Late-phase human T-cell lymphotropic virus

In early phases of human T-cell lymphotropic virus I-induced adult T-cel luemia (ATL), the malignant cell proliferation is acted with an autocrine process Involving coordinate esso of interleukin (IL) 2 and its r or.

Thirteen patients with recurrent glioblastoma were treated with adoptively transferred autologous lymphokine activated killer (LAK) cells and recombinant interleukin-2 (rIL-2). Patients' blood mononuclear cells (MNC) obtained by leukapheresis were cultured at 2.5 million MNC per ml for 3 to 5 days in media containing 1000 U rIL-2/ml. After incubation, the nonadherent MNC from all cultures (0.5-5 X 10(9] were combined and concentrated for infusion in 5 to 10 ml saline containing 10(6) U rIL-2. Nine patients received one injection of LAK cells and rIL-2 into the brain tissue immediately surrounding the tumor cavity during craniotomy for subtotal tumor removal (Group 1). On each of the 3 days after surgery, patients received boosters of 10(6) U rIL-2 delivered into the tumor cavity through a skin flap or via an Ommaya reservoir. Approximately 1 to 2 weeks after this series of injections, these patients were treated with a second cycle of LAK cells and rIL-2 injected into the tumor cavity using the reservoir. Four patients received both adoptive immunotherapy cycles by intracavitary injection (Group 2). In this relatively small patient pool, neither age, sex, Karnofsky score, treatment history, nor anticonvulsant and steroid dosage appeared to influence a patient's ability to make LAK cells. The therapy, itself, was well-tolerated by all patients although they all displayed symptoms of aseptic meningitis and increased intracranial pressure, i.e., headache, fever, malaise on the days of LAK cell and/or rIL-2 infusion. The therapy did not appear to have a significant impact on patient survival (mean, 30 weeks) especially for those patients with a high postsurgical tumor burden. As the therapy is safe, the authors believe its efficacy can best be tested in patients with a newly diagnosed or recurrent glioblastoma which lies in an area where a near-total resection is possible.

Interleukin 2 (IL-2)-mediated signaling through its high-affinity receptor involves a complex interrelationship between IL-2 and two IL-2-binding chains, IL-2R a and (3 chains. Previously with the reagents available it was difficult to define functional interactions between these two IL-2R subunits involved in IL-2 binding and signal transduction. To extend our understanding of the interplay between the two binding subunits we have done studies with the monoclonal antibody HIEI, which interferes with interaction of IL-2R a and 13 chains (IL-2Ra and IL-2R13, respectively). Furthermore, we used two forms of IL-2, recombinant native IL-2 and F42A, an IL-2 analog (Phe-42 -Ala substitution) that binds only to IL-2R(3. Analog F42A manifested 75-100% of the bioactivity of wild-type IL-2. This observation is inconsistent with the strict hierarchical IL-2-binding affinity conversion model previously proposed by Saito and coworkers [Saito Y., Sabe, H., Suzuki, N., Kondo, S., Ogura, T., Shimizu, A. & Honjo, T. (1988) J. Exp. Med. 168, 1563-1572 that predicted an ordered sequence of events in which IL-2 must first bind to IL-2Ra before its interaction with IL-2R1. Previous investigations using IL-2 variants were interpreted to show that IL-2Ra merely acts to concentrate IL-2 to the cell surface and that no other meaningful interaction occurred between IL-2Ra and IL-2R13. However, our data are inconsistent with this view.We draw this conclusion on the basis of our observation that antibody HIEI, which reacts with an epitope of IL-2Ra and interferes with interaction of this chain and IL-2R13, inhibits the IL-2-dependent proliferative effects mediated by analog F42A. Furthermore, by blocking interaction of IL-2Ra and IL-2Rj3 with the antibody HIEI, a decrease in the affinity of radiolabeled analog F42A for IL-2R(3 was seen. In our proposed model IL-2Ra contributes several functions to IL-2-mediated signaling through the high-affinity IL-2R. These functions include concentration of IL-2 within the twodimensional surface of the plasma membrane as well as alteration of the functional capacity of IL-2RB, an effect that does not require prior binding of IL-2 to IL-2Ra. The IL-2Ra-mediated augmentation of IL-2RP functions involves affinity conversion of IL-2R(3, increasing its affinity for IL-2, and may involve facilitation of IL-2-mediated signaling after binding of IL-2 to this IL-2RI3.The multichain IL-2R system is pivotal in the regulation and function of multiple cells in the immune system (1). There are three forms of cellular receptors for IL-2 based on their affinity for ligand, with Kd values 10-11 M, 10-9 M, and 10-8 M. We and others (2-6) have used monoclonal antibodies (mAbs) and radiolabeled IL-2 in crosslinking studies to chemically characterize the multiple subunits of this receptor. Initially, with the mAb anti-Tac, a 55-kDa IL-2R protein [now termed IL-2R a chain (IL-2Ra)] was identified (2, 7). Subsequently, with crosslinking methods, a 70/75-kDa IL-2-binding protein [p75, IL-2R ,B chain (IL-2R,3)] was defi...