challenges, we developed the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, which integrates direct vascularization for facile mass transfer and localized immunosuppressant delivery for islet rejection prophylaxis. Here, we investigated NICHE efficacy for allogeneic islet transplantation and long-term diabetes reversal in an immunocompetent, male rat model. We demonstrated that allogeneic islets transplanted within pre-vascularized NICHE were engrafted, revascularized, and functional, reverting diabetes in rats for over 150 days. Notably, we confirmed that localized immunosuppression prevented islet rejection without inducing toxicity or systemic immunosuppression. Moreover, for translatability efforts, we showed NICHE biocompatibility and feasibility of deployment as well as short-term allogeneic islet engraftment in an MHC-mismatched nonhuman primate model. In sum, the NICHE holds promise as a viable approach for safe and effective islet transplantation and long-term T1D management.

AB - Pancreatic islet transplantation efficacy for type 1 diabetes (T1D) management is limited by hypoxia-related graft attrition and need for systemic immunosuppression. To overcome these challenges, we developed the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, which integrates direct vascularization for facile mass transfer and localized immunosuppressant delivery for islet rejection prophylaxis. Here, we investigated NICHE efficacy for allogeneic islet transplantation and long-term diabetes reversal in an immunocompetent, male rat model. We demonstrated that allogeneic islets transplanted within pre-vascularized NICHE were engrafted, revascularized, and functional, reverting diabetes in rats for over 150 days. Notably, we confirmed that localized immunosuppression prevented islet rejection without inducing toxicity or systemic immunosuppression. Moreover, for translatability efforts, we showed NICHE biocompatibility and feasibility of deployment as well as short-term allogeneic islet engraftment in an MHC-mismatched nonhuman primate model. In sum, the NICHE holds promise as a viable approach for safe and effective islet transplantation and long-term T1D management.

KW - Rats

KW - Animals

KW - Male

KW - Diabetes Mellitus, Type 1/therapy

KW - Immunosuppression Therapy

KW - Islets of Langerhans Transplantation

KW - Immune Tolerance

KW - Immunosuppressive Agents/pharmacology

KW - Islets of Langerhans

KW - Graft Survival

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SN - 2041-1723

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JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7951

ER -

Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats

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