Effect of anti-IL-2Rα antibody on IL-2-induced Jak/STAT signaling

Jean Tkaczuk, Chao Lan Yu, Shairaz Baksh, Edgar L. Milford, Charles B. Carpenter, Steven J. Burakoff, Dianne B. McKay

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Acute allograft rejection is driven by production of cytokines such as interleukin-2 (IL-2) that activate and expand alloreactive T cells by ligating high-affinity IL-2 receptors composed of three subunit chains: α, β, γThe α chain, expressed only on activated T cells, has become an important therapeutic target. Monoclonal antibodies (mAbs) that bind IL-2Rα chains significantly decrease transplant rejection. We examined the ability of the humanized anti-IL-2Rα antibody daclizumab to block high-affinity IL-2Rs and interrupt T-lymphocyte signaling. Our evaluation focused on a pathway critical for T-cell proliferation, the Jak/STAT pathway. Daclizumab markedly inhibited phosphorylation of the Jak1, Jak3 and STAT5a/b components of the IL-2R-dependent pathway. Suppression by daclizumab was associated with internalization of IL-2Rα but not IL-2Rβγ chains. High IL-2 doses overcame daclizumab-induced blockade of Jak/ STAT phosphorylation despite absent cell surface high-affinity IL-2Rs. Under these circumstances, IL-2-mediated Jak/STAT pathway activation might be generated through residual intermediate affinity IL-2Rβγ receptors, and this was demonstrated by complete blockade of signaling when anti-IL-2Rβ monoclonal antibody was added. Humanized antibodies are an important part of strategies to induce alloantigen tolerance. Understanding the molecular events associated with their beneficial clinical effect is critical to design of future immunosuppressive strategies.

Original languageEnglish
Pages (from-to)31-40
Number of pages10
JournalAmerican Journal of Transplantation
Volume2
Issue number1
DOIs
StatePublished - Jan 2002
Externally publishedYes

Keywords

  • Daclizumab
  • IL-2
  • Intracellular signaling
  • Jak
  • Monoclonal antibody

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