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Eur J Immunol. 1999 Feb;29(2):548-55.
Induction of interferon-gamma production in Th1 CD4+ T cells: evidence for two distinct pathways for promoter activation.

Yang J, Murphy TL, Ouyang W, Murphy KM.

Department of Pathology and Center for Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.

IFN-gamma produced by CD4+ T helper 1 (Th1) cells promotes protection against intracellular pathogens. Antigen activation of Th1 cells is an important mode of IFN-gamma induction, but here we analyze a second, antigen-nonspecific pathway capable of inducing full IFN-gamma transcription. IL-12 or IL-18 alone do not induce IFN-gamma mRNA, and only modestly augment antigen-induced IFN-gamma mRNA from Th1 cells. However, IL-12 and IL-18 together fully induce IFN-gamma transcription independently of TCR-activated signals, by a mechanism that does not simply involve Stat4 and NF-kappaB activation, but requires additional protein synthesis. Cyclosporin A inhibits TCR-induced IFN-gamma production, but not IL-12/IL-18-induced IFN-gamma production, biochemically discriminating between these pathways. These results suggest that the two pathways induce IFN-gamma production through functionally segregated but spatially overlapping cis-acting elements, similar to other genes under the control of two or more promoters.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10064070&dopt=Abstract

Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2082-6. ["Cited in Books","window.top.location='/entrez/query.fcgi?tool=pmcited&cmd=search&db=books&term=10051598[pmid]'","",""],
Interferon-induced human MxA GTPase blocks nuclear import of Thogoto virus nucleocapsids.

Kochs G, Haller O.

Abteilung Virologie, Institut fur Medizinische Mikrobiologie und Hygiene, Universitat Freiburg, D-79008 Freiburg, Germany.

Interferon-induced human MxA protein belongs to the dynamin superfamily of large GTPases. It exhibits antiviral activity against a variety of RNA viruses, including Thogoto virus, an influenza virus-like orthomyxovirus transmitted by ticks. Here, we report that MxA blocks the transport of Thogoto virus nucleocapsids into the nucleus, thereby preventing transcription of the viral genome. This interaction can be abolished by a mAb that neutralizes the antiviral activity of MxA. Our results reveal an antiviral mechanism whereby an interferon-induced protein traps the incoming virus and interferes with proper transport of the viral genome to its ultimate target compartment within the infected cell.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10051598&dopt=Abstract

Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2268-73.
Systemic administration of interleukin 2 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines.

Shimizu K, Fields RC, Giedlin M, Mule JJ.

Department of Surgery, 1520 MSRB-I, University of Michigan Medical Center, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0666, USA.

We have reported previously that murine bone marrow-derived dendritic cells (DC) pulsed with whole tumor lysates can mediate potent antitumor immune responses both in vitro and in vivo. Because successful therapy was dependent on host immune T cells, we have now evaluated whether the systemic administration of the T cell stimulatory/growth promoting cytokine interleukin-2 (IL-2) could enhance tumor lysate-pulsed DC-based immunizations to further promote protective immunity toward, and therapeutic rejection of, syngeneic murine tumors. In three separate approaches using a weakly immunogenic sarcoma (MCA-207), the systemic administration of nontoxic doses of recombinant IL-2 (20,000 and 40,000 IU/dose) was capable of mediating significant increases in the potency of DC-based immunizations. IL-2 could augment the efficacy of tumor lysate-pulsed DC to induce protective immunity to lethal tumor challenge as well as enhance splenic cytotoxic T lymphocyte activity and interferon-gamma production in these treated mice. Moreover, treatment with the combination of tumor lysate-pulsed DC and IL-2 could also mediate regressions of established pulmonary 3-day micrometastases and 7-day macrometastases as well as established 14- and 28-day s.c. tumors, leading to either significant cure rates or prolongation in overall survival. Collectively, these findings show that nontoxic doses of recombinant IL-2 can potentiate the antitumor effects of tumor lysate-pulsed DC in vivo and provide preclinical rationale for the use of IL-2 in DC-based vaccine strategies in patients with advanced cancer.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10051630&dopt=Abstract

J Infect Dis. 1999 Apr;179(4):967-73.
Cytokine profile induced by Cryptosporidium antigen in peripheral blood mononuclear cells from immunocompetent and immunosuppressed persons with cryptosporidiosis.

Gomez Morales MA, La Rosa G, Ludovisi A, Onori AM, Pozio E.

Laboratory of Parasitology, Istituto Superiore di Sanita, 00161 Rome, Italy.

The proliferative response of peripheral blood mononuclear cells (PBMC) to a crude extract from Cryptosporidium parvum (CCE) was studied in persons who acquired cryptosporidiosis in the same outbreak (15 immunocompetent subjects with prior cryptosporidiosis and 22 human immunodeficiency virus [HIV]-positive persons with various levels of immunosuppression and active cryptosporidiosis) and in individual patients (8 HIV-positive patients with active cryptosporidiosis and 15 HIV-positive persons without history of cryptosporidiosis). PBMC from HIV-positive persons showed less proliferation to CCE and mitogens than did PBMC from immunocompetent subjects with prior cryptosporidiosis, independent of CD4 cell count. In immunocompetent subjects, cytokine gene expression was consistent with cytokine production, whereas in HIV-positive subjects it was not. The production of interferon-gamma in CCE-stimulated PBMC from both immunocompetent and HIV-positive subjects with cryptosporidiosis and the lack of interferon-gamma in CCE-stimulated PBMC from HIV-positive subjects without cryptosporidiosis indicate that C. parvum mainly induces a Th1 response.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10068593&dopt=Abstract

Ann Oncol. 2003 Mar;14(3):358-65.
Adjuvant therapy of cutaneous melanoma: the interferon debate.

Kefford RF.

Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Wentworthville, NSW.

Despite the use of a variety of cytotoxic and immunotherapeutic agents in adjuvant trials in patients following resection of high-risk early cutaneous melanoma, only interferon-alpha2b (IFN-alpha) has shown reproducible efficacy. High-dose IFN-alpha (HDI) is superior to observation in prolonging relapse-free survival. There is still no formal proof of a statistically significant advantage of HDI in prolonging overall survival. For this reason the continued use of observation-only control arms is justified and desirable in adjuvant melanoma trials, and, wherever possible, patients with resected high-risk and intermediate-risk melanoma should be entered on these studies. The toxicity of HDI is high, but the majority of patients complete treatment with dose modification and nearly all toxicity is rapidly reversible. There is now a useful body of information on the supportive care of patients receiving HDI, and data on cost and quality-adjusted time without symptoms and toxicity (Q-TwiST) to support its use in certain high-risk patients. Interim results from a trial of intermediate-dose IFN-alpha are promising. These, and ongoing studies of pegylated IFN-alpha, and of shorter induction-only HDI promise refinements in treatment which may improve efficacy:toxicity ratios.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12598338&dopt=Abstract [PubMed - in process]

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