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Kidney Week

Abstract: FR-PO1117

Contrasting Effects of Conventional Immunosuppressants in Establishing Murine Transplantation Tolerance

Session Information

  • Transplantation: Basic
    November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

  • 1901 Transplantation: Basic

Authors

  • Katsumata, Haruki, Tokyo Women's Medical University, Tokyo, Japan
  • Miyairi, Satoshi, Tokyo Women's Medical University, Tokyo, Japan
  • Hirai, Toshihito, Tokyo Women''s Medical University, Menlo Park, California, United States
  • Saiga, Kan, Tokyo Women''s Medical University, Menlo Park, California, United States
  • Okumi, Masayoshi, Tokyo Women's Medical University, Shinjuku, ToKyo, Japan
  • Ishii, Yasuyuki, REGiMMUNE Corporation, Tokyo, Japan
  • Yokoo, Takashi, The Jikei University School of Medicine, Minato-ku, Japan, Japan
  • Tanabe, Kazunari, Tokyo Women's Medical University, Shinjuku, ToKyo, Japan
Background

Tacrolimus (TAC) is one of the most commonly used calcineurin inhibitors (CNIs) for immunosuppression maintenance after kidney transplantation. It inhibits immune responses by suppressing T-cell receptor signaling and downstream expression of interleukin-2. An inhibitor of the mammalian target of rapamycin (mTOR-I) such as everolimus (EVL) shows immunosuppressive activity by inhibiting other pathways. Since, regulatory t cells (Treg) function depends on interleukin-2 signaling, CNIs could affect their suppressive potentials. However, mTOR-I has a weaker effect on Treg proliferation. We previously reported an approach to induce mixed chimerism by stimulating invariant natural killer T cells with liposomal formation of alpha-galactosylceramide (RGI-2001) and CD40 ligand (CD40L) blockade. We evaluated the impact of TAC or EVL on chimerism establishment and Treg in this regimen.

Methods

Recipient mice were treated with either TAC or EVL from day 1 to day 14 after bone marrow transplantation from donor mice, in addition to the regimen using sublethal irradiation, and a single injection of RGI-2001 and anti-CD40L antibodies. Then, we analyzed the proportion of donor cells and Treg in peripheral blood mononuclear cells. Isolated Treg were co-cultured with the mixture of host T cells and T-activator CD3/CD28 beads. After 4-day culture, the proliferation of responder cells was analyzed.

Results

In immunosuppressive drug-dosing phase, chimerism was comparably enhanced by TAC and EVL. Following drug discontinuation, TAC-treated mice exhibited a gradual decrease in the donor cell proportion. In contrast, EVL-treated mice sustained long-term robust chimerism. Treg of TAC-treated mice showed lower prolifration and low suppressive activity than EVL-treated mice.

Conclusion

TAC negatively impacted the regimen by interfering with Treg proliferation and activation.

Funding

  • Government Support - Non-U.S.