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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5399-5406.
Prepublished online as a Blood First Edition Paper on March 7, 2007; DOI 10.1182/blood-2006-12-062943.
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Submitted December 19, 2006
Accepted February 12, 2007
Direct inhibition of CD40L expression can contribute to the clinical efficacy of daclizumab independently of its effects on cell division and Th1/Th2 cytokine production
James T Snyder, Jijia Shen, Hooman Azmi, Jeannie Hou, Daniel H. Fowler, and Jack A Ragheb*
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD
* Corresponding author; email: jr50b{at}nih.gov.
Humanized anti-CD25 antibodies (e.g. daclizumab) have been successfully used to treat several autoimmune diseases. Paradoxically, IL-2 blockade in mice can induce autoimmunity. An interspecies difference in the relative contribution of IL-2 to CD25+Treg versus CD25+ effector cell function might explain this conundrum. Consistent with this are reports that daclizumab inhibits human CD25+ effector cell cytokine production by blocking the expression of CD40L. However, in mice IL-4 and IL-12 regulate CD40L expression. As human Th1/Th2 cytokine production is also dependent on IL-2, daclizumab's inhibition of CD40L expression could be due to an indirect, rather than a direct effect of IL-2. Here, we clarify the mechanisms underlying CD40L expression. In contrast to the mouse, human CD40L is regulated by CD28 signaling and IL-2, not the principal Th1/Th2 polarizing cytokines. We find that CD40L is expressed on naive and memory cells and inhibited by daclizumab independently of cell division. Collectively, our results indicate that daclizumab could inhibit CD25+ effector T cell function in vivo by directly blocking CD40L expression. This difference between mice and humans may help explain the paradoxical effects of IL-2R blockade in the two species.
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