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.
Humanized anti-CD25 antibodies (eg, 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(+) T regulatory cell (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 human may help explain the paradoxical effects of IL-2R blockade in the 2 species.
Snyder
James T
JT
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA.
Shen
Jijia
J
Azmi
Hooman
H
Hou
Jeannie
J
Fowler
Daniel H
DH
Ragheb
Jack A
JA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D018106:CD28 Antigens / Q000502:physiology; D023201:CD40 Ligand / Q000037:antagonists & inhibitors* / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D000077561:Daclizumab; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D007074:Immunoglobulin G / Q000494:pharmacology*; D007155:Immunologic Factors; D007376:Interleukin-2 / Q000502:physiology; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018106:CD28 Antigens; D016207:Cytokines; D007074:Immunoglobulin G; D007155:Immunologic Factors; D007376:Interleukin-2; D023201:CD40 Ligand; D000077561:Daclizumab