ABSTRACT
Preclinical and clinical studies have suggested that cancer treatment with antitumor antibodies induces a specific adaptive T cell response. A central role in this process has been attributed to CD4+ T cells, but the relevant T cell epitopes, mostly derived from non-mutated self-antigens, are largely unknown. In this study, we have characterized human CD20-derived epitopes restricted by HLA-DR1, HLA-DR3, HLA-DR4, and HLA-DR7, and investigated whether T cell responses directed against CD20-derived peptides can be elicited in human HLA-DR-transgenic mice and human samples. Based on in vitro binding assays to recombinant human MHC II molecules and on in vivo immunization assays in H-2 KO/HLA-A2+-DR1+ transgenic mice, we have identified 21 MHC II-restricted long peptides derived from intracellular, membrane, or extracellular domains of the human non-mutated CD20 protein that trigger in vitro IFN-γ production by PBMCs and splenocytes from healthy individuals and by PBMCs from follicular lymphoma patients. These CD20-derived MHC II-restricted peptides could serve as a therapeutic tool for improving and/or monitoring anti-CD20 T cell activity in patients treated with rituximab or other anti-CD20 antibodies.
Subject(s)
Antigens, CD20/immunology , CD4-Positive T-Lymphocytes/immunology , Lymphoma/drug therapy , Animals , Female , HLA-DRB1 Chains/immunology , Humans , Interferon-gamma/biosynthesis , Lymphoma/immunology , Mice , Rituximab/therapeutic useABSTRACT
CD4+ T cells differentiate into various T helper subsets characterized by distinct cytokine secreting profiles that confer them effector functions adapted to a variety of infectious or endogenous threats. Regulatory CD4+ T cells are another specialized subset that plays a fundamental role in the maintenance of immune tolerance to self-antigens. Manipulating effector or regulatory CD4+ T cells responses is a promising immunotherapy strategy for, respectively, chronical viral infections and cancer, or severe autoimmune diseases and transplantation. Adoptive cell therapy (ACT) is an emerging approach that necessitates defining robust and efficient methods for the in vitro expansion of antigen-specific T cells then infused into patients. To address this challenge, artificial antigen presenting cells (AAPCs) have been developed. They constitute a reliable and easily usable platform to stimulate and amplify antigen-specific CD4+ T cells. Here, we review the recent advances in understanding the functions of CD4+ T cells in immunity and in immune tolerance, and their use for ACT. We also describe the characteristics of different AAPC models and the way to improve their stimulating functions. Finally, we discuss the potential interest of these AAPCs, both as fundamental tools to decipher CD4+ T cell responses and as reagents to generate clinical grade antigen-specific CD4+ T cells for immunotherapy.
Subject(s)
Antigen-Presenting Cells/immunology , CD4-Positive T-Lymphocytes/immunology , Cancer Vaccines/immunology , Immunotherapy, Adoptive/methods , T-Lymphocytes, Regulatory/immunology , Antigen Presentation , CD4-Positive T-Lymphocytes/transplantation , Cell Proliferation , HLA Antigens/metabolism , Histocompatibility Antigens Class II/metabolism , Humans , T-Lymphocytes, Regulatory/transplantationABSTRACT
Monte Carlo softwares are widely used to understand the capabilities of electron microscopes. To study more realistic applications with complex samples, 3D Monte Carlo softwares are needed. In this article, the development of the 3D version of CASINO is presented. The software feature a graphical user interface, an efficient (in relation to simulation time and memory use) 3D simulation model, accurate physic models for electron microscopy applications, and it is available freely to the scientific community at this website: www.gel.usherbrooke.ca/casino/index.html. It can be used to model backscattered, secondary, and transmitted electron signals as well as absorbed energy. The software features like scan points and shot noise allow the simulation and study of realistic experimental conditions. This software has an improved energy range for scanning electron microscopy and scanning transmission electron microscopy applications.
ABSTRACT
Monte Carlo simulations have been widely used by microscopists for the last few decades. In the beginning it was a tedious and slow process, requiring a high level of computer skills from users and long computational times. Recent progress in the microelectronics industry now provides researchers with affordable desktop computers with clock rates greater than 3 GHz. With this type of computing power routinely available, Monte Carlo simulation is no longer an exclusive or long (overnight) process. The aim of this paper is to present a new user-friendly simulation program based on the earlier CASINO Monte Carlo program. The intent of this software is to assist scanning electron microscope users in interpretation of imaging and microanalysis and also with more advanced procedures including electron-beam lithography. This version uses a new architecture that provides results twice as quickly. This program is freely available to the scientific community and can be downloaded from the website: (www.gel.usherb.ca/casino).
