The etiologic agent of adult T-cell leukemia (ATL) is human T cell lymphotropic virus type I (HTLV-I). The HTLV-I proteinTax alters gene expression, including those of cytokines and their receptors, which plays an important role in early stages of ATL. Here we demonstrate that expression of interleukin-9 (IL-9) is activated by Tax via an NF-B motif in its proximal promoter, whereas IL-9 receptor-␣ (IL-9R␣) expression is not induced by Tax. However, supporting a role for IL-9/IL-9R␣ in ATL, a neutralizing monoclonal antibody directed toward IL-9R␣ inhibited ex vivo spontaneous proliferation of primary ATL cells from several patients. Fluorescence-activated cell sorter analysis of freshly isolated peripheral blood mononuclear cells from these patients revealed high level expression of IL-9R␣ on their CD14-expressing monocytes. Furthermore, purified T cells or monocytes alone from these patients did not proliferate ex vivo, whereas mixtures of these cell types manifested significant proliferation through a contact-dependent manner. Taken together, our data suggest that primary ATL cells, via IL-9, support the action of IL-9R␣/CD14-expressing monocytes, which subsequently support the ex vivo spontaneous proliferation of malignant T cells. In summary, these data support a role for IL-9 and its receptor in ATL by a paracrine mechanism. (Blood. 2008; 111:5163-5172) IntroductionAdult T-cell leukemia (ATL) is a highly aggressive neoplasm characterized by a clonal expansion of CD4 ϩ lymphocytes and by a monoclonal integration of human T cell lymphotropic virus type I (HTLV-I) provirus(es) in the tumor cells. 1,2 HTLV-I is a type C retrovirus endemic in southern Japan, the Caribbean basin, Central and Southern Africa, and South America. 3,4 Less than 5% of HTLV-I-infected persons develop either ATL or a chronic inflammatory disease of the central nervous system termed HTLV-Iassociated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the precise mechanisms of ATL leukemogenesis remain unclear, it has been suggested that the transformation of T cells in the early stages of the disease is mediated by the HTLV-I Tax protein (p40). Tax activates long terminal repeat-directed transcription by recruiting members of the cAMP response element-binding/ and activating transcription factors family to the viral promoter. In addition, Tax activates other cellular transcription factors, such as NF-B. Tax is associated with the expression of cellular genes, 5 including the cytokine 6-10 and cytokine receptor genes. 7,[11][12][13] It has been suggested that the dysregulation of cytokines and their receptors in HTLV-I-infected persons may play an important role in the early course of disease via autocrine stimulation. 9,11 Interleukin-9 (IL-9) is a T cell-derived cytokine with pleiotropic activities on various cell types. 14-16 IL-9 is mainly expressed by activated CD4 ϩ T cells. 17 The functions of IL-9 are mediated through the IL-9 receptor (IL-9R), which is a member of the hematopoietin receptor superfamily. 18 The IL-9 recept...

Adoptive immunotherapy with antigen specific cytotoxic T lymphocytes (CTL) has been shown to be effective in restoring cellular immunity to cytomegalovirus (CMV) and preventing viral reactivation following allogeneic stem cell transplantation (SCT). In order to develop a cost-effective, relatively rapid method of CMV CTL expansion, we investigated the use of a pool of overlapping CMV peptides. Since the possibility exists of vaccinating CMV sero-negative donors, and these individuals may have T cell responses predominantly against IE-1, commercially available peptide mixes for pp65 as well as IE-1 were used to stimulate CTL from ten sero-positive donors. In four of these ten donors, responses were present to pp65 only, one donor did not respond to pp65 or IE-1, four donors responded to both pp65 and IE-1, and one donor to IE-1 only. These CMV specific T cells included a mixture of CD4+ and CD8+ effectors, and specific cytotoxicity correlated with IFN-γ production. The costs associated with a 28 day maintenance course of intravenous ganciclovir, cidofovir, foscarnet, and valganciclovir, as well as the preparation and shipping a single dose of CTL, were determined. The price of generating CMV CTL using this method was comparable to or less expensive than a 28-day maintenance course for these agents, not including the costs associated with drug administration, supportive care, and the treatment of drug-related complications. Considering the relative ease, low cost, and the fact that CTL administration can result in CMV specific immune reconstitution, this option should be considered for patients with CMV reactivation, or for prophylaxis in patients at high risk for infection.

We report a stem cell transplant patient with a therapy-refractory cytomegalovirus (CMV) infection who received CMV-specific T cells from his sero-negative stem cell donor. This donor received the Towne strain CMV vaccine, and T cells were expanded using monocytes pulsed with pp65 overlapping peptides. CMV DNA decreased after the CTL infusion, and CMV-specific cytotoxicity increased. This strategy could be implemented in similar situations or with persistent viremia post-transplant.

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