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Biomedical subjects

D Finke

Publications and source records attributed to D Finke.

At least 19 recordsLinked to original sources
PubMed2006

Molecular networks orchestrating GALT development.

During evolution, the development of secondary lymphoid organs has evolved as a strategy to promote adaptive immune responses at sites of antigen sequestration. Mesenteric lymph nodes (LNs) and Peyer's patches (PPs) are localized in proximity to mucosal surfaces, and their development is coordinated by a series of temporally and spatially regulated molecular events involving the collaboration between hematopoietic, mesenchymal, and, for PPs, epithelial cells. Transcriptional control of cellular differentiation, production of cytokines as well as adhesion molecules are mandatory for organogenesis, recruitment of mature leukocytes, and lymphoid tissue organization. Similar to fetal and neonatal organogenesis, lymphoid tissue neoformation can occur in adult individuals at sites of chronic stimulation via cytokines and TNF-family member molecules. These molecules represent new therapeutic targets to manipulate the microenvironment during autoimmune diseases.

Animals↗
PubMed2003

Tissue distribution of the Ankara strain of vaccinia virus (MVA) after mucosal or systemic administration.

MVA is a candidate vector for vaccination against pathogens and tumors. Little is known about its behaviour in mucosal tissues. We have investigated the fate and biosafety of MVA, when inoculated by different routes in C57BL/6 mice. Intranasal inoculation targeted the virus to the nasal associated lymphoid tissue and the lungs, whereas systemic inoculation led to distribution of MVA in almost all lymphoid organs, lungs and ovaries. Intravaginal, intrarectal and intragastric inoculations failed to induce efficient infection. After 48 h no virus was detectable any more in the organs analyzed. Upon intranasal inoculation, no inflammatory reactions were detected in the central nervous system as well as the upper and lower airways. These results show the tropism of MVA and indicate that high doses of recombinant MVA are safe when nasally administered, a vaccination route known to elicit strong cellular and humoral immune responses in the female genital tract.

Administration, Intranasal↗
PubMed2003

Passive immunization with neutralizing antibodies interrupts the mouse mammary tumor virus life cycle.

Mouse mammary tumor virus (MMTV) infects the host via mucosal surfaces and exploits the host immune system for systemic spread and chronic infection. We have tested a neutralizing rat monoclonal antibody specific for the retroviral envelope glycoprotein gp52 for its efficiency in preventing acute and chronic mucosal and systemic infection. The antibody completely inhibits the superantigen response and chronic viral infection following systemic or nasal infection. Surprisingly however, the antibody only partially inhibits the early infection of antigen-presenting cells in the draining lymph node. Despite this initially inefficient protection from infection, superantigen-specific B- and T-cell responses and systemic viral spread are abolished, leading to complete clearance of the retroviral infection and hence interruption of the viral life cycle. In conclusion, systemic neutralizing monoclonal antibodies can provide an efficient protection against chronic retroviral amplification and persistence.

Animals↗
PubMed2002

CD4+CD3- cells induce Peyer's patch development: role of alpha4beta1 integrin activation by CXCR5.

CD4+CD3- cells are the predominant hematopoietic cells found in mouse fetal intestine. We prove their role as Peyer's patch (PP)-inducing cells by transfer into neonatal PP-deficient mice. To test the requirement of chemokines and adhesion molecules in induction of PP, we studied mice deficient in CXCR5 and/or alpha4beta1 integrin-mediated adhesion. CXCR5-/- mice have CD4+CD3- cells, which are inefficient in inducing PP formation. We show here that CXCR5/CXCL13 signaling activates alpha4beta1 integrin on CD4+CD3- cells. Blocking of beta1 integrin or VCAM-1, the ligand of alpha4beta1 integrin, inhibits PP formation. This study demonstrates the link between chemokine receptors and adhesion molecules that regulates stromal/hematopoietic cell interaction leading to PP formation.

Adoptive Transfer↗
PubMed2001

Maturation of marginal zone and follicular B cells requires B cell activating factor of the tumor necrosis factor family and is independent of B cell maturation antigen.

B cells undergo a complex series of maturation and selection steps in the bone marrow and spleen during differentiation into mature immune effector cells. The tumor necrosis factor (TNF) family member B cell activating factor of the TNF family (BAFF) (BLyS/TALL-1) plays an important role in B cell homeostasis. BAFF and its close homologue a proliferation-inducing ligand (APRIL) have both been shown to interact with at least two receptors, B cell maturation antigen (BCMA) and transmembrane activator and cyclophilin ligand interactor (TACI), however their relative contribution in transducing BAFF signals in vivo remains unclear. To functionally inactivate both BAFF and APRIL, mice transgenic for a soluble form of TACI were generated. They display a developmental block of B cell maturation in the periphery, leading to a severe depletion of marginal zone and follicular B2 B cells, but not of peritoneal B1 B cells. In contrast, mice transgenic for a soluble form of BCMA, which binds APRIL, have no detectable B cell phenotype. This demonstrates a crucial role for BAFF in B cell maturation and strongly suggests that it signals via a BCMA-independent pathway and in an APRIL-dispensable way.

Animals↗
PubMed2001

Extrafollicular plasmablast B cells play a key role in carrying retroviral infection to peripheral organs.

B cells can either differentiate in germinal centers or in extrafollicular compartments of secondary lymphoid organs. Here we show the migration properties of B cells after differentiation in murine peripheral lymph node infected with mouse mammary tumor virus. Naive B cells become activated, infected, and carry integrated retroviral DNA sequences. After production of a retroviral superantigen, the infected B cells receive cognate T cell help and differentiate along the two main differentiation pathways analogous to classical Ag responses. The extrafollicular differentiation peaks on day 6 of mouse mammary tumor virus infection, and the follicular one becomes detectable after day 10. B cells participating in this immune response carry a retroviral DNA marker that can be detected by using semiquantitative PCR. We determined the migration patterns of B cells having taken part in the T cell-B cell interaction from the draining lymph node to different tissues. Waves of immigration and retention of infected cells in secondary lymphoid organs, mammary gland, salivary gland, skin, lung, and liver were observed correlating with the two peaks of B cell differentiation in the draining lymph node. Other organs revealed immigration of infected cells at later time points. The migration properties were correlated with a strong up-regulation of alpha(4)beta(1) integrin expression. These results show the migration properties of B cells during an immune response and demonstrate that a large proportion of extrafolliculary differentiating plasmablasts can escape local cell death and carry the retroviral infection to peripheral organs.

Animals↗
PubMed2001

Changing responsiveness to chemokines allows medullary plasmablasts to leave lymph nodes.

During T cell-dependent antibody responses lymph node B cells differentiate either to plasmablasts that grow in the medullary cords, or to blasts that proliferate in follicles forming germinal centers. Many plasmablasts differentiate to plasma cells locally, but some leave the medullary cords and migrate to downstream lymph nodes. To assess the basis for this migration, changes in the responsiveness of B cells to a range of chemokines have been studied as they differentiate. Naive B cells express high levels of CCR6, CCR7, CXCR4 and CXCR5. When activated B cells grow in follicles the expression of these chemokine receptors and the responsiveness to the respective chemokines is retained. During the extrafollicular response, plasmablast expression of CXCR5 and responsiveness to B-lymphocyte chemoattractant (CXCR5) as well as to secondary lymphoid tissue chemokine (CCR7) and stromal cell-derived factor (SDF)-1 (CXCR4) are lost while a weak response towards the CCR6 chemokine LARC is maintained. Despite losing responsiveness to SDF-1, extrafollicular plasmablasts still express high levels of CXCR4 on the cell surface. These results suggest that the combined loss of chemokine receptor expression and of chemokine responsiveness may be a necessary prerequisite for cells to migrate to the medullary cords and subsequently enter the efferent lymph.

Animals↗
PubMed2001

Differential migration of in vivo primed B and T lymphocytes to lymphoid and non-lymphoid organs.

Our study describes tissue-specific migration of T and B cells during a localized anti-viral immune response. After mouse mammary tumor virus (MMTV) injection, B lymphocytes of the draining lymph node become infected and present a retroviral superantigen to CD4(+) T lymphocytes. Infected B cells receive superantigen-mediated help in a fashion comparable to classical immune responses. To investigate the fate of T and B lymphocytes that had interacted via cognate help in the same peripheral lymph node microenvironment we adoptively transferred them into naive recipients. Here we show that MMTV-infected B cells and superantigen-stimulated T cells were programmed to migrate to distinct sites of the body. Plasmablasts but not T cells migrated to the mammary gland and activated alpha4beta1 integrins were found to have a crucial role in the migration to the mammary gland. In contrast, T cells had a much higher affinity for secondary lymphoid organs and large intestine. This demonstrates that upon antigen-driven B and T lymphocyte interaction in the local draining lymph node a subset-specific homing program for B and T lymphocytes is induced.

Adoptive Transfer↗
PubMed2001

Formation of Peyer's patches.

Formation of Peyer's patches requires complex interactions between the gut epithelium, the mesenchyme, and bone-marrow-derived hematopoietic progenitors. The first Peyer's patches anlage appear around embryonic day 15.5, when the endoderm has undergone transition to a simple epithelium, the lymphatic vessels have reached the intestinal mucosa, and mesenchymal cells have started to form clusters. Recent data using knockout mice provide insight into the molecular nature of the signals that mediate Peyer's patch ontogeny. These include members of the tumor-necrosis factor family and homeostatic chemokines.

Animals↗
PubMed2000

[Metabolic disorders in children with urolithiasis].

Nephrolithiasis is a common disease of multifactorial ethiopatogenesis. The majority of stone formers has disturbances in the metabolism and excretion of stone constituents, promotors or inhibitors of crystallization. The aim of our study was to evaluate metabolic disturbances in children with nephrolithiasis in the early stages of the disease. Cases with severe urinary obstruction, infection and glomerular filtration decrease were excluded. Daily calcium, uric acid, oxalate, phosphate, sodium, potassium, chloride, citrate, and magnesium excretion was examined in 27 children (12 M, 15 F, mean age--10.4 +/- 3.9 y). Hypercalciuria (10 cases) and hiperurykosuria (8 cases) were most often found in the studied group. We concluded that early diagnosis of metabolic background of stone formation (promotors and inhibitors) enables to apply proper preventive measures.

Calcium↗
PubMed2000

[Activation of coagulation cascade in children during an idiopathic nephrotic syndrome relapse].

UNLABELLED: The objective of this study was to assess concentrations of selected markers of coagulation in children with relapse of idiopathic nephrotic syndrome during a 6-week therapy. Study groups: 22 subjects (32 relapses)--14 males, 8 females (mean age 7.15 +/- 1.5 y.) with no thrombotic complications were included into the study. All children were clinically steroid-sensitive. METHODS: Coagulation markers (platelet count, thrombin time, APTT, INR, fibrinogen 1 + 2 fragments (F1 + 2), thrombin-antithrombin complexes (TAT), serum levels of D-dimer (DD), fibrin monomers (FM) and antithrombin activity (ATIII)) were measured three times: on admission, after 2 and 6 weeks. The control group consisted of 13 healthy children. RESULTS: Serum concentration of TAT or F1 + 2 did not differ between 3 stages (p > 0.05). However, values at 0 and 2 weeks were significantly higher than in control group (p < 0.05). We found no correlation between TAT or F1 + 2 and FBG, ALB, TCH, TG levels. [table: see text] CONCLUSIONS: The coagulation cascade in relapse of NS was activated during first 6 weeks of therapy whereas metabolic disturbances (low ALB, high FGB, TCH, TG, high platelets) normalized. It is speculative whether it was caused by active immunological process but definitely it resulted in "prothrombotic state" in INS patients.

Adolescent↗
PubMed2000

[An incidence and etiology of Tenckhoff catheter in patients treated with CAPD].

Continuous ambulatory peritoneal dialysis (CAPD) is a renal replacement therapy of choice in small children, the elderly, diabetics, subjects with cardiovascular disease and with difficulties in vascular access. Frequent complication of this method is the infection of the Tenckhoff catheter exit site, definition of which has not been firmly established yet. The aim of this study was to assess the frequency of catheter exit infections, its bacterial etiology and the efficacy of antibiotic treatment. The study material consisted of 21 subjects (11 female, 10 male) treated with CAPD in 1992-99 at our department, mean age 19.8 +/- 11.8 yrs, with mean CAPD treatment time 33 +/- 27 months. They were divided into two groups: group I--patients aged > or = 5 yrs, and group II--patients aged 15 yrs. Mean catheter usage time was 15.8 +/- 14.9 months. 43 cases of catheter exit site infection was diagnosed (0.7 case of infection per patient per year). Infection frequency was found to be 1 case in 9.4 months and 1 in 26.5 months, in group I and II, respectively (p < 0.001). Catheter usage in two groups was 10.4 +/- 8.2 and 21.4 +/- 15.4 months, respectively (p < 0.01). The most frequent pathogen was S. aureus (31 cases), with 5 cases of MRSA strains found. Antibiotic treatment was applied according to Keane's recommendations and it lasted 13.2% of CAPD treatment duration. In conclusion, catheter exit site infection occurred more often in children under the age of 5 yrs, and the catheter usage time was significantly shorter in this group of patients.

Adolescent↗
PubMed1999

Development of T-B cell collaboration in neonatal mice.

The neonatal immune response is impaired during the first weeks after birth. To obtain a better understanding of this immaturity, we investigated the development of T cell interactions with B cells in mice. For this purpose, we analyzed the immune response to three T-dependent antigens in vivo: (i) the polyclonal antibody response induced by vaccinia virus; (ii) the production of polyclonal and specific antibodies following immunization with hapten-carrier conjugates; (iii) the mouse mammary tumor virus superantigen (sAg) response involving an increase in sAg-reactive T cells and induction of polyclonal antibody production. After vaccinia virus injection into neonates, the polyclonal antibody response was similar to that observed in adult mice. The antibody response to hapten-carrier conjugates, however, was delayed and reduced. Injection with sAg-expressing B cells from neonatal or adult mice allowed us to determine whether B cells, T cells or both were implicated in the reduced immune response. In these sAg responses, neonatal T cells were stimulated by both neonatal and adult sAg-presenting B cells but only B cells from adult mice differentiated into IgM- and IgG-secreting plasma cells in the neonatal environment in vivo. Injecting neonatal B cells into adult mice did not induce antibody production. These results demonstrate that the environment of the neonatal lymph node is able to support a T and B cell response, and that immaturity of B cells plays a key role in the reduced immune response observed in the neonate.

Adoptive Transfer↗
PubMed1999

Interplays between mouse mammary tumor virus and the cellular and humoral immune response.

Mouse mammary tumor virus has developed strategies to exploit the immune response. It requires vigorous immune stimulation to achieve efficient infection. The infected antigen-presenting cells present a viral superantigen on the cell surface which stimulates strong CD4-mediated T-cell help but CD8 T-cell responses are undetectable. Despite the high frequency of superantigen-reactive T cells, the superantigen-induced immune response is comparable to classical antigen responses in terms of T-cell priming, T-cell-B-cell collaboration as well as follicular and extra-follicular B-cell differentiation. Induction of systemic anergy is observed, similar to classical antigen responses where antigen is administered systemically but does not influence the role of the superantigen-reactive T cells in the maintenance of the chronic germinal center reaction. So far we have been unable to detect a cytotoxic T-cell response to mouse mammary tumor virus peptide antigens or to the superantigen. This might yet represent another step in the viral infection strategy.

Amino Acid Sequence↗
PubMed1998

Preactivation of B lymphocytes does not enhance mouse mammary tumor virus infection.

We investigated whether mouse mammary tumor virus (MMTV) favors preactivated or naive B cells as targets for efficient infection. We have demonstrated previously that MMTV activates B cells upon infection. Here, we show that polyclonal activation of B cells leads instead to lower infection levels and attenuated superantigen-specific T-cell responses in vivo. This indicates that naive small resting B cells are the major targets of MMTV infection and that the activation induced by MMTV is sufficient to allow efficient infection.

Animals↗
PubMed1995

Gamma interferon is a major mediator of antiviral defense in experimental measles virus-induced encephalitis.

Measles virus infection of the central nervous system in the murine model of experimental measles virus-induced encephalitis is successfully controlled by virus-specific T-helper lymphocytes. T cells from BALB/c mice that are resistant to measles virus encephalitis proliferate well against measles virus in vitro, and bulk cultures recognize viral nucleocapsid and hemagglutinin as well as fusion proteins. The measles virus-specific T cells secrete large amounts of interleukin 2 (IL-2), gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) but no IL-4, IL-6, or IL-10, and hence the cytokine pattern is consistent with that of subtype 1 T-helper lymphocytes. In contrast, cells obtained from measles virus-infected susceptible C3H mice recognize measles virus proteins only weakly and secrete little IFN-gamma and TNF-alpha. Treatment of infected mice with anti-TNF-alpha antibodies has no effect on survival or virus clearance from the brain. Upon neutralization of IFN-gamma in vivo, the phenotype of measles virus-specific T-helper cells isolatable from BALB/c mice is reversed from subtype 1 to subtype 2-like. Anti-IFN-gamma antibody-treated BALB/c mice are susceptible to measles virus encephalitis, and viral clearance from the central nervous system is impaired. These results indicate that IFN-gamma plays a significant role in the control of measles virus infection of the central nervous system.

Animals↗