Borderline tuberculoid leprosy and type 1 leprosy reaction in a hepatitis C patient during treatment with interferon and ribavirin.

Hepatitis C is an inflammatory disease of the liver caused by a single-stranded RNA virus belonging to the Hepacivirus genus in the Flaviviridae family, called the hepatitis C virus. After initial infection, 70% to 85% of the patients develop chronic hepatitis C with hepatic fibrosis. In addition to specific liver changes, various extrahepatic manifestations have been associated with the hepatitis C virus infection or with medications used to treat the condition. We report the case of a patient with chronic hepatitis C who presented with the signs and symptoms of borderline tuberculoid leprosy and type 1 reaction four months after the start of treatment with a pegylated interferon/ribavirin combination.

Borderline tuberculoid leprosy and type 1 leprosy reaction in a hepatitis C patient during treatment with interferon and ribavirin / Hanseniase boderline tuberculoide e reacao hansenica do tipo 1 em paciente com hepatite C durante tratamento com interferon e ribavirina

Hepatitis C is an inflammatory disease of the liver caused by a single-stranded RNA virus belonging to the Hepacivirus genus in the Flaviviridae family, called the hepatitis C virus. After initial infection, 70% to 85% of the patients develop chronic hepatitis C with hepatic fibrosis. In addition to specific liver changes, various extrahepatic manifestations have been associated with the hepatitis C virus infection or with medications used to treat the condition. We report the case of a patient with chronic hepatitis C who presented with the signs and symptoms of borderline tuberculoid leprosy and type 1 reaction four months after the start of treatment with a pegylated interferon/ribavirin combination.

A hepatite C é uma doença inflamatória fígado causada por um vírus RNA de fita simples, pertencente ao gênero Hepacivirus e à família Flaviviridae, denominado de vírus da hepatite C. Após infecção inicial 70 a 85% dos pacientes infectados evoluem para hepatite C crônica, com fibrose progressiva. Além das alterações hepáticas específicas, várias manifestações extra-hepáticas têm sido relacionadas à infecção pelo vírus da hepatite C ou às medicações utilizadas no seu tratamento. Nesse trabalho, apresenta-se caso de paciente portador de hepatite C crônica, que manifestou um quadro hanseníase boderline tuberculóide e reação hansênica do tipo I, quatro meses após início do tratamento com interferon peguilado associado à ribavirina.

Clofazimine modulates the expression of lipid metabolism proteins in Mycobacterium leprae-infected macrophages.

Mycobacterium leprae (M. leprae) lives and replicates within macrophages in a foamy, lipid-laden phagosome. The lipids provide essential nutrition for the mycobacteria, and M. leprae infection modulates expression of important host proteins related to lipid metabolism. Thus, M. leprae infection increases the expression of adipophilin/adipose differentiation-related protein (ADRP) and decreases hormone-sensitive lipase (HSL), facilitating the accumulation and maintenance of lipid-rich environments suitable for the intracellular survival of M. leprae. HSL levels are not detectable in skin smear specimens taken from leprosy patients, but re-appear shortly after multidrug therapy (MDT). This study examined the effect of MDT components on host lipid metabolism in vitro, and the outcome of rifampicin, dapsone and clofazimine treatment on ADRP and HSL expression in THP-1 cells. Clofazimine attenuated the mRNA and protein levels of ADRP in M. leprae-infected cells, while those of HSL were increased. Rifampicin and dapsone did not show any significant effects on ADRP and HSL expression levels. A transient increase of interferon (IFN)-ß and IFN-γ mRNA was also observed in cells infected with M. leprae and treated with clofazimine. Lipid droplets accumulated by M. leprae-infection were significantly decreased 48 h after clofazimine treatment. Such effects were not evident in cells without M. leprae infection. In clinical samples, ADRP expression was decreased and HSL expression was increased after treatment. These results suggest that clofazimine modulates lipid metabolism in M. leprae-infected macrophages by modulating the expression of ADRP and HSL. It also induces IFN production in M. leprae-infected cells. The resultant decrease in lipid accumulation, increase in lipolysis, and activation of innate immunity may be some of the key actions of clofazimine.

[Immune dysregulation mediated by hepatitis C virus infection].

Hepatitis C virus, which is non-cytopathic, establishes persistent infection in majority of patients after acute infection, causing various degrees of clinical liver disease. To escape and survive, hepatitis C virus may take ingenious strategies. Hepatitis C virus gene products interact host proteins to evade host immune responses in addition to the appearance of quasispecies. Against hepatitis C virus infection, host may avoid extensive tissue damage by inducing the activity of regulatory T cells. Insights into this mechanism of immune regulation may help to future development of novel therapies against hepatitis C virus.

Effect of cutaneous cell-mediated immune response to rIFNy on mycobacterium leprae viability in the lesions of lepromatous leprosy / Efeito da célula cutanea - resposta imune intermediária para rIFNy sobre viabilidade de Mycobacterium leprae nas lesöes de lepra lepromatosa

Studies were caried out to determine the effect of intra-dermal injections of recombinant human interferon-gamma (rIFNy) on the viability of Mycobacterium leprae. Twenty-three untreated and 4 treated multibacillary patients, 12 with lepromatous leprosy (LL) and 15 with bordeline lepromatous leprosy (BL), were selected for intradermal administration of rIFNy or PPD. Treated patients (LL and BL) had received multi-drug therapy according to the recommendations of the World Health Organization, i. e., rifampicxin (600 mg/month), dapsone (100 mg/day) and clofazimine (50 mg/day and 300 mg/month) for 1-4 months. Three daily doses of 10 or 30 ug rIFNy induced local induration and mononuclear leucocyte accumulation. Bacteria isolated from a punch biopsy of the site 21 days after lymphokine administration were injected into mouse foot pads and evaluated for viability and growth. The local response to rIFN (specific activity 2 x 10 7 units/mg protein) induced a delay or total inhibition of M. leprae growth in the mouse foot pad, ,indicating that the cellular response to the antigen reduced local M. leprae viability. The extent of reduction in viability depended on the dose of rIFNy injected and the extent of local induration induced by the lymphokine. With a vigorous cell-mediated immune response growth was fully inhibited. A similar but less extensive effect on M. leprae viability was observed in resapo0nse to the local injection of 5 units in 0.1 ml of purified protein derivative of tuberculin (PPD)

Role of interferon in clinical practice.

Interferons are currently the most widely used biological response modifiers. They are of high clinical value in haematological malignancies (chronic myelogenous leukaemia, multiple myeloma, non-Hodgkin lymphoma), in solid tumours (malignant melanoma, hypernephroma, pancreas neoplasms, carcinoid tumours, Kaposi's sarcoma, glioma, in ovarium, cervix and bladder carcinoma, and in basalioma) and in infectious diseases (chronic hepatitis B, chronic non-A/non-B hepatitis, chronic delta hepatitis, AIDS, Papova virus and Rhinovirus infections, leishmaniasis, leprosy) and some other conditions. Although the mechanism of action of interferons has not been explained in every detail these agents are promising therapeutic means in a number of diseases.

Immunologic defects in leprosy patients. II. Interleukin 1, interleukin 2, and interferon production in leprosy patients.

The capabilities of monocytes and lymphocytes in peripheral blood mononuclear leukocytes (PBML) to produce interleukin-1 (IL-1), IL-2, and interferon (IFN), respectively, were evaluated in various types and treatments of leprosy patients. IL-1 production in response to lipopolysaccharide was significantly lower in LL, BL, BB, and BT patients than in normal controls. However, there were no differences in IL-1 levels between TT patients and normal controls. The percentages of nonspecific-esterase-positive cells adhering to the plastic surfaces were not different in LL, BB and TT patients when compared to normal controls. However, they were significantly higher in BT and BL patients than in normal controls. When PBML from leprosy patients were stimulated with concanavalin-A (ConA) for IL-2 production, there were no differences in the IL-2 levels in treated BL/LL, untreated BL/LL, treated BT/TT, and untreated BT/TT patients compared to normal controls. Similar results were obtained when PBML were stimulated with phytohemagglutinin-P (PHA-P). However, when purified protein derivative (PPD) was used as the stimulating agent, there were significantly lower IL-2 levels in treated BL/LL, untreated BL/LL, treated BT/TT, and untreated BT/TT patients when compared to normal controls. There were also lower IL-2 levels in untreated BL/LL and BT/TT patients compared to treated BL/LL and BT/TT patients, respectively. PBML were stimulated with PHA-P or ConA for IFN production.(ABSTRACT TRUNCATED AT 250 WORDS)

Induction of antigen-specific CD4+ HLA-DR-restricted cytotoxic T lymphocytes as well as nonspecific nonrestricted killer cells by the recombinant mycobacterial 65-kDa heat-shock protein.

Acquired cell-mediated immunity to intracellular parasites like mycobacteria is dependent on antigen-specific T lymphocytes. We have recently found that mycobacteria not only induce helper T cells but also cytotoxic CD4+ and/or CD8+ T cells as well as nonspecific killer cells that lyse human macrophages in vitro. In addition, we have described that the recombinant heat-shock protein (hsp) 65 of Mycobacterium bovis BCG/M, tuberculosis is an important target antigen for CD4+CD8- cytotoxic T cells. We have now further investigated the cytotoxic effector cells that are induced by the hsp65 of BCG. Purified protein derivative of tuberculin (PPD)- or hsp65-specific cytotoxic T cells specifically lysed PPD, hsp65 of BCG and hsp65 of M. leprae-pulsed macrophages in an HLA-DR-restricted manner. Nonpulsed macrophages were lysed to a much lower but still significant extent. hsp65-induced effector cells expressed CD3, CD5, CD4, CD8 and CD56 markers. Depletion experiments showed that the antigen-specific HLA-DR-restricted killer cell was of the CD5+CD4+CD8-CD56- phenotype. Experiments using N-terminal truncated hsp65 fusion (cro-lacZ) proteins suggested that the N-terminal 65 amino acid residues of the 540 amino acid molecule are critical for the expression of the cytotoxic target epitope(s) in two individuals tested. In addition to inducing antigen-specific cytotoxic effector cells, the hsp65 also triggered nonspecific nonrestricted effector cells with lytic activity against nonpulsed autologous or allogeneic macrophages as well as K-562 and Daudi tumor cells. hsp65-stimulated effector cells produced both interferon and tumor necrosis factor-alpha. An important finding was that hsp65-stimulated effector cells strongly inhibited colony-forming unit formation from live BCG-infected autologous macrophages.

Serum interferon activity of patients with leishmaniasis

Serum from a significant proportion of 29 cutaneous and 12 mucocutaneous leishmaniasis patients exhibited interferon activity in a cytopathic assay: positive tests were obtained for 24.1% and 41.7% of the patients, respectively. Similar positive frequencies were observed in other parasitic diseases (schistosomiasis, 12.5%; toxoplasmosis, 20%; Chagas' disease, 16%; leprosy, 12.5%; tuberculosis, 30%). In contrast, none of the 44 serum samples from American visceral leishmaniasis (AVL) patients had interferon activity during the active stage of the disease. However, 13% of the samples obtained from patients recovered from AVL were positive

Serum interferon activity of patients with leishmaniasis.

Serum from a significant proportion of 29 cutaneous and 12 mucocutaneous leishmaniasis patients exhibited interferon activity in a cytopathic assay: positive tests were obtained for 24.1% and 41.7% of the patients, respectively. Similar positive frequencies were observed in other parasitic diseases (schistosomiasis, 12.5%; toxoplasmosis, 20%; Chagas' disease, 16%; leprosy, 12.5%; tuberculosis, 30%). In contrast, none of the 44 serum samples from American visceral leishmaniasis (AVL) patients had interferon activity during the active stage of the disease. However, 13% of the samples obtained from patients recovered from AVL were positive.

[Problems raised by the treatment of Kaposi's sarcoma in subjects with AIDS]. / Problèmes posés par les traitements du sarcome de Kaposi chez les sujets atteints de S. I. D. A.

Kaposi's Syndrome (K. S.) was defined as a virus induced immunogenic tumour responding to interferon. It can be used as a guideline for therapeutical trials in A. I. D. S. K. S. mortality is 13%. K. S. + O. I. (opportunistic infections) mortality reaches 70% and O. I. mortality is approximately 50%. Therefore treating O. I. is a must but it is not mentioned in the paper. Attempts made to modify immunodepression, usual K. S. treatments, experimental treatments based upon similar pathogenicity (like systemic lupus erythematosus, Hansen's disease, preneoplasia dyskeratosis) were unsuccessful. Trials with alpha recombinant interferon realised at the Sloan Kettering Memorial for Cancer in New York are summarized for 74 patients and are in preliminary interpretation. Our study is based upon 13 cases studied for 14 to 4 months and comes up to the same conclusions using 18 to 36 million units/day for 6 months (6 cases) and 3 to 4 months (7 cases). For 6 full treatments the results are: 2 K. S. were cleaned up after 8 and 3 months follow up, 4 K. S. with O. I.: 3 remissions and then relapses and 1 stabilization, for 7 current treatments: 2 had to be discontinued because of bad tolerance, 1 stabilization and 4 remissions. For all treatments a decrease and a lesser gravity of O. I. can be noted during treatment. Besides flu-like syndromes, main clinical side effects, are: asthenia, general condition impairment, 2 fits were observed for which I.N.F. cannot be clearly incriminated. Daily treatment compelling and surveillance are real drawbacks. Different types of better used interferon will probably yield interesting results (40% regression or improvement).

Inhibition of multiplication of Mycobacterium leprae by polyinosinic-polycytidylic acid.

Contrary to the results of an earlier study in which polyinosinic-polycytidylic acid [poly(I:C)] administered intraperitoneally to mice had no effect on multiplication of Mycobacterium leprae in the mouse footpad, the local administration of poly(I:C) every 12 h for 15 doses during logarithmic multiplication was found both to inhibit bacterial multiplication and to produce high tissue levels of interferon (IF). Local administration of poly(I) alone inhibited multiplication of M. leprae to almost as great a degree without at the same time producing a measurable IF titer in the footpad tissues. Mouse IF and "mock" IF both inhibited bacterial multiplication to the same degree, but administration of only the former resulted in a measurable IF titer. Polyadenylic-polyuridylic acid administered locally neither inhibited multiplication nor induced IF; fetal calf serum, administered in the same concentration as found in the preparations of IF and mock IF, was modestly inhibitory, without inducing IF. Thus, the local administration of poly(I:C) appears to have inhibited multiplication of M. leprae independently of IF induction.