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Endocrine Care: Daniel El Fassi, Claus H. Nielsen, Steen J. Bonnema, Hans C. Hasselbalch, and Laszlo Hegedüs B Lymphocyte Depletion with the Monoclonal Antibody Rituximab in Graves’ Disease: A Controlled Pilot Study J Clin Endocrinol Metab 2007; 92: 1769-1772 [Abstract] [Full text] [PDF]

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Daclizumab and Graves' ophthalmopathy

Gabriele Rossi   (6 March 2007)

Daclizumab and Graves' ophthalmopathy 6 March 2007
Gabriele Rossi, Medical Doctor medecin Sans Frontieres Belgium Send letter to journal: Re: Daclizumab and Graves' ophthalmopathy gab.rossi{at}tiscali.it Gabriele Rossi	In his study El Fassi suggests that rituximab, by interfering with B and T cell-mediated autoimmunity, might be used in the setting of refractory severe Graves’ ophthalmopathy (GO) (1). The pathogenesis of GO substantially lies on the presence of an inflammatory-cell infiltrate predominantly composed of activated T cells producing cytokines (mainly IL-1, TNF-α, IFN-γ) which, in turn, activate orbital fibroblast secretion of glycosaminoglycans, further inducing orbital fibrosis and edema (2). The ‘ideal therapy’ for this disease would be a drug able to eliminate infiltrating activated T lymphocytes (or their pathologic effects), while sparing other T cells and immunity and avoiding life- threatening side effect. Other efforts to develop such drugs (i.e., anti-TNF-γ monoclonal antibody and anticytokine agents) have been detailed by Cawood et al. (3). While rituximab may be effective, it is important to remember that this drug has been associated with an increased risk of low respiratory tract infections (4). A possible cytokine storm reaction following his intravenous infusion has also been described. Another recent drug, daclizumab, is a 144-KDa humanised immunoglobulin G1 (IgG1) monoclonal antibody that binds specifically to the α-subunit (CD25, p55α, or Tac subunit) of the high-affinity interleukin-2 receptor (IL-2R), which is exclusively expressed on activated lymphocytes, and inhibits IL-2 binding (5). Most studies using daclizumab have been conducted both in solid organ transplantation (renal, pancreas and cardiac transplantation) (6, 7) and in some autoimmune disease (psoriasis, multiple sclerosis) (8, 9). In these studies, daclizumab has been proven to be very efficacious in decreasing the number and severity of rejection episodes in transplant recipients, as well as in controlling the underline diseases in autoimmune patients, without increasing the rate of adverse effects and/or infectious complications. No anaphylactic reactions have been reported, certainly due to the low immunogenicity of this humanised molecule. Moreover it has been shown that daclizumab (which exclusively targets activated autoreactive T cells) did not cause a failure of immune system (9). Noteworthy, a recent in vitro study has suggested that IL-2R antibodies abolish IL-12- independent IFN-γ production (10), which is one of the principal cytokines involved in the pathogenesis of thyroid eye disease. Altogether these data (specific deletion of activated T lymphocytes, suppression of IFN-γ production, lack of impairment of cellular and humoral immunity, absence of major side effect), make reasonable to consider the study of daclizumab as a potential treatment for Graves’ ophthalmopathy. References 1. El Fassi D, Nielsen CH, Bonnema SJ, Hasselbalch HC, Hegedus L. 2007. B lymphocyte depletion with the monoclonal antibody Rituximab in Graves' disease: A controlled pilot study. J Clin Endocrinol Metab (Epub ahead of print) 2. Weetman AP. 2000. Graves’ disease. New Engl J Med 343:1236-1248 3. Cawood T, Moriarty P, O’Shea D. 2004. Recent developments in thyroid eye disease. BMJ 329:385-390 4. Edwards JCW, Leandro MJ, Cambridge G. 2004. B lymphocyte depletion therapy with rituximab in rheumatoid arthritis. Rheum Dis Clin North Am 30:393-403 5. Hakimi J, Mould D, Waldmann TA, Queen C, Anasetti C, Light S. 1997. Development of Zenepax: a humanized anti-Tac antibody. In: Harris WJ, Adair JR. Antibody therapeutics. New York: CRC Press 6. Adu D, Cockwell P, Ives NJ, Shaw J, Wheatley K. 2003. Interleukin-2 receptor monoclonal antibodies in renal transplantation: meta-analysis of randomised trials. BMJ 326:789 7. Beniaminovitz A, Itescu S, Lietz K, Donovan M, Burke EM, Groff B, et al. 2000. Prevention of rejection in cardiac transplantation by blockade of the interleukin-2 receptor with a monoclonal antibody. New Engl J Med 342:613-619 8. Wohlrab J, Fischer M, Taube KM, Marsch WC. 2001. Treatment of recalcitrant psoriasis with daclizumab. Br J Dermatol 144:209-210 9. Maciejewski JP, Sloand EM, Nunez O, Boss C, Young NS. 2003. Recombinant humanized anti-IL-2 receptor antibody (daclizumab) produces responses in patients with moderate aplastic anemia. Blood 102:3584-3586 10. Mcdyer JF, Li Z, John S, Yu X, Wu C, Ragheb JA. 2002. IL-2 receptor blockade inhibits late, but not early, IFN-γ and CD40 ligand expression in human T cells: disruption of both IL-12-dependent and independent pathways of IFN-γ production. J Immunol 169: 2736-2746