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Related post: hematopoietic progenitors along specific cell lineages may require downregulation of HB24 expression. Both HB9 and HB24 were found to be expressed at high levels in acute myelogenous leukemic cells as well as acute lymphocytic leukemic cells. In contrast, normal levels of HB24 and HB9 were found in RNA from bone marrow and peripheral blood B cells from patients with chronic leukemias. The levels of HB9 and HB24 were found to correlate with the clincal status of the patients with acute leukemias. A human T cell line transfected with the HB24 gene was found to induce tumors when injected into nude mice, in contrast, control cell lines failed to induce tumors. The tumors were clearly of human origin and maintained the phenotype of the transfected cell line. These studies suggest the possibility that over-expression of HB24 may have an important role in leukemogenesis. (Kehrl, Deguchi, Hong, Kozlow, Thevenin, Riva, Fauci, LIR/NIAID; Colligan, BRB/NIAID; Kirschenbaum, NIAID; Najfeld, Mayer, Mt. Sinai, NY; Katz, Georgetown; Fox, Yale). The Genetic Response of Primary T Lymphocytes to an Activation Signal: The Role of NF-kB and Other Genes in the Control of Immune Competence and Proliferation We have cloned and characterized a number of mitogen-inducible cDNAs isolated from our subtractive T cell library. Included among the encoded products of these genes are several cytokines, a transmembrane protein, a ras-related protein, a phosphatase, a steroid-receptor-like protein and several different transcription factors. Given their similarity with known proteins these rapidly induced Purchase Voveran Online gene products are likely pleiotropic effectors of the initial activation signal. Several of these proteins also resemble known signal-transducing proteins, allowing for further controls of the induced proteins by additional signals. In this scenario multiple decision points precede commitment to proliferate. A primary focus of our laboratory has been on the NF-kB transcription factor. This transcription factor is uniquely positioned during activation to play a major role in establishing immune competence: A large number of immunomodulatory factors and receptors are regulated by it. In addition, the HIV is highly responsive to NF-kB. We have for the first time cloned via our subtractive approach two genes encoding NF-kB activity, p50 and p50B. We determined that 13- 6 NF-kB is a family of homo- and fieterodimeric complexes. The predominant form of NF-kB is a p50/p65 heterodimer which is bound to its repressor IkB in the cytoplasm of cells. The preformed complex is primed for a signal which releases the inhibitor and thus allows for nuclear entry and DNA binding. In addition to p50/p65 other complexes exist, including those involving p50B, a protein unlOrder Voveran Online from activation-induced precursor molecules. These proteins are present in preformed complexes in resting cells but are also induced upon activation. This implies that NF-kB activity in cells comes in two distinct forms, one which depends on preformed complexes and another which depends on new synthesis following activation. Through the use of specific antibodies we discovered a large pool of p50 homodimers in the nucleus of resting cells. These p50 homodimers could act as competitive repressors of transactivating complexes, suggesting that they play a repressing role. These repressing homodimers in turn appear to be the target of another mitogen-inducible gene product, the Bcl-3 oncogene, which is structurally related to IkB. BcI-3, by physically Buy Voveran associating with p50, could counteract p50 homodimers, allowing KB-dependent transactivation by heterodimers like p50/p65. Our work shows that NF-kB activity Buy Cheap Voveran in cells is defined by a complex network of positively and negatively acting components. Such complexity in the components is likely to be reflected in multiple regulatory phenomena governing KB-dependent gene expression. (Siebenlist, Bours, Brown, Franzoso, Kanno, Bressler, Fauci, LIR/NIAID; Kelly, LP/NCI; Bravo, Squibb Inst. Mol. Biol.) Clinical, Immunopathoqenic, and Therapeutic Studies in the Vasculitides and Other Immune- Mediated Diseases Our protocols of cyclophosphamide (CP) and alternate day glucocorticoids (GC) for the treatment of Wegener granulomatosis (WG) and other systemic vasculitides have been extremely successful in inducing remissions in these formerly fatal diseases over the past 26 years. However, because of the long term toxicity observed with CP and the relatively high relapse rate (40-50%) over a prolonged period of time, we have been investigating the use of alternative therapies in these diseases. We have studied treatment with weekly low dose methotrexate (MTX) and GC in patients with WG and Takayasu arteritis. Fifty-two patients with WG have received MTX, including 29 with at least 6 months followup. Sixty-one percent of WG patients have achieved a MTX-induced remission and 64% have so far successfully discontinued GC therapy. Fifteen patients with Takayasu arteritis have also been treated with MTX and GC. These patients had previously either been GC-unresponsive or unable to achieve complete remission with GC therapy. In seven instances, the addition of a cytotoxic agent (CP in 6 cases, azathioprine in 1 case) also failed to provide GC-free remissions. Eight of 15 Takayasu arteritis patients thus far treated with MTX have achieved GC-free remissions and 5 additional patients who are in the process of tapering GC are taking 50% less GC than had previously been possible. Apart from Buy Voveran Online two patients having to discontinue MTX because of presumed drug-induced pneumonitis, this agent has been relatively well tolerated. The ultimate role of MTX in the treatment of these diseases is uncertain because of the small number of patients studied thus far and the short period of follow-up (mean period for WG = 15 months, and for Takayasu arteritis = 30 months). Patients with these 13- 7 diagnoses and other forms of systemic vasculitis will continue to be enrolled in each of these studies. Our studies of children with WG have demonstrated that children have a much greater incidence (48% vs 10%) of subglottic stenosis and nasal destruction (48% vs. 25%) than adults. The reasons for this distinction are unclear, but may relate to susceptibility of cartilaginous structures during periods of more rapid growth. Morbidity from disease and periods of more rapid growth. Morbidity from disease and treatment was substantial in children and encourages additional studies of alternative therapies. Treatment of systemic Purchase Voveran vasculitis would be greatly facilitated by a reliable laboratory marker of active disease. It has been suggested by others that anti-neutrophil cytoplasmic antibody titers represent such a tool in WG. However, our studies of serial titers in 53 patients indicate that this test is not adequately sensitive to be used as a sole criterion to modify treatment. (Hoffman, Leavitt, Kerr, Cid, Fauci, LIR/NIAID; Rottem, LCl/NIAID; Kleinman, Grant, LDBA/NIH; Hallahan, NIAID; Cotch, Kaslow, DMID/NIAID; Dickler, DAIT/NIAID; Lebovics, DIR/NIDCD). Pathogenesis of Chlamydia trachomatis Infections Studies have been in progress to define the clinical spectrum of chlamydial infection, to develop improved molecular diagnostic assays and to examine the pathogenesis of chlamydial infections in experimental animal models and in patients with genital, ocular and respiratory infections. Utilizing a variety of diagnostic assays, chlamydial genital infections continue to be highly prevalent among patients attending STD clinics with rates of 10 to Order Voveran 15%. Utilizing PCR, we have been able to demonstrate a marked increase in sensitivity compared to culture in identifying patients with chlamydial genital infection. PCR was positive in 75% of male partners to infected
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