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Eosinophils promote inducible NOS–mediated lung allograft acceptance
Oscar Okwudiri Onyema, Yizhan Guo, Qing Wang, Mark H. Stoler, Christine Lau, Kang Li, Christopher Daniel Nazaroff, Xingan Wang, Wenjun Li, Daniel Kreisel, Andrew E. Gelman, James J. Lee, Elizabeth A. Jacobsen, Alexander Sasha Krupnick
Oscar Okwudiri Onyema, Yizhan Guo, Qing Wang, Mark H. Stoler, Christine Lau, Kang Li, Christopher Daniel Nazaroff, Xingan Wang, Wenjun Li, Daniel Kreisel, Andrew E. Gelman, James J. Lee, Elizabeth A. Jacobsen, Alexander Sasha Krupnick
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Research Article Immunology Transplantation

Eosinophils promote inducible NOS–mediated lung allograft acceptance

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Abstract

Lungs allografts have worse long-term survival compared with other organ transplants. This is most likely due to their unique immunoregulation that may not respond to traditional immunosuppression. For example, local NO generation by inducible NOS (iNOS) is critical for lung allograft acceptance but associates with rejection of other solid organs. The source of NO in accepting lung allografts remains unknown. Here, we report that, unlike the case for other pulmonary processes in which myeloid cells control NO generation, recipient-derived eosinophils play a critical and nonredundant role in iNOS-mediated lung allograft acceptance. Depletion of eosinophils reduces NO levels to that of recipients with global deletion of iNOS and leads to a costimulatory blockade–resistant form of rejection. Furthermore, NO production by eosinophils depends on Th1 polarization by inflammatory mediators, such as IFN-γ and TNF-α. Neutralization of such mediators abrogates eosinophil suppressive capacity. Our data point to what we believe to be a unique and previously unrecognized role of eosinophil polarization in mediating allograft tolerance and put into perspective the use of high-dose eosinophil-ablating corticosteroids after lung transplantation.

Authors

Oscar Okwudiri Onyema, Yizhan Guo, Qing Wang, Mark H. Stoler, Christine Lau, Kang Li, Christopher Daniel Nazaroff, Xingan Wang, Wenjun Li, Daniel Kreisel, Andrew E. Gelman, James J. Lee, Elizabeth A. Jacobsen, Alexander Sasha Krupnick

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Figure 7

Modulation of CD8+ T cell proliferation and differentiation by E1-polarized eosinophil.

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Modulation of CD8+ T cell proliferation and differentiation by E1-polari...
(A) Proliferation, as measured by Ki67 expression among B6 CD45.1+ CD8+ T cells activated with BALB/c allogenic splenocytes, with or without the addition of E1 or E0 eosinophils. Data represent 1 of 2 experiments with 4 separate replicates per experiment. (B) In vitro differentiation, as measured by CD44 and CD62L expression on B6CD45.1+ CD8+ T cells stimulated by BALB/c allogenic splenocytes, with or without the addition of E1 or E0 eosinophils. (C) iNOS expression in CD8+ T cells activated with BALB/c allogenic splenocytes, with or without the addition of IFN-γ– and TNF-α–blocking antibodies (representative experiment of 4 separate MLRs). (D) Modulation of CD8+ T cell proliferation by E0 and E1 eosinophils in MLR of BALB/c allogenic splenocyte stimulators with IFN-γ and TNF-α blockade. (E) Schematic representation of the regulatory feedback loop between alloreactive lymphocytes and eosinophils in lung grafts. ns, P > 0.05; **P < 0.01. Comparison by Friedman’s test was used for paired data, while the Kruskal-Wallis test was used for the unpaired group of observations. Post-hoc analysis of differences and comparison of differences between pairs of data were performed with the Wilcoxon rank test and the Mann-Whitney U test for paired and unpaired observations, respectively. For the box plot, the bottom and top of the boxes represent the lower and upper quartiles, respectively; the dark band inside the box represents the median; and the top and bottom whiskers represent the maximum and minimum observed values, respectively.

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