CD52-negative NK cells are abundant in the liver and less susceptible to alemtuzumab treatment

Ryuichi Hotta, Masahiro Ohira, Toshiharu Matsuura, Izumi Muraoka, Panagiotis Tryphonopoulos, Ji Fan, Akin Tekin, Gennaro Selvaggi, David Levi, Phillip Ruiz, Camillo Ricordi, Rodrigo Vianna, Hideki Ohdan, Herman Waldmann, Andreas G. Tzakis, Seigo Nishida

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: T-cell depleting strategies have become an integral part of immunosuppressive regimens in organ transplantation. Alemtuzumab is a humanized monoclonal antibody against CD52, a cell-surface antigen on several immune cells. It has been suggested that lymphocyte depletion increases the risk of serious infections. However, this has not been observed with short-term alemtuzumab treatment in an organ transplant setting. For induction therapy using alemtuzumab following liver transplantation, we found that T- and B-cell numbers declined rapidly after alemtuzumab therapy; however, the natural killer (NK) cell number was sustained. NK cells are important effectors of innate immunity. Since the effects of alemtuzumab on NK cell functions, especially those of liver NK cells, are unknown, this study aimed to investigate this in detail. Methods: To assess the effect of alemtuzumab on NK cells, samples were obtained from 7 organ donors and examined by flow cytometry using Annexin V and propidium iodide. Phenotypical and functional differences within subsets of NK cells with different levels of CD52 expression were determined by flow cytometry and in vitro cytotoxicity assays. Results: CD52 expression on NK cells was lower than that on other lymphocyte subsets. The liver contained a large number of CD52- NK cells compared with the peripheral blood. In vitro treatment of liver-derived NK cells with alemtuzumab did not result in cell death. In contrast, co-incubation with alemtuzumab induced cell death in peripheral blood mononuclear cells and non-NK cells in the liver. Furthermore, CD52- liver NK cells were more cytotoxic and produced more IFN-γ than CD52+ NK cells after cytokine activation. Conclusion: The liver contains a large number of CD52- NK cells. These cells are refractory to alemtuzumab and have robust activity. These findings indicate that CD52- NK cells persist and could protect against infection after alemtuzumab-based lymphocyte depletion.

Original languageEnglish (US)
Article numbere0161618
JournalPLoS One
Volume11
Issue number8
DOIs
StatePublished - Aug 1 2016

Fingerprint

natural killer cells
Natural Killer Cells
Liver
liver
Lymphocytes
Therapeutics
Flow cytometry
Lymphocyte Depletion
Cell death
hepatocytes
organ transplantation
lymphocytes
Blood
alemtuzumab
Transplantation (surgical)
flow cytometry
cell death
Antibodies, Monoclonal, Humanized
Flow Cytometry
Transplants

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Hotta, R., Ohira, M., Matsuura, T., Muraoka, I., Tryphonopoulos, P., Fan, J., ... Nishida, S. (2016). CD52-negative NK cells are abundant in the liver and less susceptible to alemtuzumab treatment. PLoS One, 11(8), [e0161618]. https://doi.org/10.1371/journal.pone.0161618

CD52-negative NK cells are abundant in the liver and less susceptible to alemtuzumab treatment. / Hotta, Ryuichi; Ohira, Masahiro; Matsuura, Toshiharu; Muraoka, Izumi; Tryphonopoulos, Panagiotis; Fan, Ji; Tekin, Akin; Selvaggi, Gennaro; Levi, David; Ruiz, Phillip; Ricordi, Camillo; Vianna, Rodrigo; Ohdan, Hideki; Waldmann, Herman; Tzakis, Andreas G.; Nishida, Seigo.

In: PLoS One, Vol. 11, No. 8, e0161618, 01.08.2016.

Research output: Contribution to journalArticle

Hotta, R, Ohira, M, Matsuura, T, Muraoka, I, Tryphonopoulos, P, Fan, J, Tekin, A, Selvaggi, G, Levi, D, Ruiz, P, Ricordi, C, Vianna, R, Ohdan, H, Waldmann, H, Tzakis, AG & Nishida, S 2016, 'CD52-negative NK cells are abundant in the liver and less susceptible to alemtuzumab treatment', PLoS One, vol. 11, no. 8, e0161618. https://doi.org/10.1371/journal.pone.0161618
Hotta R, Ohira M, Matsuura T, Muraoka I, Tryphonopoulos P, Fan J et al. CD52-negative NK cells are abundant in the liver and less susceptible to alemtuzumab treatment. PLoS One. 2016 Aug 1;11(8). e0161618. https://doi.org/10.1371/journal.pone.0161618
Hotta, Ryuichi ; Ohira, Masahiro ; Matsuura, Toshiharu ; Muraoka, Izumi ; Tryphonopoulos, Panagiotis ; Fan, Ji ; Tekin, Akin ; Selvaggi, Gennaro ; Levi, David ; Ruiz, Phillip ; Ricordi, Camillo ; Vianna, Rodrigo ; Ohdan, Hideki ; Waldmann, Herman ; Tzakis, Andreas G. ; Nishida, Seigo. / CD52-negative NK cells are abundant in the liver and less susceptible to alemtuzumab treatment. In: PLoS One. 2016 ; Vol. 11, No. 8.
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abstract = "Background: T-cell depleting strategies have become an integral part of immunosuppressive regimens in organ transplantation. Alemtuzumab is a humanized monoclonal antibody against CD52, a cell-surface antigen on several immune cells. It has been suggested that lymphocyte depletion increases the risk of serious infections. However, this has not been observed with short-term alemtuzumab treatment in an organ transplant setting. For induction therapy using alemtuzumab following liver transplantation, we found that T- and B-cell numbers declined rapidly after alemtuzumab therapy; however, the natural killer (NK) cell number was sustained. NK cells are important effectors of innate immunity. Since the effects of alemtuzumab on NK cell functions, especially those of liver NK cells, are unknown, this study aimed to investigate this in detail. Methods: To assess the effect of alemtuzumab on NK cells, samples were obtained from 7 organ donors and examined by flow cytometry using Annexin V and propidium iodide. Phenotypical and functional differences within subsets of NK cells with different levels of CD52 expression were determined by flow cytometry and in vitro cytotoxicity assays. Results: CD52 expression on NK cells was lower than that on other lymphocyte subsets. The liver contained a large number of CD52- NK cells compared with the peripheral blood. In vitro treatment of liver-derived NK cells with alemtuzumab did not result in cell death. In contrast, co-incubation with alemtuzumab induced cell death in peripheral blood mononuclear cells and non-NK cells in the liver. Furthermore, CD52- liver NK cells were more cytotoxic and produced more IFN-γ than CD52+ NK cells after cytokine activation. Conclusion: The liver contains a large number of CD52- NK cells. These cells are refractory to alemtuzumab and have robust activity. These findings indicate that CD52- NK cells persist and could protect against infection after alemtuzumab-based lymphocyte depletion.",
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AU - Hotta, Ryuichi

AU - Ohira, Masahiro

AU - Matsuura, Toshiharu

AU - Muraoka, Izumi

AU - Tryphonopoulos, Panagiotis

AU - Fan, Ji

AU - Tekin, Akin

AU - Selvaggi, Gennaro

AU - Levi, David

AU - Ruiz, Phillip

AU - Ricordi, Camillo

AU - Vianna, Rodrigo

AU - Ohdan, Hideki

AU - Waldmann, Herman

AU - Tzakis, Andreas G.

AU - Nishida, Seigo

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