Lambda-Interferons Inhibit Herpes Simplex Virus Type 2 Replication in Human Cervical Epithelial Cells by Activating the JAK/STAT Pathway.

Herpes simplex virus type 2 (HSV-2) is associated with a variety of diseases that are health problems worldwide. Our early study showed that lambda-interferons (IFN-λs), induced by the activation of the Toll-like receptor 3 and retinoic acid-inducible protein I signaling pathways, contribute to inhibition of HSV-2 replication in human cervical epithelial cells. However, anti-HSV-2 mechanisms and specific differences in signaling transduction by different IFN-λs in human cervical epithelial cells remain unclear. In this study, we demonstrated potent inhibition of HSV-2 replication by IFN-λs without cytotoxicity. Investigation of the underlying mechanism(s) showed that IFN-λs induced expression of IFN-stimulated genes (ISGs) and enhanced the expression of several pattern recognition receptors (PRRs). Among the IFN-λs, IFN-λ3 induced higher levels of ISG and PRR expression. In addition, IFN-λs up-regulated a number of genes that encode components of the Janus kinase signal transducers and activators of transcription (JAK/STAT) signaling pathway. Inhibition of the JAK/STAT signaling pathway by a JAK inhibitor abolished IFN-λ-mediated anti-HSV-2 activity and induction of ISGs and PRRs, whereas the induction of ISGs and PRRs by IFN-λs was not compromised by HSV-2 infection. These findings provide further experimental evidence that IFN-λs have therapeutic potential for HSV-2 infections.

The effect of types I and III interferons on adrenocortical cells and its possible implications for autoimmune Addison's disease.

Autoimmune Addison's disease (AAD) is caused by selective destruction of the hormone-producing cells of the adrenal cortex. As yet, little is known about the potential role played by environmental factors in this process. Type I and/or type III interferons (IFNs) are signature responses to virus infections, and have also been implicated in the pathogenesis of autoimmune endocrine disorders such as type 1 diabetes and autoimmune thyroiditis. Transient development of AAD and exacerbation of established or subclinical disease, as well as the induction of autoantibodies associated with AAD, have been reported following therapeutic administration of type I IFNs. We therefore hypothesize that exposure to such IFNs could render the adrenal cortex susceptible to autoimmune attack in genetically predisposed individuals. In this study, we investigated possible immunopathological effects of type I and type III IFNs on adrenocortical cells in relation to AAD. Both types I and III IFNs exerted significant cytotoxicity on NCI-H295R adrenocortical carcinoma cells and potentiated IFN-γ- and polyinosine-polycytidylic acid [poly (I : C)]-induced chemokine secretion. Furthermore, we observed increased expression of human leucocyte antigen (HLA) class I molecules and up-regulation of 21-hydroxylase, the primary antigenic target in AAD. We propose that these combined effects could serve to initiate or aggravate an ongoing autoimmune response against the adrenal cortex in AAD.

Do ß-cells generate peroxynitrite in response to cytokine treatment?

The purpose of this study was to determine the reactive species that is responsible for cytokine-mediated ß-cell death. Inhibitors of inducible nitric oxide synthase prevent this death, and addition of exogenous nitric oxide using donors induces ß-cell death. The reaction of nitric oxide with superoxide results in the generation of peroxynitrite, and this powerful oxidant has been suggested to be the mediator of ß-cell death in response to cytokine treatment. Recently, coumarin-7-boronate has been developed as a probe for the selective detection of peroxynitrite. Using this reagent, we show that addition of the NADPH oxidase activator phorbol 12-myristate 13-acetate to nitric oxide-producing macrophages results in peroxynitrite generation. Using a similar approach, we demonstrate that cytokines fail to stimulate peroxynitrite generation by rat islets and insulinoma cells, either with or without phorbol 12-myristate 13-acetate treatment. When forced to produce superoxide using redox cyclers, this generation is associated with protection from nitric oxide toxicity. These findings indicate that: (i) nitric oxide is the likely mediator of the toxic effects of cytokines, (ii) ß-cells do not produce peroxynitrite in response to cytokines, and (iii) when forced to produce superoxide, the scavenging of nitric oxide by superoxide is associated with protection of ß-cells from nitric oxide-mediated toxicity.

In vivo pharmacology and toxicology evaluation of polyethylene glycol-conjugated interferon beta-1a.

Human interferon (IFN) ß has well established beneficial effects in treating relapsing forms of multiple sclerosis, but current first-line treatment requires frequent (from daily to weekly) parenteral administration. A 20-kDa polyethylene glycol (PEG)-conjugated IFN ß-1a (PEG-IFN ß-1a) is being developed to decrease the frequency of administration and improve patient convenience and compliance. We present pharmacokinetic (PK) and pharmacodynamic (PD) parameters, immunogenicity, and safety of PEG-IFN ß-1a in Rhesus monkeys in support of a phase 1 clinical trial. Two single-dose PK/PD studies and one 5-week repeat-dose toxicity study compliant with good laboratory practice were conducted. The PK of IFN ß-1a and PEG-IFN ß-1a were modeled with a two-compartment model, and the link between drug concentration and neopterin response (PD marker) was described with an indirect stimulatory model. PEG-IFN ß-1a showed greater exposure, longer half-life, lower clearance, and reduced volume of distribution than unmodified IFN ß-1a. Consistent with the pharmacology of type I IFNs, PEG-IFN ß-1a resulted in the elevation of neopterin concentration, a transient body temperature increase, and a reversible lymphocyte count decrease. As expected, neutralizing antibodies to PEG-IFN ß-1a formed in almost all monkeys after 5 weeks of treatment, which resulted in significantly reduced drug exposure and abrogation of neopterin induction. There were no drug-related adverse effects at doses up to 100 µg/kg (11 MIU/kg) given subcutaneously or intramuscularly once weekly for 5 weeks. The no-observed-adverse-effect level was determined to be 100 µg/kg (11 MIU/kg), the highest dose tested.

Interferón y depresión / Interferon and depression

El propósito del presente estudio es investigar la relación entre depresión y tratamiento con interferón en pacientes con esclerosis múltiple, hepatitis C crónica, melanoma y otras neoplasias. Se realizó revisión bibliográfica mediante Medline y se recurrió a los artículos originales. Esta revisión resume el conocimiento actual acerca de la prevalencia, mecanismos, factores de riesgo, curso clínico, complicaciones como el suicidio y tratamiento de la depresión inducida por interferón. Como conclusión, el manejo de la depresión inducida por interferón no debe ser exclusivo de neurólogos, gastroenterólogos, hepatólogos o especialistas en oncología sino que también implica a los psiquiatras

The aim of the present study was to investigate the relationship between depression and interferon treatment in patients with multiple sclerosis, chronic hepatitis C, melanoma, and other malignancies. The literature review utilized Medline and was supplemented by citations extracted from the original papers. This review summarizes current knowledge about prevalence, mechanisms, risk factors, clinical course, complications like suicide, and treatment of depression associated with interferon therapy. Finally, the management of depression induced by interferon is not exclusive of neurologist, gastroenterologist, hepatologist or oncologist specialists, but also concerns to psychiatrists

[Therapeutic use of interferons and their toxicity. Focus on peripheral neuropathy]. / Impiego terapeutico degli interferoni e tossicità correlata. Focus sulle neuropatie periferiche.

When evaluating the tolerability profile of interferons, the authors focus their attention on peripheral neuropathy, by assessing the epidemiological, pathogenetic, clinical, and outcome aspects, in relation with the administration of these drugs and the concurrent increase of risk factors associated with underlying diseases (including chronic viral hepatitis, solid organ malignancies, hematological disorders, autoimmune diseases, HIV infection). Even though it is often impossible to exclude a direct or indirect interferon-associated pathogenetic pathways in the occurrence of peripheral neuropathies, predominatly through immune-mediated mechanisms, the episodes reported by the international literature are steadily on the rise, paralleling the enlargement of therapeutic indications, and the availability of novel interferon formulations for clinical use. The increased indications of interferons in a broadening spectrum of clinical disorders, and especially their use in chronic hepatitis, recommend a strict monitoring of all possible adverse events, in order to reach a better epidemiological, pathogenetic, and clinical awareness of clinical events which are still infrequent, but potentially severe, such as those involving the peripheral nervous system.

High-risk surgically resected pediatric melanoma and adjuvant interferon therapy.

BACKGROUND: Pediatric patients with high-risk surgically resected melanoma are at risk for relapse, yet little is known about these young patients and how they tolerate high-dose interferon therapy. PROCEDURE: We reviewed medical records of patients (< or =18 years) with high-risk melanoma referred to the University of Michigan Pediatric Hematology-Oncology service between January 1989 and July 2003. RESULTS: Fourteen patients were identified with high-risk resected melanoma. The median age at diagnosis was 8.5 years. The median time to establish diagnosis was 9 months. Primary lesions were diagnosed as unequivocal melanoma, atypical epithelioid melanocytic proliferations, or atypical Spitz tumor with indeterminate malignant potential. Twelve patients had a positive sentinel lymph node (SLN) biopsy or a palpable regional lymph node and underwent regional lymph node dissection (LND). Two patients with unequivocal melanoma with Breslow depth >4 mm had negative SLN biopsies. Twelve patients received adjuvant high-dose interferon. The following toxicities were observed: constitutional symptoms, gastrointestinal symptoms, depression or neuropsychiatric symptoms, myelosuppression, elevated AST or ALT, hypothyroidism, and hypertension. Grade 3 or 4 toxicities were uncommon with exception of neutropenia, resulting in modification of therapy in one patient. All patients are alive and free of disease at follow-up (median 24.5 months). CONCLUSIONS: Invasive melanoma can occur in very young children. Despite early signs of malignancy, there is often a delay in diagnosis. Histologically, diagnosis may be difficult because of overlap with Spitz nevi. Pediatric patients tolerated adjuvant high-dose interferon well and may be less likely than adults to require therapy modification secondary to toxicities.

[Wound-healing properties of solid immunobiological medicinal forms for local application]. / Izuchenie ranozazhivliaiushchego deistviia tverdykh lekarstvennykh form immunobiologicheskikh preparatov dlia mestnogo primeneniia.

The results of experiments on rats showed a high healing potential of three collagen-based coating materials containing a combination of biologically active substances including human leukocyte interferon, alfalfa extract, and eubiotic bactisporin. The application of new materials significantly accelerated the healing of model wounds.

Fate of chronic myeloid leukemia patients treated with allogeneic bone marrow transplantation or chemotherapy and/or interferon at a single center: long-term results.

From April 1981 to February 2000, 105 patients with chronic myeloid leukemia (CML) underwent BMT from HLA-identical related donors at a single center. Eighty-eight patients were in chronic phase (CP), 11 patients in accelerated phase and six patients in blast crisis. Ten of these patients received a second BMT (BMT2). Comparison of BMT in CP with chemotherapy and/or alpha-IFN (n=70) was also made. Patients were given cyclophosphamide (CY) and single-dose TBI (CYTBI, n=38) or busulfan (BU) and CY (BUCY, n=67). Overall 54 patients are alive and 52 of them are disease-free with a median follow-up of 11.3 (range 1.1-19.4) years. Ten-year disease-free survival (DFS) in CP patients was better after BUCY, 61% (95% CI, 47-68%) than after CYTBI, 41% (95% CI, 23-61%) (P=0.07). For 88 patients who received a transplant in CP, results were significantly improved when BMT was performed within 1 year after diagnosis (P=0.02) or at an age < or = 25 years old (P=0.01). Ten-year survival in patients who received BMT in CP was better than in patients treated with chemotherapy (56% vs 10%; P=0.0001) or alpha-IFN-based treatment (33%; P=0.09) with survival curves crossing at 4.2 years and at 4 years, respectively. The probability of DFS after BMT2 was 60% (95% CI, 26-87%). CP patients who received BMT after CYTBI had a higher probability of relapse and transplant-related mortality than patients receiving BUCY (53% and 58% vs 9% and 34%; P=0.002 and P=0.08, respectively). All but six patients are currently on no medication and have resumed all activities without any limitation. These long-term results confirm that allogeneic BMT is the only curative approach for CML patients and should be offered to all patients with a suitable donor as soon after diagnosis as possible.

Sustained suppression of hepatitis C virus by interferon and ribavirin in hemophilic patients not responding to interferon monotherapy.

Thirty-nine hemophiliac patients, negative for human immunodeficiency virus, with chronic hepatitis C who failed to respond to interferon (IFN) at 3 million units (MU) given subcutaneously thrice weekly for at least 3 months were retreated with 5 MU IFN for 6 months followed by 3 MU IFN in combination with daily oral doses of 1 or 1.2 g ribavirin. Thirty-four patients (87%) completed the study. In 4 patients treatment was discontinued because of treatment-related symptoms; 1 patient dropped out. Dosage reduction was required in 10 patients (26%) because of ribavirin-related anemia or IFN-related side effects. By intention-to-treat analysis, 14 (37%) had a sustained virologic response with preference for those infected by genotypes other than type 1 (43% versus 12%) and with high transaminases levels (168 U/L versus 116 U/L). Thus, IFN and ribavirin combination therapy led to a sustained suppression of hepatitis in one third of hemophiliac patients resistant to conventional monotherapy.

Effective and safe interferon treatment for Japanese patients with chronic myelogenous leukemia relapse after bone marrow transplantation. The Nagoya Blood and Marrow Transplantation Group.

The purpose of this study was to assess the efficacy and safety of interferon (IFN) treatment in patients with a relapse of chronic myelogenous leukemia (CML) after bone marrow transplantation in Japan. Accordingly, we retrospectively analyzed the results obtained from 8 patients treated with IFN by the Nagoya Blood and Marrow Transplantation Group. One of 3 patients with hematologic relapse and all 5 patients with cytogenetic relapse achieved complete cytogenetic response (CCR). The median time to achieve CCR was 8 months (range, 3-16 months). One patient relapsed 9 months after starting IFN and died of blast crisis. CCR was maintained for a median duration of 47 months (range, 9-79 months) in the remaining 5 patients. The median duration of survival of these 5 patients after starting IFN was 58 months (range, 12-89 months). At the time of this report, 2 patients who did not attain CCR have survived for 81 months and 142 months after starting IFN, respectively. During IFN treatment, 1 patient showed a transient deterioration of chronic graft-versus-host disease, and no treatment-related deaths were observed. These results suggest that treatment with IFN for CML patients who relapse after bone marrow transplantation is effective and safe. A prospective study to compare IFN with donor lymphocyte infusion is necessary to establish the optimal strategy for the treatment of CML patients who relapse after bone marrow transplantation.

Collection of Ph-negative progenitor cells from interferon responsive patients with chronic myeloid leukemia: effect of granulocyte-colony-stimulating factor mobilization.

BACKGROUND AND OBJECTIVE: The observation that patients with chronic myeloid leukemia (CML) may relapse following stem cell transplantation because of Philadelphia positive cells contaminating the graft have led to a variety of strategies to reduce this contamination. This study investigate the feasibility of collective, Ph-re cells from patients with CML in chronic phase. DESIGN AND METHODS: A total of 18 patients with chronic myeloid leukemia in chronic phase who had responded to varying degrees to treatment with interferon-a (IFN) were subjected to mobilization with granulocyte colony-stimulating factors and peripheral blood progenitor cell collection. Nine patients were in complete cytogenetic remission (CCR) and nine were partial responders. IFN was stopped 2 to 4 weeks before the procedure. G-CSF was given by subcutaneous injection once daily at a dose of 10 microg/kg. RESULTS: Five patients underwent one collection procedure only, 10 underwent two procedures and 3 patients had three collections. The median number of nucleated cells (NC) per patient collected was 10.2 x 10(8)/kg (4.4-19.7) and the median number of CD34(+) cells was 2.5 x 10(6)/kg (0.4-9.4). Analyzable cytogenetic data were available for 26/34 (76%) leukapheresis procedures. The median percentage of Ph- negative metaphases for patients in CCR was 100% (73-100). Patients not in CCR had a higher level of Ph-positive cells in their collections (median 23%, range 0-79%, p=0.01). Of the nine patients in CCR, 8 had at least one apheresis from which progenitor cells were 100% Ph-negative; conversely, patients not in CCR had detectable Ph-positive cells in every collection. Four patients have undergone autologous stem cell transplantation. INTERPRETATION AND CONCLUSIONS: It was possible to collect sufficient Ph negative progenitor cells from patients in CCR but collections from other patients contained significant numbers of Ph-positive cells.

Endocrine and neurological adverse effects of the therapeutic interferons.

There is experimental evidence that the nervous central and the neuroendocrine systems can influence the immune system, which can in turn influence the brain activity. Endogenous cytokines are known to play a critical role in the pathophysiology of many diseases. The recently acquired experience on the adverse effects of therapeutic cytokines, particularly neurological and endocrine adverse effects, are further illustrative of these interferences. Interferons-alpha have been used in thousands of patients, so that the information accumulated with this group of closely related products is essential to delineate the potential and severity for non-immunological, but largely immune-mediated adverse effects to develop in patients treated with immuno-activating agents.

[Therapeutic aspects in the management of hairy cell leukemia]. / Aspects thérapeutiques de la leucémie à tricholeucocytes.

CHRONIC B CELL PROLIFERATION: An estimated 80 to 120 new cases of hairy cell leukemia are diagnosed annually in France. Median survival is 5 years for untreated patients who develop a series of infectious complications. For many years, interferon alpha was the standard therapy but the therapeutic strategy has changed with the arrival of purine analogs, deoxycoformicine and 2-CdA. THERAPEUTIC OPTIONS: We searched Medline, Pascal, and Current Contents for literature on the treatment of hairy cell leukemia over the last 10 years and discuss here available data on response rate, mechanism of action and adverse effects of different therapeutic options. BY TREATMENT: Interferon generally induces partial response and most patients relapse after treatment withdrawal. The purine analogs, desoxycoformycine and 2-chlorodeoxyadenosine, are more active than interferon inducing response in approximately 90% of the cases, even after interferon failure, complete response is achieved in 50% to 70% of patients. Relapse rate at 5 years appears to be limited to 10% n 15%. Besides infections, the main adverse effect is the constant deep and persistent decline in CD4 counts but with no special risk of opportunistic infection. The increased rate of secondary cancers in long-term survivors and its possible relationship with treatments remains a controversial topic.

Interferon as maintenance therapy in refractory malignant lymphoma.

Patients with refractory malignant lymphoma (RML) have a poor prognosis when treated with conventional chemotherapy, as less than 20% remain alive and free of disease after 5 years. The use of myeloablative chemotherapy followed by BMT has improved the complete remission (CR) rate. Nevertheless, relapse rates remain unchanged, and only a few patients remain alive and free of disease for more than 3 years. For this reason, we began a prospective randomized clinical trial to determine if IFN-alpha2B (5.0 MU three times a week for 1 year) can improve the prognosis in RML. Ninety-six patients with high or high-intermediate clinical risk RML and in CR after intensive chemotherapy were randomly assigned to receive or not to receive IFN as maintenance therapy. A median follow-up of 48.1 months, the time to treatment failure and survival were similar in both groups. Toxicity secondary to IFN administration was mild, and all patients received the planned doses of IFN. We conclude that IFN is not recommended at this dose and schedule as maintenance therapy in patients with RML who achieve CR. Different therapeutic approaches may be developed to improve outcomes for these patients.

Unanticipated human toxicology of recombinant proteins.

Recombinant human proteins play already an important role in therapy, e.g. erythropoietin and colony stimulating factors, while several promising candidates such IL-6, IL-12, thrombopoietin and others are in clinical development. Since the recombinant proteins are copies of endogenous proteins, it was assumed that they would be well tolerated. While this assumption is correct for some, other proteins proved to be a highly toxic. Therefore, preclinical safety assessment of these proteins is necessary. Based on the experience with several proteins, some guidance for the safety assessment can be given. Furthermore, data are presented demonstrating that preclinical toxicity studies have a predictive value for man. Limitations of the classical approach of safety tests and new concepts are discussed.

[Interferons in the therapy of solid tumors]. / Gli interferoni nella terapia dei tumori solidi.

Belonging to the vast family of cytokines, interferons (IFN) have recently been widely investigated concerning their possible clinical applications, both in virology and oncology. In this field results have been quite mixed but definitely encouraging. The best achievements have been obtained in hematology, and particularly in the treatment of hairy cell leukemia and chronic myelogenous leukemia, but new perspectives have also opened in the therapy of solid tumors, especially in the local treatment of superficial bladder cancer and ovarian cancer, AIDS-related Kaposi's sarcoma and malignant melanoma. IFN have in certain cases showed an efficacy comparable to that of classic treatments but with lower toxicity, and in some tumors they have even improved the results obtained so far, especially in combined therapy. We have here gathered the most recent results concerning the use of IFN in the therapy of solid tumors in order to highlight the new therapeutic opportunities available to clinical oncology.

21-day intravenous toxicity study with feline interferon in rats.

The toxicity of recombinant feline interferon, a prospective antiviral drug for cats, was examined in a subacute study. Groups of five male and five female Wistar rats were given iv feline interferon in 20 mM-NaCl at doses of 0, 5, 15 and 50 MU/kg body weight/day for 21 consecutive days. Criteria to assess toxicity included clinical observations, ophthalmoscopy, growth, food and water intake, haematology, clinical chemistry, urinalysis, organ weights, gross examination at autopsy and microscopic examination of the liver, kidneys, spleen, adrenals, heart, mesenteric lymph nodes and thymus. No treatment-related were observed even at the highest dose level. The no-observed-adverse-effect level for feline interferon in this study was therefore 50 MU/kg body weight/day.