Suppression of human anti-porcine natural killer cell xenogeneic responses by combinations of monoclonal antibodies specific to CD2 and NKG2D and extracellular signal-regulated kinase kinase inhibitor

Tae Jin Kim, Nayoung Kim, Eun Ok Kim, Jong Rip Choi, Jeffrey A. Bluestone, Kyung-Mi Lee

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Natural killer (NK) cells can destroy xenogeneic tissues by antibody-dependent cell cytotoxicity (ADCC) and direct lysis. Unlike ADCC, activating interactions between human NK receptors and their cognate ligands in pigs are not fully elucidated. We set up this study to identify human NK activating receptors recognizing porcine cells isolated from distinct organs, e.g., aorta, cornea and liver, and to provide a molecular basis for effective immunosuppressive regimens. Among the array of NK receptors tested, NKp46, 2B4, CD49d, CD48, CD2 and NKG2D, only CD2 and NKG2D were shown to be involved in both cytotoxicity and cytokine (interferon-γ and tumour necrosis factor-α) production against porcine targets. Simultaneous blocking of CD2 and NKG2D by combining its monoclonal antibodies further suppressed xenogeneic NK responses. Moreover, addition of a suboptimal dose of, an extracellular signal-regulated kinase (ERK) kinase inhibitor, to those cells maximally reduced NK cytotoxicity, suggesting that ERK plays an important role in NK-mediated xenoreactivity. These impairments in NK cells were tightly associated with defective intracellular calcium mobilization and the subsequent degranulation process. Therefore, our data demonstrate a distinct role of CD2 and NKG2D on human NK cells in recognizing porcine grafts and further provide a potentially efficacious combinational regimen using anti-CD2 and anti-NKG2D monoclonal antibodies with in a pig-to-human transplantation model.

Original languageEnglish
Pages (from-to)545-555
Number of pages11
JournalImmunology
Volume130
Issue number4
DOIs
Publication statusPublished - 2010 Aug 1

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Extracellular Signal-Regulated MAP Kinases
Natural Killer Cells
Phosphotransferases
Swine
Monoclonal Antibodies
Antibody-Dependent Cell Cytotoxicity
Natural Cytotoxicity Triggering Receptor 1
Heterophile Antibodies
Immunosuppressive Agents
Cornea
Interferons
Aorta
Tumor Necrosis Factor-alpha
Transplantation
Cytokines
Ligands
Calcium
Transplants
Liver

Keywords

  • extracellular signal-regulated kinase kinase inhibitor
  • human natural killer cells
  • immunosuppression
  • monoclonal antibodies
  • xenotransplantation

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Suppression of human anti-porcine natural killer cell xenogeneic responses by combinations of monoclonal antibodies specific to CD2 and NKG2D and extracellular signal-regulated kinase kinase inhibitor. / Kim, Tae Jin; Kim, Nayoung; Kim, Eun Ok; Choi, Jong Rip; Bluestone, Jeffrey A.; Lee, Kyung-Mi.

In: Immunology, Vol. 130, No. 4, 01.08.2010, p. 545-555.

Research output: Contribution to journalArticle

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