PD-1 and PD-L1 expression in cardiac transplantation
Section snippets
1. Animal models
The PD-1/PD-L1 pathway in the heart has been investigated in only a handful of animal studies but have been shown to play an important role in regulating allograft rejection and post-transplant immune responses [1], [2], [3] (Table 1). Wang et al [1] demonstrated PD-L1 deficiency alters the balance of peripheral lymphocytes and accelerates allograft rejection in the heart by increasing interferon-gamma production (IFN-γ), T-cell proliferation, cytotoxic T lymphocyte, and NK cell activation in
2. Human models
Published reports investigating the PD-L1/PD-1 pathway in human allograft hearts are rare. Early studies show PD-L1 is constitutively expressed in the native human heart [6,7]. We and others previously characterized fulminant immune therapy induced myocarditis secondary to PD-1/PD-L1 inhibitors, supporting evidence for severe lymphocytic proliferation with blockade of the pathway in the native human heart [8,9]. Histologic evaluation in this cohort showed strong PD-L1 expression in myocytes,
3. Results
Cardiac specimens from 18 patients (mean age 45, range 7 to 76 years), 40% female, were reviewed. Indications for transplantation included dilated cardiomyopathy, ischemic heart disease, active myocarditis, congenital heart disease and re-transplant for CAV. Immunosuppression therapy for all patients included tacrolimus, with most on an additional combination of mycophenolate mofetil and prednisone. All but 3 patients had therapeutic levels at or near the time of biopsy or explant (Table 1).
4. Discussion
We report for the first time, the baseline protein expression levels of PD-1 and PD-L1 in human transplanted hearts. We demonstrate ACR is associated with decreased PD-L1 expression in the lymphocyte cell population compared to PD-1 expression. In our patients with chronically rejecting hearts requiring re-transplantation for CAV, PD-L1 expression was nearly absent in multiple lymphocyte compartments while PD-1 expression was high. However, in non-transplanted human hearts, there was similar
5. Conclusion
Post transplantation immunosuppression alters the organ immunologic landscape in various ways. A basic understanding of the landscape of immune modulator protein expression for PD- L1 and PD-1 in the human cardiac allograft is important. Our findings support earlier animal models that report knockout of PD-L1 causes acceleration of cardiac allograft rejection.
Our preliminary results provide a critical roadmap for future knockout models of cellular rejection by defining baseline expression of
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Funding: This work was partly supported by an internal grant from the Duke Transplant Center to MB, DB and CM. This work was further supported by an NIH 1R38HL143612-01 to MB.
Declaration of competing interest: There are no conflicts of interest.