Background: Recent studies have demonstrated that inhibition of CD26 potentiates stromal cell-derived factor-1α (SDF-1α) promotes tissue regeneration and suppresses the rejection of organ transplants. This study investigated whether the combination of a CD26 inhibitor (CD26i) with granulocyte colony-stimulating factor (G-CSF) and short-term immunosuppressants modulates vascularized composite tissue allotransplant (VCA) survival in a rodent orthotopic hindlimb allotransplant model. Methods: The hindlimb allotransplantation from Brown-Norway to Lewis rats were divided into 4 groups. Group 1 (controls) did not receive any treatment. Group 2 was treated with short-term antilymphocyte serum (ALS) and cyclosporine-A (CsA). Group 3 was administrated CD26i and G-CSF. Group 4 received a combination of CD26i/G-CSF/ALS/CsA. Each subgroup comprised 10 rats. Peripheral blood and sampling of transplanted tissues were collected for immunological and histological analysis. Results: The results revealed that allotransplant survival was significantly prolonged in group 4 with CD26i/G-CSF/ALS/CsA treatment compared to those in the other groups. The IL-10 and TGF-βl levels, the percentage of CD4+/CD25+/FoxP3+ T cells, as well as the levels of SDF-1α expressions were significantly increased in group 4 compared to those in the other groups. Group 4 revealed a statistical increase of the percentage of donor cells (RT1n) expression in the recipient peripheral blood, and the mixed lymphocyte reaction showed hyporesponsiveness of the T-cells to donor alloantigens. Conclusion: The combination of CD26i/G-CSF and short-term immunosuppressants prolongs allotransplant survival by inducing immunoregulatory effects and enhancing the percentage of SDF-1α expression. This immunomodulatory approach has great potential as a strategy to increase VCA survival. # First 2 authors have equal contribution as co–first author. Financial disclosure: This work was partly supported by grant MOST 108-2314-B-037-084 -MY3 from the Ministry of Science and Technology, Taiwan and MOHW107-TDU-B-212-123006 from the Ministry of Health and Welfare, Taiwan; and in part by grants SA10801, KMUH108-8M18, KMUH108-8M29, and KMUH108-8R31 from Kaohsiung Medical University Hospital, Taiwan; KMU-TC108A02-5 and 105KMUOR06 from Kaohsiung Medical University, Taiwan. Disclaimer: We declare that we have no conflicts of interest. Competing interests: The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. Availability of supporting data: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Correspondence: Dr Yur-Ren Kuo, MD, PhD Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, 100 Tzyou 1st Rd., Kaohsiung 80756, Taiwan. Phone: +886-7-3121101, ext. 7675, Fax: +886-7-7311482 E-mail: kuoyrren@gmail.com Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
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