Biomedical subjects
Publications and source records attributed to M Peuchmaur.
An atypical case of a first branchial cleft presenting with a cutaneous fistula and an epidermoid cyst of the external auditory canal is reported. The relevant embryology of the branchial apparatus is summarized, and variations of first branchial anomalies are discussed. The relationship with a congenital cholesteatoma is discussed.
Dominant megacolon (Dom) is one of four mutations in the mouse that can produce a phenotype similar to Hirschsprung disease in human. The Dom gene product is not known, and no candidate region has been defined for a possible human homolog. In this publication we report mapping the Dom locus with high definition, using several intra-and interspecific crosses and a set of 16 Chr 15-specific microsatellites flanking this locus.
Plasma cell granuloma (PCG) is a pseudotumor of unknown origin. It is frequently accompanied by acute-phase clinical and biological signs that resume after complete surgical removal, suggesting production of soluble mediators. We therefore investigated the role of cytokines in a previously healthy 10-year-old boy with a PCG of the lung and systemic symptoms. In this case, very high serum levels of interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) were found before tumor excision, associated with inflammatory signs including major hyper-gamma-globulinemia. Pathologic analysis of the tumor showed an accumulation of fibroblasts and plasma cells producing immunoglobulins. Local production of IL-1 beta and IL-6 could be demonstrated at the messenger RNA (mRNA) level by the reverse transcriptase polymerase chain reaction and could be attributed to inflammatory cells by in situ hybridization and immunohistochemistry, whereas plasma cells exhibited membrane expression of the IL-6 receptor. Postsurgery follow-up showed rapid normalization of serum IL-1 beta and IL-6, whereas inflammatory protein levels decreased. This confirms the local production of cytokine within the PCG and raises the question of whether a dysregulation of cytokine production initiates the disease.
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To investigate the role of IL-6 as a growth factor in EBV-induced B lymphoproliferative disorders in immune-suppressed patients, we analyzed two B cell lines derived from two different patients for IL-6 production, expression of the p80 chain of the IL-6 receptor, and the effects on cell growth in vitro and in vivo of neutralizing mAbs specific for IL-6. One of the cell lines (LCL41) was shown to produce large amounts of IL-6 and to express IL-6 receptors. Its in vitro growth was weakly inhibited by the anti-IL-6 MAb. After inoculation into SCID mice, this cell line provoked human B cell tumors, the growth of which was controlled by the anti-IL-6 mAb. Indeed, four i.v. infusions of 0.1 mg at days 30 to 42 after i.p. inoculation of cells led to complete remission in most mice and long term survival in 40% of cases. In contrast, the other B cell line (LCL48) produced smaller amounts of IL-6; its growth was not inhibited in vitro by the anti-IL-6 Ab and was poorly blocked in vivo in SCID mice (40% of remissions and 20% of long-term survival). In addition, a clone derived in vivo in SCID mice from LCL48 was completely IL-6-independent. These results demonstrate that B cell tumors transformed in vivo by EBV in immune-suppressed patients are heterogeneous with respect to IL-6 requirements for proliferation. An antitumoral effect in some of them can be achieved by neutralizing the IL-6-dependent proliferative loop.
To understand the selective accumulation of memory T helper lymphocytes and of macrophages in delayed-type hypersensitivity (DTH) granulomas, we studied the in situ production of RANTES, a chemokine initially characterized on the basis of its in vitro chemotactic properties for each of these cell populations. RANTES gene expression was studied by in situ hybridization in 15 human lymph nodes presenting typical DTH lesions related to either sarcoidosis or tuberculosis. A positive signal was detected in all cases. Labeling was specific for the DTH lesions, as very few if any positive cells were detected in the normal residual lymphoid tissue surrounding them or in reactive lymph nodes involved in a B lymphocyte response. RANTES gene expression was associated with the production of the protein, which was detected by immunochemistry in DTH lymph nodes. The morphological characteristics and distribution of positive cells in in situ hybridization and immunochemical experiments indicated that macrophages and endothelial cells, two cell populations not previously reported to produce RANTES, contributed to its production in DTH reactions. The ability of macrophages and endothelial cells to produce RANTES was confirmed by in vitro studies with alveolar macrophages and umbilical vein endothelial cells. In view of the chemotactic properties of RANTES for a limited range of cell populations, these results suggest that RANTES production in DTH granulomas may play a role in the selective accumulation of macrophages and memory T helper lymphocytes characterizing this type of cell-mediated immune reaction, and that macrophages and endothelial cells are involved in this production.
This study was carried out to determine the frequency and composition (biliary and/or pancreactic) of duodenogastric reflux (DGR) in children with severe gastro-intestinal disorders on total parenteral nutrition (TPN), and to assess its consequences in terms of gastric histology (gastric per endoscopic biopsies) and secretion (acid, pepsin and sialic acid output). Sixteen children (mean age: 20 months) with severe gastro-intestinal disorders requiring TPN (mean duration: 9.5 months) were studied. DGR was demonstrated by measuring gastric choline and trypsin outputs. Serum gastrin levels were measured in all patients. Seven children (44%) had a DGR, with a significant increase in choline output (p < 0.02). Trypsin output was elevated in one patient only. Exudative gastritis and increased sialic acid output occurred in the presence and in the absence of DGR. DGR did not alter the basal acid and pepsin secretions. The serum gastrin levels were normal except in one case. These results show that DGR occurs frequently in children suffering from severe gastro-intestinal disorders on TPN, that it is mainly of biliary origin and that exudative gastritis is very frequent but not correlated with DGR. It suggests that DGR causes little injury in children on TPN, perhaps because of their decreased pancreatic secretion.
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BACKGROUND: Transforming growth factor beta (TGF-beta) is an immunomodulatory cytokine regulating the proliferation and differentiation of various cell types. It also contributes to the maintenance of tissue architecture by influencing the production of extracellular matrix components. TGF-beta has been detected in bronchoalveolar lavage fluid from normal human lung, but the nature and distribution of cells containing TGF-beta in this organ remain unknown. METHODS: Fourteen normal human lung specimens were studied by immunohistochemistry with a monoclonal antibody recognizing TGF-beta 1, TGF-beta 2 and TGF-beta 3. RESULTS: TGF-beta was detected in all cases. Bronchial epithelial cells contained the largest amounts of TGF-beta. In these cells the staining was brightest at the apical pole. Macrophages and smooth muscle cells also contained TGF-beta, although less than epithelial cells. No TGF-beta was detected in other cell populations, including endothelial cells, fibroblasts, and pneumocytes. CONCLUSIONS: The bronchial epithelial compartment appears to be the main location of TGF-beta in the normal human lung, suggesting that this cytokine has a pivotal role in the immunological properties of the bronchial mucosa.
The presence of cytotoxic cells and their activation status were analyzed in tissue sections of 26 follicular lymphomas. To this end, expression of the perforin and granzyme B genes was studied by in situ hybridization experiments, and expression of the TIA-1 antigen was analyzed by immunohistochemistry. Cells expressing the granzyme B gene and the perforin gene were detected in all cases. Their density was, however, highly heterogeneous from case to case, ranging from 160 to 7,040 positive cells/cm2 of tissue sections. TIA-1-positive cells were also evidenced in the 10 follicular lymphomas tested. Virtually all cytotoxic cells were located in interfollicular areas. Double labeling immunochemical experiments showed that most cytotoxic cells belonged to the CD8+ T lymphocyte population, although few CD4+ T lymphocytes and CD56+ natural killer cells also expressed the TIA-1 antigen. These findings show that development of a malignant B lymphocyte proliferation is associated with a host-derived immune response involving intratumoral cytotoxic T lymphocytes. Further studies comparing the density of such cells with the final outcome are required to determine whether the intensity of this immune response has a prognostic value.
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BACKGROUND: Interferon alfa and cytotoxic drugs have synergistic effects in patients with non-Hodgkin's lymphoma. In 1986, we designed a clinical trial to evaluate the benefit of concomitant administration of recombinant interferon alfa with a regimen containing doxorubicin in patients with follicular non-Hodgkin's lymphoma. METHODS: The trial involved 242 patients with advanced low-grade follicular non-Hodgkin's lymphoma selected on the basis of clinical, radiographic, and biologic criteria. All patients were treated with a regimen consisting of cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP), given monthly for six cycles and then every two months for one year. After randomization, 123 patients also received interferon alfa-2b at a dosage of 5 million units three times weekly for 18 months. The remaining 119 patients received chemotherapy alone. RESULTS: As compared with the patients treated with CHVP only, the patients treated with CHVP plus interferon alfa had a higher overall rate of response (85 percent vs. 69 percent, P = 0.006), a longer median event-free survival (34 months vs. 19 months, P < 0.001), and a higher rate of survival at 3 years (86 percent vs. 69 percent, P = 0.02). Granulocyte toxicity was greater in the patients treated with CHVP plus interferon alfa than in those treated with CHVP alone. There were no treatment-related deaths. Interferon alfa had to be stopped because of toxic effects (fatigue and hepatitis) in 13 patients (11 percent). CONCLUSIONS: The addition of interferon alfa to a regimen containing doxorubicin increased the rate of response, event-free survival, and overall survival in patients with advanced follicular non-Hodgkin's lymphoma, without serious toxicity, although some patients were unable to tolerate the side effects.
Both cytokines produced by activated monocytes and T cells and direct cell-to-cell contact with antigen-primed T cells during inflammatory reactions are known to induce the expression of several adhesion proteins on endothelial cells. In this prospective longitudinal study, we analyzed the expression of ELAM-1, VCAM-1, and ICAM-1 on myocardial allograft biopsy specimens taken from 16 cardiac allograft recipients either for routine monitoring or for the investigation of suspected rejection. Infiltrating T cells were identified using anti-CD3 antibodies. Three to six sequential biopsies taken at one-week intervals were analyzed by means of conventional histology and immunohistochemistry. Seven patients did not develop rejection during the study; their biopsies were negative for VCAM-1 and ELAM-1, although faint ICAM-1 staining was present on capillaries, reflecting constitutive expression. Three patients entered the study with clear-cut clinical and histologic signs of acute rejection. Intense VCAM-1 and ICAM-1 expression was detected on capillary and postcapillary venules, together with a heavy CD3+ T cell infiltrate; VCAM-1 was also expressed on arteriolar endothelial cells. ELAM-1 was undetectable in all three cases. Six patients developed acute rejection during the course of the study. In four, ELAM-1 and VCAM-1 were expressed on both capillary and postcapillary venules one or two weeks before the histological diagnosis of rejection (heavy CD3+ cell infiltrate). Importantly, ELAM-1 expression was short-lived and had disappeared by the time CD3+ cellular infiltrate was detected, thus extending in vivo the finding that ELAM-1 expression is usually transient in vitro. Only VCAM-1 expression was observed in the other two patients, one week prior to the histological diagnosis of rejection. These results suggest that ELAM-1 and VCAM-1 might represent early predictive markers of acute cardiac allograft rejection. ELAM-1 expression is, however, usually transient, necessitating frequent testing.
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Granulocyte/macrophage-colony stimulating factor (GM-CSF) induces in vitro activation of Langerhans' cells. The association of GM-CSF and tumour necrosis factor alpha (TNF alpha) induces the differentiation of Langerhans' cells from CD34 positive haematopoietic progenitors. Intradermal administration of recombinant GM-CSF is associated with local accumulation of Langerhans' cells. We investigated the presence of GM-CSF in tissue samples of 10 patients with Langerhans' cell histiocytosis. Four patients had skin involvement, three had bone and three had diffuse disease. Eight normal skin samples were analysed as controls. Immunohistochemistry was performed on frozen tissue samples with two specific monoclonal antibodies directed against two different epitopes of GM-CSF. We detected GM-CSF in all the histiocytosis tissue samples. The GM-CSF was detected within the cytoplasm of all the tumoral Langerhans' cells. We did not find GM-CSF in any other cell type. These results suggest that GM-CSF may be implicated in the pathogenesis of Langerhans' cell histiocytosis.
Interleukin-6 is a major B lymphocyte growth factor, and may play a role in the proliferation of malignant B lymphocytes. In order to provide arguments supporting such a role, the intratumoral production of IL-6 was studied by in situ hybridization and immunohistochemistry in 53 neoplastic tissues from B cell chronic lymphocytic leukemia or B lymphomas. IL-6-producing cells were detected in all samples but 5. However, the number of IL-6 producing cells was variable amongst the different cases. Increased density of IL-6-producing cells was highly dependent on the presence of malignant immunoblasts within the neoplastic clone. IL-6 was produced in a paracrine way, macrophages and endothelial cells being the main producers of the cytokine while malignant immunoblasts expressed the IL-6 receptor. Taken together, these results suggest that IL-6 may indeed act as a growth factor for malignant cells in some B lymphoproliferations and that this paracrine loop could be the target of new therapeutic approaches.