Kidney-induced systemic tolerance of heart allografts in mice
Chao Yang, … , Robert B. Colvin, Alessandro Alessandrini
Chao Yang, … , Robert B. Colvin, Alessandro Alessandrini
Published September 17, 2020
Citation Information: JCI Insight. 2020;5(18):e139331. https://doi.org/10.1172/jci.insight.139331.
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Research Article Transplantation

Kidney-induced systemic tolerance of heart allografts in mice

Abstract

In swine and nonhuman primates, kidney allografts can induce tolerance of heart allografts, leading to their long-term, immunosuppression-free survival. We refer to this phenomenon as kidney-induced cardiac allograft tolerance (KICAT). In this study, we have developed a murine model for KICAT to determine the underlining cellular/molecular mechanisms. Here, we show that spontaneously accepted DBA/2J kidneys in C57BL/6 recipients induce systemic tolerance that results in the long-term acceptance of DBA/2J heart allografts but not third-party cardiac allografts. The state of systemic tolerance of hearts was established 2 weeks after transplantation of the kidney, after which time, the kidney allograft is no longer required. Depletion of Foxp3+ T cells from these mice precipitated rejection of the heart allografts, indicating that KICAT is dependent on Treg function. Acceptance of kidney allografts and cotransplanted heart allografts did not require the thymus. In conclusion, these data show that kidney allografts induce systemic, donor-specific tolerance of cardiac allografts via Foxp3 cells, and that tolerance is independent of the thymus and continued presence of the kidney allograft. This experimental system should promote increased understanding of the tolerogenic mechanisms of the kidney.

Authors

Chao Yang, Jifu Ge, Ivy Rosales, Qing Yuan, Edward Szuter, Ellen Acheampong, Paul S. Russell, Joren C. Madsen, Robert B. Colvin, Alessandro Alessandrini

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Figure 5

Depletion of Foxp3+ cells on cardiac graft survival.

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Depletion of Foxp3+ cells on cardiac graft survival. (A) Schematic repre...
(A) Schematic representation of the experimental design to assess the effect of early depletion of Foxp3+ Tregs on cardiac graft survival in KICAT. DBA/2 kidneys were first transplanted into unilaterally nephrectomized WT or Foxp3DTR B6 recipients; 14 days later, kidney grafts were removed and recipients received cervical DBA/2 heart transplants, combined with either DT or saline treatment, cardiac grafts survival was then monitored. Animals were divided into the following groups: group A (Foxp3DTR B6 recipient + DT); group B (Foxp3DTR B6 recipient + saline); group C (WT B6 recipient + DT). (B) Schematic representation of experimental design to assess the effect of late depletion of Foxp3+ Tregs on cardiac graft survival in KICAT. DBA/2 kidneys were first transplanted into unilaterally nephrectomized Foxp3DTR B6 recipients; 14 days later, kidney grafts were removed and recipients received cervical DBA/2 heart transplants. One hundred days after transplantation of cardiac allografts, recipient animals received DT treatment (group D), and survival of cardiac allografts was monitored. (C) Double immunohistochemical staining of CD3 (brown) and Foxp3 (blue) of DBA/2 heart allografts from long-term tolerant recipients (>day 70), including cotransplant recipients (left), and rejected cardiac grafts (≤day 7) (right). Scale bars: 200 μm. (D) Survival curves of cardiac grafts in each experimental group described in B and C (group A, n = 5; group B, n = 4; group C, n = 4; group D, n = 4). Graft survival curves were constructed by the Kaplan-Meier method. ****P < 0.0001, log-rank test.