Search

An overview of various cell engineering techniques being developed for modern conservative and reconstructive periodontology is presented. The accelerated development of cellular engineering technologies poses to medicine and, in particular, periodontics, the task of early implementation of the results of such experiments into patient management protocols. The main groups of promising techniques that are closest to practical healthcare are: isolation and use of stem cells; synthesis of biologically active (inductive) signaling molecules; development of scaffolds that ensure three-dimensional tissue growth.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for hematopoietic malignancies. The graft-derived donor lymphocytes are capable of eliminating the residual recipient malignant cells in the course of allogeneic immune response, thus decreasing the chances of a relapse of the disease. Foreign peptides of the recipient presented by the MHC molecules are able to elicit the immune response immunologically. These polymorphic peptides are known as minor histocompatibility antigens (MiHAs). MiHAs occur due to the nonsynonymous single nucleotide polymorphisms in human genome. Transfusion of T cells specific to MiHAs presented predominantly in the cells of hematopoietic origin will allow the targeted elimination of residual malignant clones avoiding undesirable damage to healthy tissues. To induce the immune response, the donor must be homozygous by the MiHA allele and the recipient must either be homozygous or heterozygous by the alternative MiHA allele. The therapeutic mismatch occurs in 25% of cases under the optimal frequency of allelic variants. Minor antigen ACC-1Y originates from polymorphism in the BCL-2A1 gene; its immunogenic mismatch occurrence approaches the theoretical maximum. In addition, BCL2A1 is overexpressed in cells of various lymphomas. ACC-1Y is presented on allele HLA-A*24:02, which is relatively frequent in the Russian population. Combination of these factors makes the minor antigen ACC-1Y a promising target for immunotherapy. Transfusion of donor CD8^(+) lymphocytes modified with transgenic MiHA-specific TCR is one of the promising methods of posttransplant leukemia therapy and relapse prophylaxis. We obtained a sequence of high-affinity ACC-1Y-specific TCR after the antigen-specific expansion of T cells derived from a healthy ACC-IY^(-/-) donor. We cloned this sequence into the lentiviral vector and obtained the assembled viral particles. Further, we transduced the CD8^(+) lymphocyte culture and demonstrated its antigen-specific cytotoxic activity. It is suggested that CD8^(+) lymphocytes modified by the described method could be potentially transferred to recipients as a therapy against relapse after allo-HSCT.

In view of the explosion of the present clinical use of monoclonal antibodies (mAbs), not only in the treatment of cancer, but also of autoimmune diseases, I was asked to review the development of mAbs in tumor diagnosis and therapy, with some illustrations of our own contribution in the field. The initial use of radiolabeled mAbs for tumor targeting and radioimmunotherapy led to the extensive clinical application of unlabeled, "humanized" mAbs for cancer therapy, which I describe with a critical perspective. The introduction of recombinant bispecific antibodies, capable of bridging T lymphocytes with tumor cells and inducing killing of the cancer cells, was found to be mostly active in the treatment of hematological malignancies. Most interestingly, the use of mAbs not directed to the tumor cells, but to inhibitory receptors expressed by cytotoxic T lymphocytes, which trigger them to kill the cancer cells, represents a new form of active cancer immunotherapy. My motivation in writing this review was related to my long-term interactions with several Russian scientists, mentioned at the end of this article.

Immunotherapy is one of the most rapidly progressing and promising fields in antitumor therapy. It is based on the idea of using immune cells of patient or healthy donors for elimination of malignant cells. T lymphocytes play a key role in cell-mediated immunity including the response to tumors. Recently developed approaches of altering antigen specificity of T cells consist of their genetic modification (introduction of additional T cell receptor or chimeric antigen receptor), as well as the use of bispecific molecules that crosslink target and effector cells. These approaches are used to retarget T lymphocytes with arbitrary specificity against tumor antigens in the context of antitumor immunotherapy. The high potential of T cell immunotherapy was demonstrated in a number of clinical trials. In the future, it is possible to develop approaches to the therapy of a wide spectrum of tumors. The selection of the optimal antigen is the main challenge in successful T cell immunotherapy, as it largely determines the effectiveness of the treatment, as well as the risk of side effects. In this review we discuss potential methods of modification of T cell specificity and targets for immunotherapy.

The review is devoted to the widely discussed problems of the feasibility of "systems biology" and "P4-personalized (systems) medicine" from the standpoint of complex living systems. The following conclusions are made. 1. It is impossible to reach the ultimate goals of systems biology and medicine based solely on data of genomics and other 'omics'. Systems biology may be efficient for an approximate description of certain functional modules provided that there are experimental data for the majority of the components of the system under study. 2. P4-personalized (systems) medicine based on systems biology is unrealistic fundamentally and technically, as well as from the economic point of view. 3. A possible way is to search for the targets common for all or for large groups of individuals, and the development of postgenomic generalized medicine. 4. Also realistic are some of currently developing options of personalized medicine, such as e. g. the use of patient stem cells that are returned to the patient after culturing, or of gene-modified infiltrating T-lymphocytes in so-called chimeric antigen receptor (CAR) cancer therapy. CAR therapy is a personalized treatment that uses T-lymphocytes taken from a patient and gene-modified in such a way that to recognize and kill cancer cells. 5. Despite of numerous claims, the paradigms of the postgenomic sciences were not changed. Traditional approaches of molecular biology, genetics, biochemistry, and physiology still remain in force in the postgenomic era. They are enforced due to the data obtained by 'omics'. These data may be a base for putting forward and testing hypotheses about the mechanisms of functional processes.

A stable cell line based on HEK293 cells that expresses proteasome subunit PSMD14 fused to the fluorescent protein EGFP and HTBH tag has been selected. This chimera was shown to be incorporated completely into proteolitic active proteasomes. The created cell line can be used for further fluorescent studies of proteasomes localization in the cell.

In thoracic department of the National Cancer Institute studied the effectiveness of dendritic cell autovaccine in the postoperative period in non-small-cell lung cancer patients. The results, showing good tolerance dendritic cell autovaccine. Shows the formation of the expressed antigen immune response after repeated injections dendritic cell autovaccine, as manifested after 4 revaccination. Results of survival patients non-small-cell lung cancer who received postoperative dendritic cell autovaccines demonstrate the high efficiency of the method and its applicability with a minimum of side effects. Further study of survival of patients non-small-cell lung cancer who received immunotherapy treatment, monitoring of compliance with the best mode of repeated injections.