Objective
Four areas of immunological research are particularly promising for possible immunotherapy of chronic arthritis. These are T-cell biology (1), definition of triggering and target antigens (2), immunogenetics (3) and cytokine research (4). In all four areas research is presently being conducted in many institutes from several European countries, and in all areas the need for better communication and coordination was unanimously felt to be urgently needed. In each of these four areas specific objectives have been formulated for a Concerted Action which has been planned for three years.
It should be stressed that these research areas are strongly interrelated and one of the main objectives of this concerted action is to achieve good communication between the scientists involved in several aspects as well as optimal coordination of the different activities. To this purpose two sets of specific objectives which are primarily organizational have been added to the objectives described for these 4 research areas. These are: coordination and centralization of pre-clinical research in non-human primates (5) and standardization of clinical trials (6).
A working relationship has been established between basic researchers, clinicians and companies in Europe interested in immunotherapy of rheumatoid arthritis (RA). Four areas of research are: T-cell biology; definition of triggering and target antigens; immunogenetics; cytokine research.
T-cell biology:
Monoclonal anti T-cell antibodies were produced, in particular antibody MT412 which has high affinity and specificity for the V1 domain of the CD4 molecule and low antigen modulating activity. A mouse/human chimeric form of the antibody was prepared consisting of the human IgG1 constant region of the heavy chain and of the constant region of the kappa light chain clinical trials have shown positive effects.
A study of therapeutic T-cell vaccination using T-cell autologous clones or lines from synovium or synovial fluid showed no clear clinical improvement.
Definition of triggering and target antigens and immunomanipulation:
Many participating laboratories were supplied with various hsp60 containing preparations to study the relevance of these molecules in both experimental models of arthritis and in human chronic arthritis. In children with juvenile rheumatoid arthritis responses of synovial T-lymphocytes to human hsp60 turned out to be most prominent, especially in patients with oligoarticular forms of arthritis. Since this form of arthritis is a spontaneously remitting form of the disease, the findings suggest that responses to endogenous hsp60 are part of regulatory T-cell control.
Immunogenetics:
Repositories have been established for cells from multiplex RA families and human lencocyte antigen (HLA) class II transfectants for distribution to European researchers for genetic and functional studies.
Interference with cytokines:
A common European standard for cytokine determination in fluids derived from arthritic patients has been agreed.
Standardization of clinical trials:
Two simple clinical assessments and one laboratory determination have been agreed for the study of drugs in RA.
1. T cell biology
1.1 Immune intervention with monoclonal anti-T cell antibodies
- consensus on the choice of specific antibodies for treatment.
- standardization of therapeutic antibodies
- standardization and evaluation of clinical trials aimed at therapy development
1.2 Therapeutic T cell vaccination
- protocol development and standardization
- repository for cells, vaccines, sera and other patient materials
2. Definition of triggering and target antigens and immunomanipulation
- to evaluate the molecular and immunological interrelationships between the various experimental models of arthritis induced by bacterial antigens in which heat shock proteins may be involved
- to coordinate the production and distribution to participants of bacterial and human heat shock proteins
3. Immunogenetics
- coordination of HLA typing of patients and cells included in the different trials and studies and standardization of the techniques used
- coordination of functional studies
4. Interference with cytokines
- standardization of cytokines used among members %l - distribution of cytokines
- standardization of measurements of cytokines and cytokine receptors
- banks of cells, serum and synovial fluids derived from a defined patient group
- pre-trial investigations with potential cytokine inhibitors
5. Preclinical research in non-human primates
- pre-clinical testing of promising immunotherapeutical modalities
6. Standardization of clinical trials
- to prepare a recommended standard protocol
- the introduction and evaluation of novel ways of measuring disease activity.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences zoology mammalogy primatology
- medical and health sciences clinical medicine rheumatology
- natural sciences biological sciences cell biology
- medical and health sciences basic medicine pharmacology and pharmacy pharmaceutical drugs vaccines
- medical and health sciences basic medicine immunology immunotherapy
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Coordinator
2300 RC Leiden
Netherlands
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