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Suppressing Liver Natural Killer Cells Activation by Cotransplantation of Preactivated Mesenchymal Stem Cells Contributes to Improvement of Islet Graft Survival

Ishida, Nobuki; Ishiyama, Kohei; Saeki, Yoshihiro; Tanaka, Yuka; Ohdan, Hideki

doi: 10.1097/

Department of Gastroenterological and Transplant Surgery, Hiroshima University, Hiroshima, Japan.

Introduction: We have previously reported that enhancement of TNF-related apoptosis-inducing ligand (TRAIL)-mediated liver NK-cells activity after intraportal islet transplantation (IT) inhibits engraftment of islets. Recently, mesenchymal stem cells (MSCs) have been used to treatment of graft-versus-host disease following allogenic hematopoietic stem cell transplantation. MSCs could suppress donor alloreactive T cells as well as donor NK cells cytotoxicity. This immunomodulatory effect of MSCs adversely affects the graft-versus-leukemia effect, making it useful as a therapy during islet transplantation. In this study, we examined the immunomodulatory effect of MSCs on NK-cells activation and islet graft survival after IT.

Methods: To analyze the phenotypical alterations in liver NK cells after syngeneic IT, liver mononuclear cells were collected 3 days after intraportal administration of 300 islets with or without MSCs (5 × 104) from C57BL/6 mice. We confirmed that PGE2 production by MSCs, which has a suppressive effect on NK cells, was maximally enhanced after 24-hr stimulation with inflammatory cytokines (IFN-γ, TNF-α, and IL-1β). Therefore, we examined the suppressive effect of preactivated MSCs, which were cultured for 24 hr in the presence of inflammatory cytokines before IT. Additionally, we examined whether the transplantation of islets with either naive or preactivated MSCs improved islet graft survival in streptozotocin-induced diabetic mice.

Results: CD69 and TRAIL expressions in liver NK cells obtained from IT mice were significantly higher than that from naive mice (72.3 ± 10.1% vs. 29.0 ± 5.6%, p < 0.01; 43.2% ± 6.7% vs. 37.4% ± 6.6%, p < 0.01, respectively). These expressions in liver NK cells after cotransplantation of islets with naive MSCs were not suppressed, however cotransplantation of islets with preactivated MSCs significantly suppressed CD69 and TRAIL expressions in liver NK cells (vs. 41.6 ± 6.7%, p < 0.01; vs. 36.8 ± 3.8%, p < 0.05, respectively). Similarly, cotransplantation of islets with preactivated MSCs notably improved islet graft survival (5/6), whereas cotransplantation of islets with naive MSCs could not improve islet graft survival (0/5).

Conclusion: This is the first report to show that cotransplantation of preactivated MSCs suppress NK-cells activation after IT, which could contribute to the improvement of islet graft survival.

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