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

• Published in: American journal of transplantation Vol. 20; no. 6; pp. 1538 - 1550
• Main Authors: Lee, Frances T., Dangi, Anil, Shah, Sahil, Burnette, Melanie, Yang, Yong‐Guang, Kirk, Allan D., Hering, Bernhard J., Miller, Stephen D., Luo, Xunrong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.06.2020
• Subjects: Animals; B-Lymphocytes; basic (laboratory) research/science; Beta cells; CD4 antigen; CD44 antigen; CD45 antigen; Diabetes mellitus (insulin dependent); Graft rejection; Graft Rejection - prevention & control; Graft Survival; Helper cells; Immune response; Immunomodulation; Immunomodulators; immunosuppression/immune modulation; Immunotherapy; Infiltration; Islet cells; islet transplantation; Islets of Langerhans Transplantation; Lymphocytes T; Macrophages; Mice; Monoclonal antibodies; Pancreatic islet transplantation; Rapamycin; rejection; Rituximab; Splenocytes; Swine; Th17 Cells; tolerance; Transplantation, Heterologous; Transplants & implants; xenoantigen; Xenografts; xenotransplantation; immunosuppression/immune modulation; islet transplantation; xenotransplantation; xenoantigen; rejection; tolerance; basic (laboratory) research/science
• ISSN: 1600-6135; 1600-6143; 1600-6143
• DOI: 10.1111/ajt.15763

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. To assess and control human immune responses against xenogeneic transplantation of porcine islet cells, this study uses a unique humanized mouse model of porcine islet transplantation that ultimately elucidates the important roles of human B and Th17 cells in the mechanisms of antixenoislet rejection.