Rejection of xenogeneic porcine islets in humanized mice is characterized by graft-infiltrating Th17 cells and activated B cells

Frances T. Lee, Anil Dangi, Sahil Shah, Melanie Burnette, Yong Guang Yang, Allan D. Kirk, Bernhard J. Hering, Stephen D. Miller, Xunrong Luo

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Xenogeneic porcine islet transplantation is a promising potential therapy for type 1 diabetes (T1D). Understanding human immune responses against porcine islets is crucial for the design of optimal immunomodulatory regimens for effective control of xenogeneic rejection of porcine islets in humans. Humanized mice are a valuable tool for studying human immune responses and therefore present an attractive alternative to human subject research. Here, by using a pig-to-humanized mouse model of xenogeneic islet transplantation, we described the human immune response to transplanted porcine islets, a process characterized by dense islet xenograft infiltration of human CD45+ cells comprising activated human B cells, CD4+CD44+IL-17+ Th17 cells, and CD68+ macrophages. In addition, we tested an experimental immunomodulatory regimen in promoting long-term islet xenograft survival, a triple therapy consisting of donor splenocytes treated with ethylcarbodiimide (ECDI-SP), and peri-transplant rituximab and rapamycin. We observed that the triple therapy effectively inhibited graft infiltration of T and B cells as well as macrophages, promoted transitional B cells both in the periphery and in the islet xenografts, and provided a superior islet xenograft protection. Our study therefore indicates an advantage of donor ECDI-SP treatment in controlling human immune cells in promoting long-term islet xenograft survival.

Original languageEnglish (US)
Pages (from-to)1538-1550
Number of pages13
JournalAmerican Journal of Transplantation
Volume20
Issue number6
DOIs
StatePublished - Jun 1 2020

Bibliographical note

Funding Information:
This work was made possible from the grant support offered by the Northwestern University Transplant Surgery Scientist Training T32 grant (FTL) and by the Juvenile Diabetes Research Foundation (JDRF‐SRA‐259‐S‐B, to AD, YY, BH, SDM, XL). We thank the Immunobiology Flow Cytometry Core, the Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Core and Pathology Core Facilities, as well as the Center for Advanced Microscopy and Nikon Imaging Center at Northwestern University for helping us with flow cytometric analyses, histologic preparation of samples and image acquisition resources, respectively.

Publisher Copyright:
© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons

Keywords

  • basic (laboratory) research/science
  • immunosuppression/immune modulation
  • islet transplantation
  • rejection
  • tolerance
  • xenoantigen
  • xenotransplantation

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