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LETTER TO THE EDITOR |
Effect of rituximab in refractory SLE: inhibition of Th1?
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan
Correspondence to: H. Okamoto, Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho Shinjuku, Tokyo 162-0054, Japan. E-mail: hokamoto{at}ior.twmu.ac.jp
SIR, The report by Tokunaga et al. [1] clearly demonstrates that rituximab, a chimeric monoclonal antibody specific for human CD20, is highly effective against the life-threatening disease systemic lupus erythematosus (SLE). Furthermore, the authors demonstrate that rituximab not only reduces B-cell numbers and IgG levels, but also down-regulates CD40 and CD80 on B cells of treated patients. Interestingly, all of the five patients they studied had central nervous system (CNS) involvement (two had consciousness disorder and three had sensory disorder).
The balance between T-helper type 1 cells (Th1 cells) and Th2 cells in SLE patients remains controversial. Some reports have suggested that SLE is a disease in which the actions of peripheral Th2 cells predominate over those of Th1 cells [2, 3]. Other reports, however, suggest a predominance of Th1 cells in SLE patients having class IV lupus nephritis as defined by the World Health Organization (WHO) [4]. We recently reported that the level of the Th1 chemokine interferon-inducible protein 10 (IP-10)/CXCL10 is increased in the cerebrospinal fluid of patients with CNS lupus and demonstrated that CNS involvement in SLE is an immunological disorder of Th1 predominance [5].
Several reports have shown that both CD40/CD40L and CD80/CD28 interactions are a prerequisite for the development of Th1 lineage cells [6–8]. Therefore, rituximab-induced down-regulation of CD40 and CD80 on B cells might inhibit the activation and development of Th1 dominance by preventing CD40/CD40L and CD80/CD28-mediated downstream interactions, and thereby result in the suppression of Th1-predominant immunological disorders such as CNS lupus. Given the inhibitory effects of rituximab on interactions between CD40/CD40L and CD80/CD28, this drug is somewhat analogous to CTLA4-Ig, a human fusion protein combining the extracellular portion of the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) with the Fc region of human IgG [9]. In this case, however, rituximab inhibits not only B-cell functions but also Th1-cell activation and has an advantage over CTLA4-Ig, which is reported to inhibit only CD80/CD28 interactions. A comparative clinical study between rituximab and CTLA4-Ig is needed to reveal whether rituximab is more effective than CTLA4-Ig for the treatment of lupus. Taken all the data together, rituximab is an efficient immunosuppressive strategy. As we pointed out previously, clinicians should be aware of the risk of the development of severe infections following treatment with rituximab [10]. In this regard, the strategy proposed by Tokunaga et al. is well considered since they successfully treated their patients with only a few injections of rituximab.
The authors have declared no conflicts of interest.
References
- Tokunaga M, Fujii K, Saito K et al. Down-regulation of CD40 and CD80 on B cells in patients with life-threatening systemic lupus erythematosus after successful treatment with rituximab. Rheumatology 2005;44:176–82.
[Abstract/Free Full Text] - Funauchi M, Ikoma S, Enomoto H, Horiuchi, A. Decreased Th1-like and increased Th2-like cells in systemic lupus erythematosus. Scand J Rheumatol 1998;27:19–24.
- Okamoto H, Koizumi K, Yamanaka H, Saito T, Kamatani N. A role for TARC/CCL17, a CC chemokine, in systemic lupus erythematosus. J Rheumatol 2003;30:2369–73.[Medline]
- Akahoshi M, Nakashima H, Tanaka Y et al. Th1/Th2 balance of peripheral T helper cells in systemic lupus erythematosus. Arthritis Rheum 1999;42:1644–8.[CrossRef][ISI][Medline]
- Okamoto H, Katsumata Y, Nishimura K, Kamatani N. Interferon-inducible protein 10/CXCL10 is increased in the cerebrospinal fluid of patients with central nervous system lupus. Arthritis Rheum 2004;50:3731–2.[CrossRef][Medline]
- Kamanaka M, Yu P, Yasui T et al. Protective role of CD40 in Leishmania major infection at two distinct phases of cell-mediated immunity. Immunity 1996;4:275–81.[CrossRef][ISI][Medline]
- Bagenstose LM, Agarwal RK, Silver PB et al. Disruption of CD40/CD40-ligand interactions in a retinal autoimmunity model results in protection without tolerance. J Immunol 2005;175:124–30.
[Abstract/Free Full Text] - Odobasic D, Kitching AR, Tipping PG, Holdsworth SR. CD80 and CD86 costimulatory molecules regulate crescentic glomerulonephritis by different mechanisms. Kidney Int 2005;68:584–94.[CrossRef][Medline]
- Kremer JM, Westhovens R, Leon M et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003;349:1907–15.
[Abstract/Free Full Text] - Okamoto H, Kamatani N. Rituximab for rheumatoid arthritis. N Engl J Med 2004;351:1909–9.
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