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. 2013 Oct;13(10):2558-66.
doi: 10.1111/ajt.12423. Epub 2013 Aug 22.

Induction of cardiac allograft tolerance across a full MHC barrier in miniature swine by donor kidney cotransplantation

M L Madariaga  1 , S G Michel, M Tasaki, V Villani, G M La Muraglia 2nd, S Sihag, J Gottschall, E A Farkash, A Shimizu, J S Allan, D H Sachs, K Yamada, J C Madsen
Affiliations

Induction of cardiac allograft tolerance across a full MHC barrier in miniature swine by donor kidney cotransplantation

M L Madariaga et al. Am J Transplant. 2013 Oct.

Abstract

We have previously shown that tolerance of kidney allografts across a full major histocompatibility complex (MHC) barrier can be induced in miniature swine by a 12-day course of high-dose tacrolimus. However, that treatment did not prolong survival of heart allografts across the same barrier. We have now tested the effect of cotransplanting an allogeneic heart and kidney from the same MHC-mismatched donor using the same treatment regimen. Heart allografts (n = 3) or heart plus kidney allografts (n = 5) were transplanted into MHC-mismatched recipients treated with high-dose tacrolimus for 12 days. As expected, all isolated heart allografts rejected by postoperative day 40. In contrast, heart and kidney allografts survived for >200 days with no evidence of rejection on serial cardiac biopsies. Heart/kidney recipients lost donor-specific responsiveness in cell-mediated lympholysis and mixed-lymphocyte reaction assays, were free of alloantibody and exhibited prolonged survival of donor, but not third-party skin grafts. Late (>100 days) removal of the kidney allografts did not cause acute rejection of the heart allografts (n = 2) and did not abrogate donor-specific unresponsiveness in vitro. While kidney-induced cardiac allograft tolerance (KICAT) has previously been demonstrated across a Class I disparity, these data demonstrate that this phenomenon can also be observed across the more clinically relevant full MHC mismatch. Elucidating the renal element(s) responsible for KICAT could provide mechanistic information relevant to the induction of tolerance in recipients of isolated heart allografts as well as other tolerance-resistant organs.

Keywords: Heart transplantation; kidney transplantation; miniature swine; tolerance.

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Conflict of interest statement

Disclosure

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Figures

Figure 1
Figure 1. Histology from heart biopsies
(A) Heart biopsy at POD 29 after heart alone transplant showing ISHLT 3R (animal #21109). (B–D) Serial heart biopsies of tolerant animal, #20977, at POD 25 (B), POD 60 (C) and POD 189 (D). (E and F) Heart biopsy of long-term tolerant animal, #21016, showing no cardiac allograft vasculopathy in the left main coronary artery (E) or in the left anterior descending coronary artery (F). ISHLT, Society for Heart and Lung Transplantation; POD, postoperative day.
Figure 2
Figure 2. CML assays from heart/kidney recipients (n = 5)
Percent specific lysis at 100:1 effector:target ratio is plotted as a function of postoperative day. Response against donor-type (SLAdd) targets (-●-) and response against third-party (York) targets (-■-). CML, cell-mediated lympholysis.
Figure 3
Figure 3. MLR assays from heart/kidney recipients (n = 5)
Stimulation indices to donor-type (SLAdd, -●-) and third-party (York, -■-) peripheral blood mononuclear cells are plotted as a function of postoperative day. MLR, mixed-lymphocyte reaction.
Figure 4
Figure 4. Alloantibody response
Levels of circulating anti-SLAdd IgM (left) and IgG (right) alloantibody were measured by flow cytometry in heart alone (#s 21257, 21109, 21189) and heart/kidney (#s 21202, 21019, 21018, 20977, 21016) recipients. Data were normalized to the mean fluorescence intensity of negative control values to plot normalized mean fluorescence intensity as a function of postoperative day (POD).
Figure 5
Figure 5. Alloantibody response
Immunofluorescence staining of POD 40 alloheart biopsies with IgM or IgG alloantibody. In a representative heart alone recipient (#21109), heart grafts have positive IgM and IgG staining (A and B, respectively). In a representative heart/kidney recipient (#21019), heart grafts are negative for IgM and IgG staining (C and D, respectively). POD, postoperative day.
Figure 6
Figure 6. Skin graft
One long-term tolerant heart/kidney animal (#21019) underwent skin grafting on POD 162 with placement of autologous (SLAcc), donor (SLAdd) and third-party (SLAaa) skin grafts. Photos taken on Day 78 after skin grafting. POD, postoperative day.
See this image and copyright information in PMC

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