Regulating the expression of CD80/CD86 on dendritic cells to induce immune tolerance after xeno-islet transplantation

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• 作者：Nengwen Ke^a ; ¹ ; ^{kenengwen@scu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Anping Su^a ; ¹ ; ^{suanpingping@126.com" class="auth_mail" title="E-mail the corresponding author} ; Wei Huang^b ; Peter Szatmary^b ; Zhaoda Zhang^c ; ^{zhangzhaodake@126.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AO/PI ; acridine orange/propidium iodide ; APCs ; antigen presenting cells ; CTLA-4 ; T-lymphocyte-associated protein 4 ; DCs ; dendritic cells ; FCS ; Fecal calf serum ; FoxP3 ; forkhead box P3 ; HBSS ; Hanks&rsquo ; balanced salt solution ; IDO ; indoleamine 2 ; 3-dioxygenase ; IEQ ; islet equivalent number ; IPGTT ; intraperitoneal glucose tolerance test ; IS ; immunological synapse ; IL ; interleukin ; INF-γ ; interferon γ ; MLR ; mixed lymphocyte reactions ; PBS ; phosphate-buffered saline ; TGF-β ; transforming growth fact
• 刊名：Immunobiology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：221
• 期：7
• 页码：803-812
• 全文大小：2949 K

文摘

Antigen present cells (APCs) have been demonstrated to play dual roles in immune tolerance. Recently, compelling evidence indicates that APCs that express CD80, but not CD86 can protect allograft. We investigated whether modulation of CD80 in dendritic cells (DCs) offer protection for xeno-islets.

Methods

In vitro, isolated mature murine DCs received untransfection, transfection with CD86 siRNA or negative control siRNA. The DCs were used in mixed lymphocyte reaction in which rat islets and murine splenocytes were further added. On day 3 of co-culturing, the proliferation of lymphocytes was measured and interleukin (IL)-2, IL-4, IL-10, transforming growth factor β (TGF-β), interferon γ (INF-γ) and indoleamine 2,3-dioxygenase (IDO) from the supernatants were determined. Islets viability and function were also assessed. In vivo, streptozotocin-induced diabetic mice underwent rat islets transplantation were pre-treated with above DCs. At designated time, xeno-islets were subjected to histopathology, immunohistochemistry, survival time and functional tests. Peripheral blood T lymphocyte profiles were also examined.

Results

CD86-silenced-DCs had unchanged expression of CD80 and significantly suppressed the proliferation of lymphocytes. CD86-silenced-DCs simultaneously reduced IL-2 and INF-γ and increased IL-10, TGF-β and IDO, while had minimal effect on IL-4. The CD86-silenced-DCs also improved cell viability and function of xeno-islets when compared to untransfection and transfection control groups. In xeno-islets transplanted diabetic mice, transfer of CD86-silenced-DCs resulted in improved histopathology and dramatically prolonged survival time of the islets. These effects were also mirrored by the functional tests. Further analysis revealed that CD86-silenced-DCs had up-regulated levels of CD4⁺CD25⁺T cells in the peripheral blood compared to the other groups.

Conclusions

CD86-silenced-DCs induced immune tolerance of rat xeno-islets in recipient diabetic mice with up-regulated peripheral blood CD4⁺CD25⁺T cells.