[T Lymphocytes with Modified Specificity in the Therapy of Malignant Diseases].

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.

Multiple Sclerosis Is Associated with Immunoglobulin Germline Gene Variation of Transitional B Cells.

The regulatory functions of the B-cell compartment play an important role in the development and suppression of the immune response. Disruption of their anti-inflammatory functions may lead to the acceleration of immunopathological processes, and to autoimmune diseases, in particular. Unfortunately, the exact mechanism underlying the functioning and development of regulatory B cells (Breg) has not yet been fully elucidated. Almost nothing is known about their specificity and the structure of their B-cell receptors (BCRs). In this research, we analyzed the BCR repertoire of the transitional Breg (tBreg) subpopulation with the CD19+CD24highCD38high phenotype in patients with multiple sclerosis (MS), using next-generation sequencing (NGS). We show, for the first time, that the immunoglobulin germline distribution in the tBreg subpopulation is different between MS patients and healthy donors. The registered variation was more significant in patients with a more severe form of the disease, highly active MS (HAMS), compared to those with benign MS (BMS). Our data suggest that during MS development, deviations in the immunoglobulin Breg repertoire occur already at the early stage of B-cell maturation, namely at the stage of tBregs: between immature B cells in the bone marrow and mature peripheral B cells.

Polyreactive monoclonal autoantibodies in multiple sclerosis: functional selection from phage display library and characterization by deep sequencing analysis.

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that primarily affects young and middle-aged people. It is widely accepted that B lymphocyte activation is required for MS progression. Despite the fact that the exact triggering mechanisms of MS remain enigmatic, one may suggest that MS can be induced by viral or bacterial infection in combination with specific genetic and environmental factors. Using deep sequencing and functional selection methodologies we characterized clones of poly- and cross-reactive antibodies that are capable of simultaneous recognition of viral proteins and autoantigens. The latter, in turn, possibly may trigger MS progression through molecular mimicry. It was identified that two cross-reactive antigens are probably recognized by light or heavy chains individually. According to the high structural homology between selected autoantibodies and a number of various antiviral IgGs, we suggest that a wide range of pathogens, instead of a single virus, be regarded as possible triggers of MS.