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Department of Dermatology, Universitatsklinikum Düsseldorf, Düsseldorf, Germany
To the EditorI read with interest the recent article by Marchetti et al. [1]. Besides the fact that 22 individuals (3 of whom were lost to follow-up) represent a rather small sample size to assess the clinical value of adjunctive interleukin (IL)2, the authors claim that IL-2 adjuvant therapy is associated with a reduced risk of human immunodeficiency virus (HIV)related clinical events; however, given the small sample size, this statement should be reserved for currently ongoing larger phase 2 and 3 trials (e.g., SILCAAT [Study of IL-2 in People with Low CD4+ T Cell Counts on Active Anti-HIV Therapy] and ESPRIT [Evaluation of Subcutaneous Proleukin in a Randomized International Trial]).
Moreover, it is incorrect to call their results the "first evidence, in a randomized study, of a potential clinical benefit of IL-2 therapy" [1, p. 613] by referring to the incidence of thrush and herpes zoster. In 1998, we published a study suggesting a clinical benefit in individuals treated with adjunctive highly active antiretroviral therapy (HAART) [2]. In that study, 44 patients were randomly assigned to receive IL-2 (9 × 106 IU/day) for 5 consecutive days, either every 6 weeks or whenever the CD4 cell count dropped below the 1.25-fold of baseline, and were compared with 20 control patients who were receiving HAART alone. Besides significant increases in CD4 cell counts and reduced lymphocyte activation markers (major histocompatibility complex class II, CD25, and CD38), we looked for delayed-type hypersensitivity reactions against common recall antigens that increased in both IL-2 groups but did not reach statistical significance. Of note, delayed-type hypersensitivity reactions against the recombinant gp41 MN protein of HIV improved significantly (P < .05) in this trial, and no opportunistic infections in either of the IL-2 groups were observed, compared with 3 control patients with Kaposi sarcoma. Moreover, dermatological indicator diseases of declining immunocompetence, such as thrush, condyloma, and herpes simplex, occurred less frequently in the IL-2 groups.
In addition, the authors refer to CD25 as the "high-affinity IL-2 receptor" [1, p. 613], which is incorrect. IL-2 binds to 2 different receptors, which are composed of 3 different chains: the (CD25), the (CD122), and the (CD132). IL-2 binds to the - receptor with intermediate affinity (dissociation constant factor [Kd] 10-9) and to the -- receptor with high affinity (Kd10-11), whereas low-affinity receptors (CD25) lack an intracytoplasmic tail with signaling function [3]. The c or common cytokine chain (CD132) is also shared by IL-4, IL-7, IL-9, and IL-15 and is constitutively transcribed in lymphocytes [4, 5]. Although expression of CD25 is classically induced by antigenic stimulation, IL-2 alone is sufficient to induce expression of CD25 and progression of T cells through the cell cycle [6]. These discrepancies are frequently found in the literature and probably relate to the lack of reagents in the past; consequently, the expression levels of the and chains of the IL-2 receptor have not been tested. Therefore, it remains unknown whether the expression of CD25 is an indication of cells expressing the high-affinity IL-2 receptor and, thus, are more likely to proliferate in response to IL-2.
References
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Nelson BH, Willerford DM. Biology of the interleukin-2 receptor. Adv Immunol 1998; 70:181.
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