Uuden testamentin eksegetiikka

Osastoon kuuluvat UT:n editiot ja sen käsikirjoituksia koskevat julkaisut, UT:n apokryfikirjojen käännökset, Nag Hammadin tekstit, ajanhistorialliset tekstit, evankeliumisynopsikset sekä nk. apostolisten isien tekstit, kreikan kieliopit ja apuneuvot. Lisäksi kommentaarit jakautuvat kommentaarisarjoihin ja yksittäisiin kommentaareihin. Tutkimusosiossa sijaitsee UT:n kanonisia kirjoja koskevan tutkimuksen lisäksi myös UT:n ajan- ja uskonnonhistoriaa, gnostilaisuutta sekä apostolisia isiä koskevaa tutkimusta.

Yleinen kirkkohistoria

Lähteet ja tutkimukset on sijoitettu osastossa yhdeksi kokonaisuudeksi. Lähteiden joukossa on etenkin merkittävien teologien kootut teokset. Lisäksi on saatavilla runsaasti jakamattoman kirkon ja roomalaiskatolisen kirkon konsiilien dokumentteja. Kirkkohistorian tutkimus kohdistuu 2. vuosisadalta nykypäiviin, ja on keskittynyt etenkin Euroopan, toissijaisesti Venäjän ja Yhdysvaltojen kirkkohistoriaan. Osasto sisältää myös Saksan kirkkotaistelun (1933-45) lähteitä ja aikalaisdokumentteja sekä tutkimuksia kirkkojen asemasta ja toiminnasta tuona aikana. Kirkkotaistelusta on tullut suomalaisessa tutkimuksessa erityisalue, jossa kiinnostus on kohdistunut nk. tunnustuskirkon ja nk. saksalaisten kristittyjen vaiheisiin.

Expression of killer cell immunoglobulin-like receptors (KIRs) by natural killer cells during acute CMV infection after kidney transplantation.

Human cytomegalovirus (CMV) infection may be a serious complication related to immunosuppression after solid organ transplantation. Due to their cytotoxicity, T-cells and natural killer (NK) cells target and clear the virus from CMV-infected cells. Although immunosuppressive drugs suppress T-cell proliferation and activation, they do not affect NK cells that are crucial for controlling the infection. The regulation of NK cells depends on a wide range of activating and inhibitory receptors such as the family of killer-cell immunoglobulin-like receptors (KIRs). Several human genetic studies have demonstrated the association of KIR genes with the clearance of infections. Since the respective activities of the different KIR proteins expressed by NK cells during CMV infection have not been extensively studied, we analyzed the expression of KIRs in a cohort of 22 CMV-IgG(+) renal transplant patients at the time of CMV reactivation, after antiviral therapy and 6 months later. Our data revealed a marked expression of KIR3DL1 during the acute phase of the reactivation. We set up an in vitro model in which NK cells, derived either from healthy donors or from transplanted patients, target allogeneic fibroblasts, CMV-infected or uninfected. Our results demonstrate a significant correlation between the lysis of CMV-infected fibroblasts and the expression of KIR3DL1. Blocking experiments with antibodies to MHC-I, to NKG2D and to NKG2C confirmed the importance of KIR3DL1. Consequently, our results suggest that KIR proteins and especially KIR3DL1 could play an important role during CMV-infection or CMV reactivation in immunosuppressed patients.

Cis association of Ly49A with MHC class I restricts natural killer cell inhibition.

Natural killer (NK) cell function is negatively regulated by inhibitory receptors interacting with major histocompatibility complex class I molecules expressed on target cells. Here we show that the inhibitory Ly49A NK cell receptor not only binds to its H-2D(d) ligand expressed on potential target cells (in trans) but also is constitutively associated with H-2D(d) in cis (on the same cell). Cis association and trans interaction occur through the same binding site. Consequently, cis association restricts the number of Ly49A receptors available for binding of H-2D(d) on target cells and reduces NK cell inhibition through Ly49A. By lowering the threshold at which NK cell activation exceeds NK cell inhibition, cis interaction allows optimal discrimination of normal and abnormal host cells.

A Role for cis Interaction between the Inhibitory Ly49A receptor and MHC class I for natural killer cell education.

Natural killer (NK) cells show enhanced functional competence when they express inhibitory receptors specific for inherited major histocompatibility complex class I (MHC-I) molecules. Current models imply that NK cell education requires an interaction of inhibitory receptors with MHC-I expressed on other cells. However, the inhibitory Ly49A receptor can also bind MHC-I ligand on the NK cell itself (in cis). Here we describe a Ly49A variant, which can engage MHC-I expressed on other cells but not in cis. Even though this variant inhibited NK cell effector function, it failed to educate NK cells. The association with MHC-I in cis sequestered wild-type Ly49A, and this was found to relieve NK cells from a suppressive effect of unengaged Ly49A. These data explain how inhibitory MHC-I receptors can facilitate NK cell activation. They dissociate classical inhibitory from educating functions of Ly49A and suggest that cis interaction of Ly49A is necessary for NK cell education.

Generation of short-term murine natural killer cell clones to analyze Ly49 gene expression.

Natural killer (NK) cellsexpress receptors specific for class I major histocompatibility complex (MHC) molecules. In the mouse, the class I specific receptors identified to date belong to the polymorphic Ly49 receptor family. Engagement of Ly49 receptors with their respective MHC ligands results in negative regulation of NK cell effector functions, consistent with a critical role of these receptors in "missing self" recognition. The Ly49 receptors analyzed so far are clonally distributed such that multiple distinct Ly49 receptors can be expressed by individual NK cells (for review see refs. 1-3). The finding that most NK cells that express the Ly49A receptor do so from a single Ly49A allele (whereby expression can occur from the maternal or the paternal chromosome) may thus reflect a putative receptor distribution process that restricts the number of Ly49 receptors expressed in a single NK cell (3-5).

Transgenic expression of Ly49A on T cells impairs a specific antitumor response.

Inhibitory MHC receptors determine the reactivity and specificity of NK cells. These receptors can also regulate T cells by modulating TCR-induced effector functions such as cytotoxicity, cytokine production, and proliferation. Here we have assessed the capacity of mouse T cells expressing the inhibitory MHC class I receptor Ly49A to respond to a well-defined tumor Ag in vivo using Ly49A transgenic mice. We find that the presence of Ly49A on the vast majority of lymphocytes prevents the development of a significant Ag-specific CD8+ T cell response and, consequently, the rejection of the tumor. Despite minor alterations in the TCR repertoire of CD8+ T cells in the transgenic lines, precursors of functional tumor-specific CD8+ T cells exist but could not be activated most likely due to a lack of appropriate CD4+ T cell help. Surprisingly, all of these effects are observed in the absence of a known ligand for the Ly49A receptor as defined by its ability to regulate NK cell function. Indeed, we found that the above effects on T cells may be based on a weak interaction of Ly49A with Kb or Db class I molecules. Thus, our data demonstrate that enforced expression of a Ly49A receptor on conventional T cells prevents a specific immune response in vivo and suggest that the functions of T and NK cells are differentially sensitive to the presence of inhibitory MHC class I receptors.

Ly49E-dependent inhibition of natural killer cells by urokinase plasminogen activator.

The Ly49 natural killer (NK)-cell receptor family comprises both activating and inhibitory members, which recognize major histocompatibility complex (MHC) class I or MHC class I-related molecules and are involved in target recognition. As previously shown, the Ly49E receptor fails to bind to a variety of soluble or cell-bound MHC class I molecules, indicating that its ligand is not an MHC class I molecule. Using BWZ.36 reporter cells, we demonstrate triggering of Ly49E by the completely distinct, non-MHC-related protein urokinase plasminogen activator (uPA). uPA is known to be secreted by a variety of cells, including epithelial and hematopoietic cells, and levels are up-regulated during tissue remodeling, infections, and tumorigenesis. Here we show that addition of uPA to Ly49E-positive adult and fetal NK cells inhibits interferon-gamma secretion and reduces their cytotoxic potential, respectively. These uPA-mediated effects are Ly49E-dependent, as they are reversed by addition of anti-Ly49E monoclonal antibody and by down-regulation of Ly49E expression using RNA interference. Our results suggest that uPA, besides its established role in fibrinolysis, tissue remodeling, and tumor metastasis, could be involved in NK cell-mediated immune surveillance and tumor escape.

Rapid death and regeneration of NKT cells in anti-CD3epsilon- or IL-12-treated mice: a major role for bone marrow in NKT cell homeostasis.

Natural killer T (NKT) cells express a T cell receptor (TCR) and markers common to NK cells, including NK1.1. In vivo, NKT cells are triggered by anti-CD3epsilon MAb to rapidly produce large amounts of IL-4 and by IL-12 to reject tumors. We show here that anti-CD3epsilon MAb treatment rapidly depletes the liver (and partially the spleen) of NKT cells and that homeostasis is achieved 1 to 2 days later via NKT cell proliferation that occurs mainly in bone marrow. Similar results were obtained in mice treated with IL-12. Collectively, our data demonstrate that peripheral NKT cells are highly sensitive to activation-induced cell death and that bone marrow plays a major role in restoring NKT cell homeostasis.

Ly49D engagement on T lymphocytes induces TCR-independent activation and CD8 effector functions that control tumor growth.

Recent data showing expression of activating NK receptors (NKR) by conventional T lymphocytes raise the question of their role in the triggering of TCR-independent responses that could be damaging for the host. Transgenic mice expressing the activating receptor Ly49D/DAP12 offer the opportunity to better understand the relevance of ITAM signaling in the biology of T cells. In vitro experiments showed that Ly49D engagement on T lymphocytes by a cognate MHC class I ligand expressed by Chinese hamster ovary (CHO) cells or by specific Ab triggered cellular activation of both CD4 and CD8 populations with modulation of activation markers and cytokine production. The forced expression of the ITAM signaling chain DAP12 is mandatory for Ly49D-transgenic T cell activation. In addition, Ly49D stimulation induced T lymphocyte proliferation, which was much stronger for CD8 T cells. Phenotypic analysis of anti-Ly49D-stimulated CD8 T cells and their ability to produce high levels of IFN-gamma and to kill target cells indicate that Ly49D ligation generates effector cytotoxic CD8 T cells. Ly49D engagement by itself also triggered cytotoxic activity of activated CD8 T cells. Adoptive transfer experiments confirmed that Ly49D-transgenic CD8 T cells are able to control growth of CHO tumor cells or RMA cells transfected with Hm1-C4, the Ly49D ligand normally expressed by CHO. In conclusion, Ly49D engagement on T cells leads to T cell activation and to a full range of TCR-independent effector functions of CD8 T cells.

Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity.

The protease activity of the paracaspase Malt1 has recently gained interest as a drug target for immunomodulation and the treatment of diffuse large B-cell lymphomas. To address the consequences of Malt1 protease inactivation on the immune response in vivo, we generated knock-in mice expressing a catalytically inactive C472A mutant of Malt1 that conserves its scaffold function. Like Malt1-deficient mice, knock-in mice had strong defects in the activation of lymphocytes, NK and dendritic cells, and the development of B1 and marginal zone B cells and were completely protected against the induction of autoimmune encephalomyelitis. Malt1 inactivation also protected the mice from experimental induction of colitis. However, Malt1 knock-in mice but not Malt1-deficient mice spontaneously developed signs of autoimmune gastritis that correlated with an absence of Treg cells, an accumulation of T cells with an activated phenotype and high serum levels of IgE and IgG1. Thus, removal of the enzymatic activity of Malt1 efficiently dampens the immune response, but favors autoimmunity through impaired Treg development, which could be relevant for therapeutic Malt1-targeting strategies.

Utilização de uréia em misturas com sulfato de amônio ou com gesso na cultura de milho

Aspectos qualitativos e quantitativos devem ser considerados na adubação nitrogenada de cobertura na cultura de milho. Este estudo teve por objetivo avaliar, nos municípios de Votuporanga (SP) e Uberlândia (MG), o efeito de diferentes misturas de grânulos, contendo N e S, na produtividade de milho. Em um Argissolo Vermelho eutrófico A moderado textura arenosa (120 g kg-1 de argila) de Votuporanga, foram estimadas as perdas por volatilização de N-NH3, das misturas de grânulos constituídas por uréia (U) e sulfato de amônio (SA), ou U e gesso agrícola, aplicadas no primeiro parcelamento de cobertura nitrogenada. Em Uberlândia, em Latossolo Vermelho ácrico típico fase Cerrado subcaducifólio muito argiloso (720 g kg-1), foram determinados a distribuição de N-inorgânico e S-sulfato em profundidade, após a aplicação das misturas em cobertura, e os custos de aplicação dessas fontes. Os experimentos foram instalados em delineamento de blocos casualizados, com quatro repetições, e as misturas de grânulos aplicadas em superfície, na entre linha de cultivo. Em Votuporanga, foram acompanhados dois experimentos: safra 2005/2006 e safrinha 2006. Na safra de 2005/2006, foram comparados quatro tratamentos de cobertura: testemunha, sem N, uréia+sulfato de amônio farelado (U+SAfa), uréia+gesso granulado (U+Gesso gr) e uréia+gesso em pó (U+Gesso pó), aplicados em dois parcelamentos de 45 kg ha-1 de N cada, nos estádios de cinco a seis folhas e 12 a 13 folhas. As perdas de N-NH3 volatilizado em função do N aplicado foram de 45,9, 56,6 e 61,1 % das misturas U+SAfa, U+Gesso pó e U+Gesso gr, respectivamente. A produtividade de grãos não mostrou diferença significativa entre os tratamentos, sendo, em média, de 5.362 kg ha-1. Na safrinha, uréia+sulfato de amônio granulado (U+SAgr) foi incluído nos tratamentos. Neste experimento, as misturas de grânulos foram aplicadas em doses de 50 kg ha-1 de N cada, em cobertura, nos estádios de três a quatro folhas e seis a sete folhas. A produtividade de grãos foi similar entre as fontes de U+SA e U+Gesso, sendo em média de 5.332 kg ha-1. Em Uberlândia, foram comparados os cinco tratamentos testados no experimento - safrinha de Votuporanga. As misturas de grânulos foram aplicadas em dose única de 90 kg ha-1 de N, no estádio de quatro a cinco folhas. Os maiores teores de N-mineral total foram detectados na camada de 0 a 10 cm de profundidade, em todos os tratamentos (abaixo de 3 mg dm-3), diminuindo em profundidade, enquanto o S-sulfato concentrou-se entre as camadas de 10 a 60 cm. Os tratamentos de U+Gesso e U+SA apresentaram, em média, produtividades de 11.364 e 10.300 kg ha-1 de grãos, respectivamente. O custo de aplicação de U+Gesso gr foi 27,7 % superior aos custos médios de aplicação de U+SAgr e U+SAfa, devido a seu menor teor de N, e 7,8 % superior em relação aos custos diretos totais por hectare. A mistura NK com aplicação posterior de U+Gesso pó apresentou custo de aplicação similar ao da U+Gesso gr, devido à dupla operação de aplicação do primeiro. Os resultados em ambas as regiões permitem concluir que o milho respondeu de forma similar à aplicação em cobertura das fontes mistas, U+SA e U+Gesso, independentemente da granulometria dos produtos, e que os custos de aplicação das formas U+Gesso foram superiores aos das misturas U+SA.

NLRC5 deficiency selectively impairs MHC class I- dependent lymphocyte killing by cytotoxic T cells.

Nucleotide-binding oligomerization domain-like receptors (NLRs) are intracellular proteins involved in innate-driven inflammatory responses. The function of the family member NLR caspase recruitment domain containing protein 5 (NLRC5) remains a matter of debate, particularly with respect to NF-κB activation, type I IFN, and MHC I expression. To address the role of NLRC5, we generated Nlrc5-deficient mice (Nlrc5(Δ/Δ)). In this article we show that these animals exhibit slightly decreased CD8(+) T cell percentages, a phenotype compatible with deregulated MHC I expression. Of interest, NLRC5 ablation only mildly affected MHC I expression on APCs and, accordingly, Nlrc5(Δ/Δ) macrophages efficiently primed CD8(+) T cells. In contrast, NLRC5 deficiency dramatically impaired basal expression of MHC I in T, NKT, and NK lymphocytes. NLRC5 was sufficient to induce MHC I expression in a human lymphoid cell line, requiring both caspase recruitment and LRR domains. Moreover, endogenous NLRC5 localized to the nucleus and occupied the proximal promoter region of H-2 genes. Consistent with downregulated MHC I expression, the elimination of Nlrc5(Δ/Δ) lymphocytes by cytotoxic T cells was markedly reduced and, in addition, we observed low NLRC5 expression in several murine and human lymphoid-derived tumor cell lines. Hence, loss of NLRC5 expression represents an advantage for evading CD8(+) T cell-mediated elimination by downmodulation of MHC I levels-a mechanism that may be exploited by transformed cells. Our data show that NLRC5 acts as a key transcriptional regulator of MHC I in lymphocytes and support an essential role for NLRs in directing not only innate but also adaptive immune responses.

Matrix metalloproteinase 9 (MMP-9/gelatinase B) proteolytically cleaves ICAM-1 and participates in tumor cell resistance to natural killer cell-mediated cytotoxicity.

Shedding of intercellular adhesion molecule 1 (ICAM-1) is believed to play a role in tumor cell resistance to cell-mediated cytotoxicity. However, the mechanism whereby ICAM-1 is shed from the surface of tumor cells remains unclear. In this study, we have addressed the possibility that matrix metalloproteinases are implicated in ICAM-1 shedding. Our observations suggest a functional relationship between ICAM-1 and matrix metalloproteinase 9 (MMP-9) whereby ICAM-1 provides a cell surface docking mechanism for proMMP-9, which, upon activation, proteolytically cleaves the extracellular domain of ICAM-1 leading to its release from the cell surface. MMP-9-dependent shedding of ICAM-1 is found to augment tumor cell resistance to natural killer (NK) cell-mediated cytotoxicity. Taken together, our observations propose a mechanism for ICAM-1 shedding from the cell surface and provide support for MMP involvement in tumor cell evasion of immune surveillance.

Recovery of degraded pasture in Rondônia: macronutrients and productivity of brachiaria brizantha

Pasture is the main form of land use in Amazonia. Over time the pasture grass loses vigor and yields decrease, indicating a certain degree of degeneration. The main causes of degradation are lack of pasture maintenance and subsequent weed infestation, the choice of regionally unsuitable forage species and excessive grazing. The main purpose of this study was to evaluate the impact of different recovery managements on soil chemical properties and grass yield of a degraded pasture in Rondônia. For this purpose, an experiment was installed in October 2001, consisting of five treatments: C = control; HA = harrowing + NPK + micronutrients; HE = Herbicide + NK + micronutrients; R = No-tillage rice + NPK + micronutrients; and S = No-tillage soybean + PK + micronutrients. The following N, P and K sources were used: ammonium sulfate for N, calcined phosphate for P and potassium chloride for K. The experiment was arranged in a randomized block design with four replications. The shoot dry matter yield of the grass was analyzed as of the 35th month of experimentation, in a dry and a rainy period. Phosphorus fertilization resulted in significant increases in Ca2+ and Mg2+ and increasing trend of P in the topsoil in the initial months of the experiment in treatments HA and S and increases in Ca2+ and P (trend) in the treatment R. The cumulative production of Brachiaria brizantha, from Sep/2004 to Mar/2005, was 30,025, 28,267 and 27,735 kg ha-1 shoot dry matter in the treatments HA, R and S, respectively. These values differed significantly from treatments C and HE, with 17,040 and 17,057 kg ha-1, respectively. It was concluded that phosphorus fertilization associated to pasture reform was effective to raise the dry matter yield of Brachiaria brizantha. Rice or soybean under no-tillage is recommended as a practice of pasture recovery, due to the residual effect of fertilization.