Biomedical subjects
Publications and source records attributed to M Goldman.
A case of bacillary angiomatosis infection presenting as a skin nodule in a renal transplant recipient was found. The patient was taking cyclosporine, prednisone, and mycophenolate mofetil at the time of presentation. The bacillary angiomatosis responded to 6 months of therapy with oral erythromycin.
Blockade of the CD40/CD40L pathway of monocyte/macrophage activation represents a promising strategy for the treatment of several inflammatory disorders. So far, most pharmacological agents developed for that purpose target CD40L (CD154) expressed on activated T cells. Herein, we provide evidence that triazolopyrimidine, a chemical compound primarily developed for the prevention of arterial thrombosis, strongly inhibits the response of human monocytes to CD40 ligation. First, we found that triazolopyrimidine inhibits the production of IL-12, TNF-alpha, and IL-6 by monocytes activated by coculture with fibroblasts transfected with the CD40L gene as well as the induction of procoagulant activity at their membrane. This was related to a decreased expression of CD40 on monocytes exposed to triazolopyrimidine, an effect that was already apparent at the mRNA level. Furthermore, the addition of triazolopyrimidine to monocytes cultured with IL-4 and GM-CSF prevented their differentiation into fully competent dendritic cells (DC) as DC differentiated in the presence of triazolopyrimidine expressed less CD40 at their surface and were profoundly deficient in the production of IL-12 upon exposure to CD40L transfectants. We conclude that triazolopyrimidine strongly inhibits the CD40 pathway of monocyte activation at least in part by downregulating the gene expression of CD40.
Mycophenolate mofetil (MMF) is a new immunosuppressive agent currently used in organ transplantation and under evaluation in immune-mediated inflammatory disorders such as rheumatoid arthritis. Although MMF was shown to inhibit purine nucleotide synthesis in lymphocytes, it is still unclear whether it might also exert direct antiinflammatory actions in vivo. To address this question, we evaluated the effects of MMF administration on the responses of mice to a single challenge with bacterial lipopolysaccharide (LPS). We observed that MMF treatment inhibits the release of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) upon LPS injection whereas it promotes IL-10 production. In parallel, MMF was found to protect mice from LPS-induced lethality. Inhibition of TNF-alpha release was also observed in IL-10-deficient mice indicating that it does not exclusively depend on the upregulation of IL-10 endogenous synthesis. In view of the differential effects of MMF on the LPS-induced production of TNF-alpha and NO on one hand and that of IL-10 on the other hand, we conclude that beside its immunosuppressive action at the lymphocyte level, MMF is also endowed with antiinflammatory properties.
Each year, a vast number of individuals are infected with the endemic fungi. An expanding population, along with further land development in endemic areas, will likely continue to place individuals at risk for exposure to these organisms. A high index of suspicion may be required to diagnose histoplasmosis, blastomycosis, or coccidioidomycosis, particularly for patients who do not reside in endemic areas. Although the majority of patients with histoplasmosis, blastomycosis, and coccidioidomycosis experience self-limited infections, treatment is necessary for patients with severe pneumonitis as well as various forms of chronic pulmonary and disseminated infections. The newer azole agents--itraconazole and fluconazole--are useful in the treatment of these infections and have provided alternatives to long-term therapy with amphotericin B for many patients.
Azodicarbonamide was recently identified as a new anti-HIV agent that targets the zinc finger domains of the HIV-1 NCp7 nucleocapsid protein. Here, we demonstrate that azodicarbonamide inhibits in a dose-dependent manner the responses of purified human CD4+ T lymphocytes stimulated either by monoclonal antibodies against CD3 and CD28 or by allogeneic dendritic cells. These suppressive effects involve a direct action on the calcium mobilization machinery, as azodicarbonamide strongly inhibited the calcium influx induced either by antibodies against CD3 and CD28 or the chemokine RANTES, as well as by thapsigargin, an activator of depletion-activated calcium channels. In vivo, administration of azodicarbonamide into mice blunted their response to polyclonal T-cell activation induced by the injection of monoclonal antibody against CD3 and resulted in delayed rejection of skin allografts. In addition to its anti-HIV properties, azodicarbonamide is a new immunosuppressive agent that might have therapeutic applications in T cell-mediated inflammatory disorders.
BACKGROUND: Since March 1990, all blood donations in Canada are screened for antibodies to hepatitis C virus (HCV). Because HCV may cause chronic asymptomatic hepatitis, in February 1995, the Canadian Red Cross began targeted HCV lookback studies. STUDY DESIGN AND METHODS: From March 1990 to March 1997, the Quebec Center of the Canadian Red Cross collected 1,750,846 donations, and there were 561 anti-HCV-positive repeat donors, from whom 3,196 blood components had been issued to the hospitals. Hospital blood bank directors were asked to test recipients and return results to the Quebec Center. One hundred nine hospitals were surveyed to determine methods and resources involved in lookback. The transfusion medicine service at the Royal Victoria Hospital (RVH) developed a standard operating procedure for performing lookbacks and analyzed the costs and outcomes of lookbacks. RESULTS: As of April 1998, information has been received on 2329 (73%) of components; 1020 patients had died of unrelated causes, 590 were untraceable, and 353 were tested. Of those tested, 215 (61%) were anti-HCV positive; their average age was 47, and at least 53 percent were already aware of their HCV status. Few hospitals had received any additional resources to perform lookbacks. At the RVH, lookback on 182 components resulted in the identification of nine seropositive recipients, average age 70, who did not previously know their HCV status; four of these patients had abnormal alanine aminotransferase levels. The cost of lookback per newly diagnosed case of HCV was estimated at $2727 (US) for the Quebec Center and $6014 (US) for the RVH. CONCLUSION: Targeted lookback in the province of Quebec on 3196 components has resulted in the identification of 101 seropositive recipients who did not previously know their HCV status.
In a prospective, randomized, double-blind trial, 149 patients with advanced human immunodeficiency virus (HIV) infection were randomized to receive itraconazole capsules (200 mg daily) and 146 to receive a matched placebo. Both groups were monitored for evidence of fungal infections. Baseline characteristics of the two groups were similar. Failure of prophylaxis occurred in 29 (19%) of the itraconazole recipients and 42 (29%) of the placebo recipients (P = .004; log-rank test). There were 6 invasive fungal infections in the itraconazole group (4, histoplasmosis; 1, cryptococcosis; 1, aspergillosis) and 19 in the placebo group (10, histoplasmosis; 8, cryptococcosis; 1, aspergillosis) (P = .0007; log-rank test). Itraconazole significantly delayed time to onset of histoplasmosis (P = .03; log-rank test) and cryptococcosis (P = .0005; log-rank test). Prophylaxis failure due to recurrent or refractory mucosal candidiasis occurred with similar frequency in the two groups (itraconazole, 15%; placebo, 16%). A survival benefit was not demonstrated. Itraconazole generally was well tolerated. Primary prophylaxis with itraconazole capsules prevents histoplasmosis and cryptococcosis in patients with HIV infection.
We studied the effects of interferon-beta (IFN-beta) on the differentiation of dendritic cells (DC) obtained by culturing plastic-adherent peripheral blood mononuclear cells (PBMC) from a total of 30 healthy volunteers in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). First, we found that the addition of IFN-beta at the initiation of the culture did not modify DC morphology but caused a reproducible and statistically significant upregulation of HLA-DR, CD86, and CD80 surface expression. CD1a expression was significantly reduced, and CD40 expression was unchanged. We then determined the influence of IFN-beta on the production of cytokines by DC. DC differentiated in the presence of IFN-beta secreted significantly less IL-12 (p40 and p70) both spontaneously and on activation by fibroblasts transfected with the CD40L gene. This effect of IFN-beta was dose dependent and selective, as it was not observed for IL-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha). As a consequence, DC differentiated in the presence of IFN-beta induced significantly less IFN-gamma secretion by alloreactive T cells, whereas they were more efficient than control DC in eliciting IL-5 secretion. We conclude that the direct action of IFN-beta on DC causes inhibition of their ability to secrete IL-12 in response to CD40 ligation and to elicit Th1 type responses.
Because of the critical role of the CD40-CD40 ligand (CD40L) pathway in the induction and effector phases of immune responses, we investigated the effects of CD40 ligation on the control of Trypanosoma cruzi infection. First, we observed that supernatants of murine spleen cells stimulated by CD40L-transfected 3T3 fibroblasts (3T3-CD40L transfectants) prevent the infection of mouse peritoneal macrophages (MPM) by T. cruzi. This phenomenon depends on de novo production of nitric oxide (NO) as it is prevented by the addition of N-nitro-L-arginine methyl ester, a NO synthase inhibitor. NO production requires interleukin (IL)-12-mediated gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) synthesis as demonstrated by inhibition experiments using neutralizing anti-IL-12, anti-IFN-gamma, and anti-TNF-alpha monoclonal antibodies (MAb). We found that an activating anti-CD40 MAb also directly stimulates IFN-gamma-activated MPM to produce NO and thereby to control T. cruzi infection. To determine the in vivo relevance of these in vitro findings, mice were injected with 3T3-CD40L transfectants or 3T3 control fibroblasts at the time of T. cruzi inoculation. We observed that in vivo CD40 ligation dramatically reduced both parasitemia and the mortality rate of T. cruzi-infected mice. A reduced parasitemia was still observed when the injection of 3T3-CD40L transfectants was delayed 8 days postinfection. It was abolished by injection of anti-IL-12 MAb. Taken together, these data establish that CD40 ligation facilitates the control of T. cruzi infection through a cascade involving IL-12, IFN-gamma, and NO.
Trypanosoma cruzi, a parasitic protozoan, is the etiological agent of Chagas' disease. Despite the many immune system disorders recognized in this infection and the crucial role played by dendritic cells (DC) in acquired immune responses, it was not known whether these cells could be infected by T. cruzi trypomastigotes and the consequences of such an infection on their immune functions. We now provide evidence that human monocyte-derived DC can be infected by T. cruzi and can support its intracellular multiplication. Interestingly, this infection has functional consequences on immature DC and on their maturation induced by lipopolysaccharide (LPS). First, after T. cruzi infection, the basal synthesis of interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-alpha) was impaired. Furthermore, the process of maturation of DC induced by LPS was drastically affected by T. cruzi infection. Indeed, secretion of cytokines such as IL-12, TNF-alpha, and IL-6, which are released normally at high levels by LPS-activated DC, as well as the up-regulation of HLA-DR and CD40 molecules, was significantly reduced after this infection. The same effects could be induced by T. cruzi-conditioned medium, indicating that at least these inhibitory effects were mediated by soluble factors released by T. cruzi. Taken together, these results provide new insights into a novel efficient mechanism, directly involving the alteration of DC function, which might be used by T. cruzi to escape the host immune responses in Chagas' disease and thus might favor persistent infection.
C57BL/6 mice injected with the 145-2C11 anti-CD3 mAb and grafted with MHC class II disparate bm12 skin develop a chronic rejection characterized by interstitial dermal fibrosis, a marked eosinophil infiltrate, and an obliterative intimal vasculopathy. Because these changes occur in the absence of alloreactive antibodies, we examined the contribution of cytokines in their pathogenesis. Chronically rejected grafts showed a marked accumulation of both IL-4 and IL-5 mRNA. Mixed lymphocyte reaction experiments established that mice undergoing chronic rejection were primed for IL-4, IL-5, and IL-10 secretion. In vivo administration of anti-IL-4 mAb completely prevented allograft vasculopathy as well as graft eosinophil infiltration and dermal fibrosis. Injection of anti-IL-5 mAb or the use of IL-5-deficient mice as recipients also resulted in the lack of eosinophil infiltration or dermal fibrosis, but these mice did develop allograft vasculopathy. Administration of anti-IL-10 mAb did not influence any histologic parameter of chronic rejection. Thus, in this model, IL-4- and IL-5-mediated tissue allograft eosinophil infiltration is associated with interstitial fibrosis. IL-4, but not eosinophils, is also required for the development of obliterative graft arteriolopathy.
BACKGROUND: Hemodialysis (HD) patients suffer from several immune defects that make them prone to develop bacterial infections, in particular respiratory tract infections (RTIs). PATIENTS AND METHODS: As previous studies have shown that oral immunotherapy with an immunomodulating bacterial extract (IBE) is effective against RTIs, we decided to test its efficacy and safety in HD patients during a double-blind placebo-controlled prospective study. 40 HD patients with a documented history of RTIs in the previous year were treated for 24 weeks of the endemic season with one capsule daily of IBE (n = 21) or placebo (PL, n = 19). Clinical examinations, measurements of Mac-1 and gp150.95 on circulating phagocytes and routine laboratory evaluations were performed at week 0, 4, 12 and 24. Patients were also examined at each dialysis session allowing an accurate recording of any infectious episode, its treatment and of any untoward effect. RESULTS: During the last period of the study (weeks 13-24), IBE significantly reduced the number of patients with RTIs and consequently of antibiotic treatment courses as compared to PL (p = 0.018), whereas no difference was detected between IBE and PL during periods I (weeks 0-4) and II (weeks 5-12). There was no difference between IBE and PL for other, non respiratory infections. IBE was associated at several time points with an increased expression on phagocytes of adhesion molecules involved in phagocytosis (Mac-1 and gp150.95). However, the expression of these molecules was not predictive for the occurrence of RTI. IBE was on the whole as well tolerated as PL, 7 patients presented side effects (5 IBE, 2 PL, NS) which led to drop-out in 4 cases (3 IBE, 1 PL). No serious side effect was recorded, gastrointestinal upset being the most prevalent type. CONCLUSION: The results of this study indicate that immunomodulation with selected bacterial extracts constitutes a promising approach for the prevention of bacterial airway infections in groups at risk, such as HD patients.
Clinical studies have demonstrated beneficial effects of interferon-beta (IFN-beta) therapy in multiple sclerosis (MS) patients. However, the mechanism of action of IFN-beta in MS remains unknown. IFN-beta has even been demonstrated to enhance isolated T cell secretion of IFN-gamma, a cytokine proven to be deleterious in MS. However, IFN-beta inhibits IFN-gamma secretion of T cells, when they are stimulated by antigen presenting cells (APC). We therefore decided to study the effects of IFN-beta on the in vitro differentiation of dendritic cells (DC), a major class of APC. First, we found that the addition of IFN-beta at the initiation of the differentiation did not modify DC morphology, but enhanced the expression of molecules involved in antigen presentation (HLA-DR, B7/1 and B7/2). However, DC, differentiated in the presence of IFN-beta, secreted less interleukin-12 (IL-12) both spontaneously and upon activation by CD40-ligand bearing cells. As a consequence, DC differentiated in the presence of IFN-beta induced less IFN-gamma secretion by alloreactive T cells. We conclude that the direct action of IFN-beta on DC results in inhibition of their ability to secrete IL-12 and to elicit Thelper-1 (Th-1) type responses. These results are of particular interest in MS, in which a critical role for IL-12 has recently been suggested by a number of clinical and experimental observations.
BACKGROUND: Chronic rejection remains a leading cause of allograft loss. Histologically, it is characterized by arterial intimal thickening and parenchymal fibrosis. The immune mechanisms triggering chronic rejection are still uncompletely understood. METHODS: We performed major histocompatibility complex (MHC) class H-incompatible skin grafts from C-H2bm12 (bm12, H2bm12) into C57BL/6 (C57BL/6, H2b) recipients immunosuppressed with a short course of anti-CD3 monoclonal antibodies to prevent acute rejection. RESULTS: More than 80% of grafts survived for prolonged periods, but eventually all displayed macroscopic and microscopic evidence of chronic rejection. At histology, there was a progressive arterial intimal thickening as well as intense dermal fibrosis. This was accompanied by an inflammatory infiltrate consisting of lymphocytes and macrophages, but also of a considerable number of eosinophils. Mice with chronic rejection were unable to generate anti-donor MHC class II cytotoxic T lymphocyte activity at either 20 or 60 days after transplant. Furthermore, transplantation of bm12 skins on C57BL/6-congenic, Ig knock-out mice was associated with the development of a chronic rejection that was identical to that occurring in wild-type C57BL/6 animals, indicating that alloantibodies are not necessary in this model. CONCLUSIONS: (1) Skin grafts may undergo chronic rejection with the characteristic lesions of vasculopathy and fibrosis; (2) chronic rejection of MHC class II-disparate skins may occur in the absence of direct cytotoxic T lymphocyte activity or alloantibodies.
OBJECTIVE: As HIV infection most commonly occurs via a mucosal surface, and as gastrointestinal symptoms are very frequent among HIV-infected patients, we investigated the functional properties of residual lymphocytes in the duodenal mucosa from HIV-infected individuals. DESIGN: Duodenal biopsies and blood samples were obtained from 19 HIV-infected patients [Centers for Disease Control and Prevention (CDC) stage III] and from 19 controls. METHODS: Phenotypic analysis of lymphocytes was performed by flow cytometry and/or immunocytochemistry. Interferon gamma (IFN-gamma), interleukin (IL) 4 and immunoglobulin secretions were analysed by enzyme-linked immunospot techniques. The phenotype of cytokine-producing cells was analysed by flow cytometry. RESULTS: The proportions of duodenal T lymphocytes from HIV-infected patients spontaneously secreting IFN-gamma or IL-4 were not lower than those from healthy controls. In patients with a high intestinal mucosal viral load, they were higher than in controls (P < 0.05). The proportions of immunoglobulin-secreting cells were significantly raised in HIV-infected patients for the three main isotypes. CONCLUSIONS: T- and B-cell populations of the intestinal mucosa remain functional or are even activated in patients with AIDS, even when the numbers of both mucosal and circulating CD4+ lymphocytes are strongly decreased.
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The effects of gamma radiation and low temperature hydrogen peroxide gas plasma (HPGP) sterilization on structure and cyclic mechanical properties were examined for orthopedic grade ultra-high-molecular-weight polyethylene (UHMWPE) and compared to each other as well as to no sterilization (control). Density was monitored with a density gradient column and was found to be directly influenced by the sterilization method employed: Gamma radiation led to an increase, while plasma did not. Oxidation of the polymer was studied by observing changes in the carbonyl peak with Fourier transform infrared spectrometry and was found to be strongly affected by both gamma radiation and subsequent aging, while plasma sterilization had little effect. Gamma radiation resulted in embrittlement of the polymer and a decreased resistance to fatigue crack propagation. This mechanical degradation was a direct consequence of postradiation oxidation and molecular evolution of the polymer and was not observed in the plasma-sterilized polymer. Both gamma radiation and plasma sterilization led to improved wear performance of the UHMWPE compared to the nonsterile control material.