Antibody to the dendritic cell surface activation antigen CD83 prevents acute graft-versus-host disease

Allogeneic (allo) hematopoietic stem cell transplantation is an effective therapy for hematological malignancies but it is limited by acute graft-versus-host disease (GVHD). Dendritic cells (DC) play a major role in the allo T cell stimulation causing GVHD. Current immunosuppressive measures to control GVHD target T cells but compromise posttransplant immunity in the patient, particularly to cytomegalovirus (CMV) and residual malignant cells. We showed that treatment of allo mixed lymphocyte cultures with activated human DC-depleting CD83 antibody suppressed alloproliferation but preserved T cell numbers, including those specific for CMV. We also tested CD83 antibody in the human T cell–dependent peripheral blood mononuclear cell transplanted SCID (hu-SCID) mouse model of GVHD. We showed that this model requires human DC and that CD83 antibody treatment prevented GVHD but, unlike conventional immunosuppressants, did not prevent engraftment of human T cells, including cytotoxic T lymphocytes (CTL) responsive to viruses and malignant cells. Immunization of CD83 antibody-treated hu-SCID mice with irradiated human leukemic cell lines induced allo antileukemic CTL effectors in vivo that lysed 51Cr-labeled leukemic target cells in vitro without further stimulation. Antibodies that target activated DC are a promising new therapeutic approach to the control of GVHD

Instructional design in foreign language teaching

This paper offers a presentation of two original multimedia educational resources with interactive online tasks in the German language developed within the course “Teacher”s and translator”s electronic resource” in cooperation with the students of the Faculty of Foreign Languages and International Communication of Tver State University. The purpose of our projects assumes, in the first place, deliberate formation of a learning environment meeting the needs of a target audience. In the process of working over the projects, the authors took into consideration the principles of instructional design that served as a theoretical basis for the development of educational materials. Instructional design is viewed by the authors of the article as a separate branch of practical pedagogy which primarily focuses on the application of pedagogical knowledge in practice, namely, development of high-quality efficient educational resources with the use of modern information technologies. The distinctive feature of the theory of instructional design is consideration of not so much the cognitive parameters and mental processes characterising the learning process as the efficient methods and learning formats stimulating these cognitive processes. The most important result of our work is the conclusion that the projects developed with regard for the principles of instructional design under the ADDIE model contribute to enhancement of students’ cognitive abilities and increase the amount and quality of information assimilated by them; at the same time, the learning becomes more systemic and practice-oriented from the first stages of project analysis and planning. The novelty of our approach specifically lies in practical treatment of instructional design as a tool for development of learning materials, invigoration of learning activities and tutor support of students

Comparison of predicted and actual consequences of missense mutations

Each person's genome sequence has thousands of missense variants. Practical interpretation of their functional significance must rely on computational inferences in the absence of exhaustive experimental measurements. Here we analyzed the efficacy of these inferences in 33 de novo missense mutations revealed by sequencing in first-generation progeny of N-ethyl-N-nitrosourea–treated mice, involving 23 essential immune system genes. PolyPhen2, SIFT, MutationAssessor, Panther, CADD, and Condel were used to predict each mutation's functional importance, whereas the actual effect was measured by breeding and testing homozygotes for the expected in vivo loss-of-function phenotype. Only 20% of mutations predicted to be deleterious by PolyPhen2 (and 15% by CADD) showed a discernible phenotype in individual homozygotes. Half of all possible missense mutations in the same 23 immune genes were predicted to be deleterious, and most of these appear to become subject to purifying selection because few persist between separate mouse substrains, rodents, or primates. Because defects in immune genes could be phenotypically masked in vivo by compensation and environment, we compared inferences by the same tools with the in vitro phenotype of all 2,314 possible missense variants in TP53; 42% of mutations predicted by PolyPhen2 to be deleterious (and 45% by CADD) had little measurable consequence for TP53-promoted transcription. We conclude that for de novo or low-frequency missense mutations found by genome sequencing, half those inferred as deleterious correspond to nearly neutral mutations that have little impact on the clinical phenotype of individual cases but will nevertheless become subject to purifying selection