Biomedical subjects
Publications and source records attributed to Philippe Moreau.
We describe 4 cases of zygomycosis that occurred after prolonged use of voriconazole in severely immunocompromised patients with hematologic disease. An invasive infection was present in 3 patients who died soon after the diagnosis at 12, 13, and 45 days. Physicians should be mindful of this potential risk after treatment with voriconazole.
We undertook this study to develop uniformly accepted criteria for the definition of organ involvement and response for patients on treatment protocols for immunoglobulin light-chain amyloidosis (AL). A consensus panel was convened comprising 13 specialists actively involved in the treatment of patients with amyloidosis. Institutional criteria were submitted from each, and a consensus was developed defining each organ involved and the criteria for response. Specific criteria have been developed with agreed on definitions of organ and hematologic response as a result of discussions at the 10th International Symposium on Amyloid and Amyloidosis held in Tours, France, April 2004. These criteria now form the working definition of involvement and response for the purposes of future data collection and reporting. We report criteria that centers can now use to define organ involvement and uniform response criteria for reporting outcomes in patients with light-chain AL.
In patient with newly diagnosed multiple myeloma (MM), randomized studies have shown that autologous stem-cell transplantation (ASCT) is superior to conventional chemotherapy, and ASCT is now standard care, at least for younger patients. The best conditioning regimen is melphalan 200 mg/m2, and the best stem-cell source is unselected peripheral progenitor cells. Recent results of the IFM94 trial show that double ASCT is superior to single ASCT, at least in patients who do not achieve a 90% response after one transplant. By combining biologic markers (beta2-microglobulin, albumin) and genetic markers (hypodiploidy, chromosome 13 deletion) it is possible to accurately predict prognosis after ASCT. The results of allogeneic SCT remain disappointing due to a high transplant mortality. Strategies combining ASCT and reduced-intensity allogeneic SCT are currently being studied.
HLA-G is a nonclassical human major histocompatibility complex class I molecule. It may promote tolerance, leading to acceptance of the semiallogeneic fetus and tumor immune escape. We show here that two viruses-herpes simplex virus type 1 (HSV-1), a neuronotropic virus inducing acute infection and neuron latency; and rabies virus (RABV), a neuronotropic virus triggering acute neuron infection-upregulate the neuronal expression of several HLA-G isoforms, including HLA-G1 and HLA-G5, the two main biologically active isoforms. RABV induces mostly HLA-G1, and HSV-1 induces mostly HLA-G3 and HLA-G5. HLA-G expression is upregulated in infected cells and neighboring uninfected cells. Soluble mediators, such as beta interferon (IFN-beta) and IFN-gamma, upregulate HLA-G expression in uninfected cells. The membrane-bound HLA-G1 isoform was detected on the surface of cultured RABV-infected neurons but not on the surface of HSV-1-infected cells. Thus, neuronotropic viruses that escape the host immune response totally (RABV) or partially (HSV-1) regulate HLA-G expression on human neuronal cells differentially. HLA-G may therefore be involved in the escape of certain viruses from the immune response in the nervous system.
Autologous stem cell transplantation (ASCT) is currently considered the standard of care for younger patients with newly diagnosed multiple myeloma based on 3 randomized trials that have shown it is superior to conventional chemotherapy. However, the introduction of novel agents like thalidomide, bortezomib, or lenalidomide may improve the results of standard-dose therapy. For instance, in combination, melphalan/prednisone/thalidomide yields complete response rates comparable with those achieved with ASCT. Different strategies have been proposed to improve the results of ASCT. A randomized trial has shown that tandem ASCT is superior to single ASCT in terms of event-free survival (EFS) and overall survival. Four other randomized trials have produced results in favor of tandem ASCT. However, the benefit remains marginal and patients with poor initial characteristics still have poor outcomes. Further intensification has been tested with encouraging results in patients with high b2-microglobulin levels and chromosome 13 deletion. "Total Therapy II" with intensified induction and post-ASCT chemotherapy also appears to improve outcomes. Another possibility is the use of novel agents in combination with ASCT as part of induction therapy or as maintenance therapy after ASCT. Preliminary results of a French Intergroup study show a significant prolongation of EFS in patients receiving maintenance therapy with thalidomide. Results achieved with allogeneic stem cell transplantation remain disappointing. Although initial results of ASCT followed by reduced-intensity allogeneic stem cell transplantation were promising, with more follow-up, relapses and chronic graft-versus-host disease have limited the enthusiasm. Allogeneic stem cell transplantation should be proposed only in the context of a clinical trial.
We investigated the expression of insulin-like growth factor-1 receptor (CD221) in normal, reactive and malignant plasma cells. We show that CD221 is aberrantly expressed on human myeloma cells, that higher levels of CD221 are observed in patients and human myeloma cell lines with the most aggressive 14q32 translocations, and that CD221 expression has a negative prognostic impact in patients with multiple myeloma.
We retrospectively investigated the outcome of 30 newly diagnosed patients with mantle cell lymphoma treated with high-dose therapy and autologous stem cell transplantation in first response. With a median follow-up of 55 months, the 5-year overall-survival is 62%, the 5-year progression-free-survival is 40% and no secondary malignancy has occurred.
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The incidence of mucormycosis, defined as systemic infection caused by fungi of the class Phycomycetes has been increasing over the past 2 decades, especially in profoundly immunocompromised hosts. We report a new case in a patient presenting with post-transplant high-grade non-Hodgkin's lymphoma who received a prolonged treatment with voriconazole and caspofungin for an invasive pulmonary aspergillosis. Definite diagnosis of mucormycosis was made by liver biopsy of nodules mimicking progressive lymphoma. The patient died 1 week after the diagnosis of mucormycosis despite the administration of liposomal amphotericin B. The role of voriconazole and caspofungin in the emergence of mucormycosis is discussed.
We analysed the regulation of human leucocyte antigen (HLA)-E, -F and -G genes, focusing on the SXY module, a promoter region that controls major histocompatibility complex (MHC) class II expression and participates in the expression of classical HLA class I molecules. It comprises the X1, X2 and Y boxes, bound by RFX, X2-BP/ATF/CREB and NFY factors, respectively. The complex recruits the master control factor CIITA. The SXY module is conserved in HLA-E and HLA-F gene promoters, whereas in the HLA-G promoter, the only conserved boxes are S and X1. Chromatin immunoprecipitation assays, performed on HLA-G positive and negative cell lines, demonstrated the in situ binding of RFX5 and CIITA to HLA-E and HLA-F, but not to HLA-G, promoters. In B cells from bare lymphocyte syndrome patients lacking RFX5 or CIITA, we observed lower steady-state levels of HLA-E and HLA-F transcripts but did not find any significant decrease in the cell-surface expression of HLA-E/classical HLA class I. In RFX5-deficient fibroblasts, the cell-surface expression of HLA molecules was decreased. RFX5 and CIITA are thus not involved in HLA-G expression and their importance for the surface expression of HLA-E/classical HLA class I molecules may vary depending on the cell type.
We assessed the activity and safety of liposomal nystatin, a broad-spectrum antifungal agent, for invasive aspergillosis in patients refractory to or intolerant of amphotericin B. Thirty-three patients were enrolled, received at least one dose of the study drug, and were evaluable for safety. Twenty-six patients had confirmed probable or definite aspergillosis and were fully eligible. Most patients had a hematological malignancy (53.8%) or hematopoietic stem cell transplantation (23.0%), were neutropenic (61.5%), and were refractory to previous amphotericin B (92.3%). The median duration of previous amphotericin B treatment was 16.5 days (range, 5 to 64 days). Aspergillosis was definite in 3 cases and probable in 23 cases. Liposomal nystatin was initiated at a dose of 4 mg/kg of body weight/day. Twenty-five patients were evaluable for response: a complete response was achieved for one patient, and a partial response was achieved for six. Thus, the overall response rate is 7 of 25 (28%; 95% confidence interval, 12 to 49%). Seventeen (68.0%) of the 25 evaluable patients died during therapy or within 1 month after the end of therapy. The primary cause of death was invasive aspergillosis for nine patients and underlying malignancy for eight patients. The most frequent side effects included chills, shivering, and fever, leading to discontinuation of therapy for two patients. Grade 1 decline in renal function was seen for 10 (30.3%) patients, and hypokalemia was seen for 13 (39.4%). We conclude that liposomal nystatin can be effective for salvage therapy of invasive aspergillosis. Infusion-related adverse events have been observed frequently.
BACKGROUND AND OBJECTIVES: CD45 is a critical regulator of signaling threshold in immune cells. There are clinical and animal studies suggesting that the CD45-negative phenotype is the phenotype of progressive multiple myeloma (MM). The aims of this study were to confirm this hypothesis and to test the prognostic value of CD45 expression in newly diagnosed MM patients. DESIGN AND METHODS: In a retrospective study of 95 newly diagnosed MM patients treated with high dose therapy we used 4-color flow cytometry to determine CD45 expression and correlated the immunophenotipic data with clinical data. RESULTS: Thirty of 95 patients (31.5%) lacked CD45 expression at diagnosis. The CD45 phenotype significantly affected the overall survival (OS) of the patients, like the most common presenting prognostic parameters analyzed including b-2-microglobulin, age and 14q32 translocations. CD45 negative MM patients had a significantly worse OS than did CD45 positive cases of MM: 28.7% cumulative survival at 4 years, median 42 months vs not reached; p = 0.004. Furthermore, CD45 remained the only parameter adversely affecting OS in multivariate analysis. INTERPRETATION AND CONCLUSIONS: The CD45 negative phenotype could reflect the phenotype of progressive disease in relation to the intrinsic malignancy of the MM clone. Indeed, CD45 negative myeloma cells appear to have a greater capacity to circulate, disseminate and clone as well as being less sensitive to apoptosis.
CD20 has been reinvestigated in 66 patients with multiple myeloma (MM). Twelve of the patients (18%) expressed CD20, including 5 of 50 patients at diagnosis presenting 100% CD20+ cells. Seven (58%) of 12 CD20+ patients with MM had a small mature plasma cell morphology as opposed to 4 (7%) of 54 with CD20- MM (P =.0001). Of note, 10 (83%) of 12 patients with CD20+ MM had t(11;14) as opposed to 5 of 54 (9%) CD20- patients (P <.001). All the patients with 100% CD20+ cells presented with t(11;14) and 4 of 5 with a small mature plasma cell morphology. Thus, 66% of the patients with t(11;14) expressed CD20, whereas only 4% of the 51 patients lacking such translocation expressed CD20 (P <.0001). In conclusion, CD20 expression is associated with small mature plasma cell morphology and with t(11;14) in patients with MM.
Based on our previous demonstration that quinine could be used clinically to reverse P-glycoprotein-mediated resistance, we designed a multicenter, randomized trial aiming to determine whether quinine would improve the survival of adult patients (15-60 years old) with de novo acute myelogenous leukemia (AML). These patients randomly received (n = 213) or did not receive (n = 212) a 30 mg/kg/day continuous intravenous infusion of quinine in combination with induction chemotherapy combining idarubicine and cytarabine and, depending on bone marrow examination at day 20, an additional course of cytarabine and mitoxantrone. The mean steady-state quinine concentration was 7.8 mg/L and the mean multidrug resistance reversing activity of serum was 1.96. Complete remission (CR) was obtained in 344 patients (80.9%) without significant influence of quinine. Of the patients in complete remission, 82 were assigned to receive HLA-matched bone marrow transplants, whereas 262 were assigned to 2 courses of intensive consolidation chemotherapy, with or without quinine, depending on initial randomization. The 4-year actuarial overall survival (OS) of the 425 eligible patients was 42.0% +/- 2.5%, without significant influence of quinine. Of 160 patients who could be studied, 54 demonstrated rhodamine 123 efflux. In these patients, quinine significantly improved the CR rate from 12 of 25 (48.0%) to 24 of 29 (82.8%) (P =.01). However, there was no significant difference in OS. Neither mdr1 gene nor P-glycoprotein expression influenced the outcome. We conclude that quinine does not improve the survival of adult patients with de novo AML, even though it improves CR rate in a small subgroup of patients defined by rhodamine 123 efflux.
The HLA-G molecule plays an important role in immune tolerance, protecting the fetus from maternal immune attack, and probably contributes to graft tolerance and tumor escape from the host immune system. HLA-G expression is tightly regulated and involves mechanisms acting in part at the transcriptional level. Nevertheless, almost all regulatory sequences that govern constitutive and inducible HLA class I gene transcription are disrupted in the HLA-G gene promoter, suggesting an unusual regulatory process. In further investigating the molecular mechanisms of HLA-G gene activation, we evaluated the influence of epigenetic mechanisms on seven HLA-G-negative cell lines that exhibit various phenotypes. Exposure of cells to histone deacetylase inhibitors, or to the demethylating agent 5-aza-2'-deoxycytidine, revealed that HLA-G gene transcription is inhibited by DNA methylation. Reversal of methylation-mediated repression may directly induce HLA-G cell-surface expression, supporting the idea that HLA-G might be activated by such a mechanism during malignancy, inflammation, and allogenic reactions.
Human leukocyte antigen (HLA)-G retains the capacity to modulate immune responses, favoring the establishment of tolerance in solid-tissue allotransplants. To better understand the mechanisms that promote corneal allograft survival, we investigated whether HLA-G was an immunoregulatory factor involved in corneal immunology. We therefore sought HLA-G expression in corneal tissues. Corneal transplantation consists in replacing the center of a diseased cornea with normal corneal tissue. Two corneal parts are not used in such surgery: diseased central corneal tissue and peripheral normal cornea. For this study, we used healthy corneas obtained from deceased donors and diseased corneas obtained from patients with pseudophakic bullous keratopathy or keratoconus who had undergone corneal transplantation. Immunohistochemical analysis carried out on the cryopreserved corneas showed a positive immunohistochemical staining with anti-HLA-G, anti-HLA-A, -B, and -C, and anti-HLA class I monoclonal antibodies. Staining was obtained for keratocytes, epithelial cells, and endothelial cells from both healthy and pathologic human corneas, revealing the presence of HLA class I proteins, including HLA-G. HLA-G transcripts were detected in normal cornea by reverse transcriptase-polymerase chain reaction with a classical pattern of alternative splicing. The detection of HLA-G protein in adult corneas leads to the conclusion that this protein may contribute to the maintenance of the privileged immune status of cornea.
Human leukocyte antigen (HLA)-G molecules are generated by an alternative splicing of the primary transcript of the gene and display specialized function in regulating the immune response. Although HLA-G gene polymorphism is low, it may influence levels of protein expression and, in some cases, has been associated with pregnancy diseases. The HLA-G gene exhibits 14 alleles generating six proteins with minor variations and a null allele. HLA-G allelic variants may be also characterized by a 14 bp deletion-insertion polymorphism located in the 3' UT region of the HLA-G gene. The presence of the 14 bp insertion is known to generate an additional splice whereby 92 bases are removed from the start of exon 8. To analyze the effect of this deletion on the stability of HLA-G mRNAs, we performed actinomycin D treatments on both JEG-3 choriocarcinoma cell line and M8 melanoma cell line transfected with HLA-G*010102 allele. We observed that HLA-G mRNAs having the 92-base deletion are more stable than the complete mRNA forms, suggesting that this region may be involved in the mechanisms controlling post-transcriptional regulation of HLA-G molecule associated with allelic variants.
Over the past few years, HLA-G, the non-classical HLA class I molecule, has been the center of investigations that have led to the description of its specific structural and functional properties. Although located in the HLA class I region of chromosome six, the HLA-G gene may be distinguished from other HLA class I genes by its low polymorphism and alternative splicing that generates seven HLA-G proteins, whose tissue-distribution is restricted to normal fetal and adult tissues that display a tolerogeneic function toward both innate and acquired immune cells. We review these points, with special emphasis on the role of HLA-G in human pathologies, such as cancer, viral infection, and inflammatory diseases, as well as in organ transplantation.