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

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.

Xenogeneic Sertoli cells modulate immune response in an evolutionary distant mouse model through the production of interleukin‐10 and PD‐1 ligands expression

“…We further studied the effect of XtSCs transplantation on the immune system in vivo. Several studies have confirmed the protective role of Tregs in the modulation of immune response to xenografts, 38 whereas CD4 + IL‐17A + cells were associated with graft rejection in xenogeneic transplantation 39 . Although the in vitro model did not show any changes in these T‐cell populations, in vivo transplantation of XCs induced upregulation of CD4 + RORγt + cells, which was not observed after XtSCs transplantation, while the Treg population remained unchanged in both XtSC and XC groups.…”

Clinically available immunosuppression averts rejection but not systemic inflammation after porcine islet xenotransplant in cynomolgus macaques

“…68 Finally, we cultured isolated islets for 6-9 days before transplantation, which is beneficial in attenuating IBMIR by reducing tissue factor content. 69 In Cohorts 1-3, the immunosuppressive regimen including rapamycin and CTLA4-Ig 70-74 plus-minus leflunomide 3,23,75 or rituximab, 20,[76][77][78][79][80] resulted in rejection that was associated with (i) expansion of circulating T cells, including TEM, granzyme B + , and IFNγ + cells CD4 + and CD8 + as well as IL-17 + CD4 + T cells, (ii) elicitation of anti-pig IgG antibodies in some recipients, (iii) dense islet infiltrates with CXCR3 + T cells and islets staining for the chemokine IP-10, and…”

Particulate‐Based Single‐Dose Local Immunosuppressive Regimen for Inducing Tolerogenic Dendritic Cells in Xenogeneic Islet Transplantation

“…Multiple studies have reported prolonged xenograft survival when xenogeneic islets were transplanted into different diabetic models using cocktail immunosuppressive regimens. [46][47][48] We have recently reported the intraperitoneal administration of immunosuppressive agents comprising anti-CD19 mAb, clodronate liposomes, anti-CD154 mAb, FK, and rapamycin in pig-to-mouse islet transplantation. In this case, however, the systemic immunosuppressive regimen did not produce satisfactory outcomes, suggesting a need for more potent immunosuppression.…”