Islet transplantation in the discordant tilapia-to-mouse model: a novel application of alginate microencapsulation in the study of xenograft rejection

Abstract

Background. Tilapia islet xenograft rejection is characterized by infiltration with macrophages (Mφs), eosinophils (Eφs), and T lymphocytes. The presence of these cells indicates they contribute to rejection; therefore, an attempt was made to assess their role through host immunomodulation. Methods. Tilapia islet cells were transplanted under the kidney capsule of streptozotocin diabetic Balb/c mice, which were then treated with one of several immunomodulatory regimes targeting Mφs, Eφs, or T cells. Mφs were depleted using either silica or liposome-entrapped Cl2MDP. Eφ migration was blocked using monoclonal antibodies (mAbs) targeting interleukin (IL)-4 or IL-5. T-cell function was altered with mAbs targeting CD3, CD4, or CD8. Finally, T helper (Th)1 and Th2 activity was altered by depleting essential Th1 or Th2 cytokines with mAbs or by promoting a Th1 response with the injection of exogenous IL-12. The effects of antibody-mediated immunomodulation on graft survival were initially screened by cotransplanting alginate-encapsulated, mAb-secreting hybridoma cells into the peritoneal cavity at the time of islet transplantation. Significant prolongation was then confirmed using purified antibodies injected at the time of islet transplantation. Rejected grafts were examined histologically, and immunohistochemistry was used to assess the cellular infiltrates for each of the treatment groups. Results. Modulation of Mφs and Eφs alone did not significantly delay functional rejection of tilapia islet grafts (maximal mean graft survival time [mGST]=7.1±1.7 and 9.4±3.4, respectively) compared with untreated controls (mGST=8.2±1.0). Treatment of transplanted animals with antibodies against CD3 or CD4 significantly promoted graft survival (maximal mGST=16.3±5.8 and 34.0±11.6, respectively), whereas targeting CD8 and Th1 and Th2 cytokines showed no prolonging effect (maximal mGST=7.8±2.9 and 9.5±4.3, respectively). Conclusion. Our results indicate that rejection in the tilapia-to-mouse model follows a pattern similar to other models of discordant islet cell xenotransplantation.