CD26 costimulatory blockade improves lung allograft rejection and is associated with enhanced interleukin-10 expression

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• 作者：Yoshito Yamada ; MD ; PhD^a ; ^b ; ¹ ; Jae-Hwi Jang ; PhD^a ; ¹ ; Ingrid De Meester ; PhD^c ; Lesley Baerts ; PhD^c ; Gwendolyn Vliegen ; MSc^c ; Ilhan Inci ; MD^a ; Ichiro Yoshino ; MD ; PhD^b ; Walter Weder ; MD^a ; Wolfgang Jungraithmayr ; MD ; PhD^a ; ^{wolfgang.jungraithmayr@usz.ch" class="auth_mail" title="E-mail the corresponding author}
• 关键词：mouse lung transplantation ; acute rejection ; CD26/DPP4 ; Th17 ; IL-10
• 刊名：Journal of Heart and Lung Transplantation
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：35
• 期：4
• 页码：508-517
• 全文大小：5124 K

文摘

The ectoenzyme CD26/dipeptidyl peptidase 4 (DPP4) has costimulatory activity that contributes to T cell activation and proliferation. Here, we aimed to target this costimulatory activity for the attenuation of the alloreactive Th17–cell response during acute rejection after mouse lung transplantation.

Methods

To test the CD26-costimulatory blockade in vitro, mixed lymphocyte reaction was performed between major histocompatibility complex class I and II fully mismatched cells (CD4⁺ splenocytes, C57BL/6, responders, and antigen-presenting cells, BALB/c, stimulators) by adding the CD26 inhibitor vildagliptin (0–15 μg). Lung transplantation between BALB/c (donor) and C57BL/6 (recipient) mice was performed, including controls, CD26-inhibited (CD26-I, daily administration of vildagliptin [GLSynthesis, Worcester, MA], 10 mg/kg subcutaneous), and CD26 knockout (CD26KO) mice was performed. Analysis on Day 1 and 5 after transplant included immunohistochemistry, fluorescence-activated cell sorting, and enzyme-linked immunosorbent assay (ELISA) for immune cell detection and their key cytokines.

Results

In vitro, there was a significant reduction of the Th17 cytokines interleukin (IL)-17 and IL-21. In vivo, CD26-I–treated and CD26KO mice showed significantly preserved macroscopic and histologic characteristics on Day 5 (p < 0.01), a higher partial pressure of arterial oxygen/fraction of inspired oxygen ratio (p ≤ 0.05), fewer infiltrating CD3⁺ T cells (p < 0.01), but more interstitial macrophages on Day 1 (p < 0.01) compared with control. Fewer IL-17⁺ cells were found in CD26-I allografts on Day 1 (p = 0.05). Higher levels of IL-10 in CD26-I and CD26KO allografts on day 5 were seen (p < 0.05). IL-10/CD206 double-staining (alternative macrophages) revealed more positive cells in CD26-I and CD26KO on Day 1 and 5 (p < 0.01).

Conclusions

CD26 costimulatory blockade promotes lung allograft acceptance via reduced T cell infiltration, less expression of IL-17, and increased expression of IL-10, likely to be derived from alternatively activated macrophages.