Effects of combined administration of FK 506 and the purine biosynthesis inhibitors mizoribine or mycophenolic acid on lymphocyte DNA synthesis and T cell activation molecule expression in human mixed lymphocyte cultures

Our objective was to obtain new information on the in vitro antilymphocytic action of the cytokine synthesis inhibitor FK 506 and the purine biosynthesis inhibitors mycophenolic acid (MPA; the active moiety of RS61443) and mizoribine (MZB) when used alone or in combination. When added at the initiation of six-day human mixed lymphocyte cultures (MLC), FK 506, MPA or MZB exhibited dose-dependent inhibition of T-lymphocyte DNA synthesis. FK 506, however, was 100-fold more potent than MPA, and 10000-fold more potent than MZB. Combination of FK 506 with either MPA or MZB, each at suboptional concentrations, produced no more than additive inhibitory effects on 3H thymidine incorporation. Two-colour flow cytometric analysis of lymphocytes revealed that none of the drugs affected cell surface activation molecule expression (CD25 = IL-2R 55 kD α-chain, HLA-DR or CD71 = transferrin receptor [TR]) on allostimulated CD4+ or CD8+ cells harvested at three days of culture. By day six, however, all three agents, at levels which markedly inhibited proliferation, suppressed the expression of activation markers on both CD4+ and CD8+ cells. Also at day six, inhibition of activation molecule expression on CD4+ cells was achieved with the combination of FK 506 and either MPA or MZB at concentrations which, on their own, were ineffective. These data provide new, additional information on the in vitro antilymphocytic action of FK 506, MPA and MZB when used alone and in combination. © 1993

Costimulatory molecule-deficient dendritic cell progenitors (MHC class II⁺, CD80(dim), CD86^-) prolong cardiac allograft survival in nonimmunosuppressed recipients

We have shown previously that granulocyte-macrophage colony-stimulating factor-stimulated mouse bone marrow-derived MHC class II+ dendritic cell (DC) progenitors that are deficient in cell surface expression of the costimulatory molecules B7-1 (CD8O) and B7-2 (CD86) can induce alloantigen- specific T-cell anergy in vitro. To test the in vivo relevance of these findings, 2 x 106 B10 (H2(b)) mouse bone marrow-derived DC progenitors (NLDC 145+, MHC class II+, B7-1(dim), B7-2(-/dim)) that induced T-cell hyporesponsiveness in vitro were injected systemically into normal C3H (H2(k)) recipients. Seven days later, the mice received heterotopic heart transplants from B10 donors. No immunosuppressive treatment was given. Median graft survival time was prolonged significantly from 9.5 to 22 days. Median graft survival time was also increased, although to a lesser extent (16.5 days), in mice that received third-party (BALB/c; H2(d)) DC progenitors. Ex vivo analysis of host T-cell responses to donor and third-party alloantigens 7 days after the injection of DC progenitors (the time of heart transplant) revealed minimal anti-donor mixed leukocyte reaction and cytotoxic T lymphocyte reactivity. These responses were reduced substantially compared with those of spleen cells from animals pretreated with 'mature' granulocyte- macrophage colony-stimulating factor + interleukin-4-stimulated DC (MHC class II(bright), B7-1+, B7-2(bright)), many of which rejected their heart grafts in an accelerated fashion. Among the injected donor MHC class II+ DC progenitors that migrated to recipient secondary lymphoid tissue were cells that appeared to have up-regulated cell surface B7-1 and B7-2 molecule expression. This observation may explain, at least in part, the temporary or unstable nature of the hyporesponsiveness induced by the DC progenitors in nonimmunosuppressed recipients

Pesticide regulatory risk assessment, monitoring, and fate studies in the northern zone: recommendations from a Nordic-Baltic workshop

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Regulation of T Cell Homeostasis and Responses by Pten

The generation of lipid products catalyzed by PI3K is critical for normal T cell homeostasis and a productive immune response. PI3K can be activated in response to antigen receptor, co-stimulatory, cytokine, and chemokine signals. Moreover, dysregulation of this pathway frequently occurs in T cell lymphomas and is implicated in lymphoproliferative autoimmune disease. Akt acts as a central mediator of PI3K signals, downstream of which is the mTOR pathway, controlling cell growth and metabolism. Members of the Foxo family of transcription factors are also regulated by Akt, thus linking control over homing and migration of T cells, as well cell cycle entry, apoptosis, and DNA damage and oxidative stress responses, to PI3K signaling. PTEN, first identified as a tumor suppressor gene, encodes a lipid phosphatase that, by catalyzing the reverse of the PI3K “reaction,” directly opposes PI3K signaling. However, PTEN may have other functions as well, and recent reports have suggested roles for PTEN as a tumor suppressor independent of its effects on PI3K signaling. Through the use of models in which Pten is deleted specifically in T cells, it is becoming increasingly clear that control over autoimmunity and lymphomagenesis by PTEN involves multi-faceted functions of this molecule at multiple stages within the T cell compartment

The Proliferative Capacity of Individual Naive CD4+T Cells Is Amplified by Prolonged T Cell Antigen Receptor Triggering

Strong antigenic encounter by T cells rapidly induces immunological synapse formation and surface T cell receptor (TCR) downregulation. Although surface TCR expression can remain low for several days, T cells can still sustain antigenic signaling. It has been unclear whether prolonged antigenic signaling occurs in the absence of surface TCR replenishment, being maintained by a few “nondownregulatable” surface TCRs that might reside in a synaptosomal structure. Alternatively, the low surface TCR level induced by antigen might represent a dynamic state of expression involving continual surface TCR replenishment, reengagement by antigen, and ongoing downregulation. To resolve this issue, we studied in vivo–generated, dual-specificity primary naive CD4+ T cells. On these cells, antigenic stimulus exclusively downregulated antigen-specific, but not antigen-nonspecific, TCRs. In addition to providing a means to track TCR engagement, this also allowed us to use the antigen nonspecific TCR to track TCR expression in isolation from TCR engagement by antigen. Surface TCR replenishment began within the first day of stimulation, and occurred synchronously with continuous antigen-specific TCR engagement and downregulation. Furthermore, by enhancing CD25 expression, extended signaling through surface-replenishing TCRs significantly amplified the number of daughter cells generated by naive CD4+ T cells that had already committed to proliferate. This effect required TCR engagement and could not be substituted for by interleukin 2. These data demonstrate that TCR triggering and consumption can occur over an extended period of time, with a significant impact on the effector responses evoked from naive CD4+ T cells

Теоретико-методичні основи вивчення теми «текстові задачі практичного змісту» в шкільному курсі математики

In modern schools, we often encounter the problem that students lose interest in learning. Tasks of practical content are designed to increase interest in school mathematics education. The orientation of the research of problems of practical content involves the orientation of methods in the process of solving problems and the formation of strong skills of independent activity in schoolchildren and the education of persistent interest in the subject. Also, practical tasks help to highlight interdisciplinary connections, make you delve deeper into theoretical aspects, and form a complete picture. In the process of solving such problems, students develop cognitive, informational and social competence. Learning becomes useful and, at the same time, exciting and interesting for students. Word problems in the school mathematics course play a very important role and are divided by functions, by the requirements of the task, by types. The article is devoted to the analysis of the theoretical and methodological foundations of problems of practical content and their solution. The purpose of the work is the classification of text problems according to various parameters based on the analysis of scientific and methodological literature on this topic. Word problems of such types as movement problems, work problems, buying and selling problems, interest problems, mixtures and alloys are selected for consideration. The main results of the publication include recommendations for creating a mathematical model of the problem condition using tables, depending on its type. Problems of various types are presented, which are solved by constructing a corresponding mathematical model of the problem condition. This approach to studying the topic "Word problems" is used in my own experience of teaching mathematicsВ сучасній школі все найчастіше ми зустрічаємося з проблемою, що учні втрачають інтерес до навчання. Задачі практичного змісту покликані підвищити зацікавленість до шкільної математичної освіти. Спрямованість дослідження задач практичного змісту передбачає орієнтацію методів в процесі вирішення завдань та формування у школярів міцних навичок самостійної діяльності та виховання стійкого інтересу до предмета. Також, практичні задачі допомагають висвітити міжпредметні зв’язки, заставляють глибше зануритися в теоретичні аспекти, сформувати цілісну картину. У процесі розв'язання таких задач в учнів формуються пізнавальна, інформаційна та соціальна компетентності. Навчання стає корисним і, водночас, захопливим та цікавим для учнів. Текстові задачі в шкільному курсі математики мають велике значення та розподіляються за функціями, за вимогою поставленої задачі, за типами. Стаття присвячена аналізу теоретико-методичних основ задач практичного змісту та їх розв’язання. Метою роботи є класифікація текстових задач за різними параметрами на основі аналізу науково-методичної літератури з цієї теми. Для розгляду обрано текстові задачі таких типів, як задачі на рух, на роботу, на купівлю-продаж, на відсотки, суміші та сплави. До основних результатів публікації відносяться рекомендації створення математичної моделі умови задачі за допомогою таблиць залежно від її типу. Наведено задачі різних типів, які розв’язуються за допомогою складання відповідної математичної моделі умови задачі. Цей підхід до вивчення теми «Текстові задачі» використовується у власному досвіді навчання математик

IMP Dehydrogenase Inhibitors as Immunomodulators

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74880/1/j.1749-6632.1993.tb35869.x.pd