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OBJECTIVE: Regulatory T cells play an important role in the prevention of autoimmunity and have been shown to be effective in the treatment of experimental colitis, a T cell-mediated and organ-specific disease. We previously demonstrated that intrinsic CD25+ regulatory T cells modulate the severity of collagen-induced arthritis (CIA), which, in contrast to colitis, is a systemic antibody-mediated disease and an accepted model of rheumatoid arthritis. We undertook this study to determine whether regulatory T cells have the potential to be used therapeutically in arthritis. METHODS: We transferred CD4+,CD25+ T cells into mice exhibiting arthritis symptoms, both immunocompetent mice and mice subjected to lethal irradiation and rescued with syngeneic bone marrow transplantation. RESULTS: A single transfer of regulatory T cells markedly slowed disease progression, which could not be attributed to losses of systemic type II collagen-specific T and B cell responses, since these remained unchanged after adoptive transfer. However, regulatory T cells could be found in the inflamed synovium soon after transfer, indicating that regulation may occur locally in the joint. CONCLUSION: Our data indicate that CD25+ regulatory T cells can be used for the treatment of systemic, antibody-mediated autoimmune diseases, such as CIA. [ABSTRACT FROM AUTHOR]

Mouse thymic stromal cells growing in vitro have been stained with fluorescent antibodies to identify the cells found in these cultures. By means of anti-cytokeratin antibody 35β H11, it could be shown that hearty all the cells in the cultures were epithelial. Three other antibodies which hind to specific regions of the thymus were used to detect subpopulations of the epithelial cells. Cells growing as confluent carpets stained with antibody ER-TR5, which is specific for medullary epithelium. Antigens for two other antibodies, MD2 (known to label cells at the medullary side of the cortical-medullary junction) and CDR1 (which reacts with cortical epithelium) were expressed on the cultured cells only after the addition of exogenous signals. MD2 antigen was expressed on a very small percentage of the cells incorporated into networks as well as a few dispersed cells, and seemed related to the activity of fibroblasts. CDR1 antigen appeared on the majority of the cells organized into networks and those dispersed in the cultures. Gamma-interferon (IFN-γ) and IL-2, lymphokines usually associated with T-cell reactivity, were found to be involved in its expression. It was possible to isolate the CDR1 subpopulation from the cultures by means of the antigen present on the surface of these cells. [ABSTRACT FROM AUTHOR]

The influence of the route of priming and the dose of sheep red blood cells (SRBC) on the IgM, IgG and IgA-plaque-forming cell (PFC) activity in mouse bone marrow during the secondary response to SRBC was studied. After intraperitoneal and subcutaneous priming the number of IgM, IgG and IgAPFC during the secondary response increased with the number of SRBC used for priming. After intravenous (i.v.) priming the priming dose—secondary response relationship was found to be an optimum curve for IgM-PFC as well as for IgGand IgA-PFC. A peak secondary response in the bone marrow was found after priming with 107 and with 108 SRBC i.v. The appearance of IgG- and IgA-memory cells in the bone marrow after i.v. immunization with SRBC was shown to be dependent on the priming dose: the appearance of IgG-memory cells required a higher dose of SRBC than the appearance of IgM-memory cells, and the appearance of IgA-memory cells required even more antigen.The effect of the booster dose upon the PFC activity was studied in mice primed with 107 SRBC i.v. and boosted with 104, 106, or 109 SRBC i.v. 2 months later. IgM-PFC as well as IgG- and IgA-PFC were present in spleen and bone marrow at each booster dose tested. In each group of mice the PFC activity in the bone marrow rose to a level which surpassed the level in the other lymphoid organs between the 7th and 10th day after the booster injection. Thus, independently of the booster dose, mouse bone marrow is the major source of PFC during the late phase of the secondary response to SRBC. Mice boosted with 109 SRBC i.v. showed a prolonged presence of IgM-, IgG- and IgA-PFC in the thymus. Light and electron microscopic studies revealed the presence of plasma cells and macrophages studded with phagocytosed material in the thymic medulla of these mice, thus providing evidence for a real PFC response within the thymus. A thymic PFC response was absent in mice boosted with either 104 or 106 SRBC i.v. Therefore the thymic PFC activity during the secondary response to SRBC does depend on the booster dose. [ABSTRACT FROM AUTHOR]

Immunosuppressive retrovirus-related proteins, like p15E, are involved in tumour-associated immunosuppression. In the present study we investigated whether such proteins could be used as targets in tumour immunotherapy using MoAbs. Immunotherapy was performed in mice inoculated with the Rauscher virus-transformed myeloid cell line RMB-1. RMB-1 cells express retroviral antigens at their cell surface. In order to obtain constant scrum litres of MoAbs over a prolonged period of time during therapy, anti-p15E antibody-producing hybridoma cells were encapsulated in alginate and injected intraperitoneally in tumour-bearing mice. Using this technique, serum antibody titres of 50-100/mg/ml were obtained, which remained constant over a period of at least 3 weeks. Therapy experiments were performed using anti-p15E antibodies 19F8, which recognizes both cell surface-associated as well as circulating pi 5E. and ER-IS5, which did not react with surface-bound p15E beyond background, but which neutralizes circulating p15E. Inoculation of alginates containing anti-p15E hybridoma cell lines in RMB-1 tumour-bearing mice showed inhibition of tumour cell growth. In survival experiments, 19F8 cured eight of 23 tumour-bearing mice. The p 15E neutralizing antibody ER-IS5 caused a significant longer survival, but therapy with this MoAb alone was not sufficient to cure the animals of the RMB-1 tumour. [ABSTRACT FROM AUTHOR]

Previously, we have reported that neutralization of surface lymphotoxin (LT-αβ) in mice which expressed an LT-P receptor-Fc fusion protein, driven by the cytomegalovirus promoter, resulted in an array of anatomic abnormalities. We now report that mice which express a tumor necrosis factor (TNF) receptor p60-Fc fusion protein (which neutralizes TNF and soluble LT-α3 activity) develop unique lymphoid abnormalities. Our data demonstrate that some aspects of peripheral lymphoid organ development require both surface LT-αβ and TNF interacting with their specific receptors. However, these related cytokines are also capable of signaling distinct developmental events. Splenic MAdCAM-1 expression, follicular dendritic cell localization and normal Peyer's patch development all require both surface LT-4 and TNF activity. Marginal zone formation and splenic B cell localization primarily require surface LT-αβ-LT-β receptor interactions. Primary follicle formation was dependent upon TNF receptor(s) engagement. Interestingly spleen, lymph nodes and Peyer's patches from TNF receptor p60-Fc-expressing mice all develop different abnormalities, suggesting distinct pathways of development in these lymphoid organs. Thymus development appears to be independent of these signaling pathways. These results demonstrate that TNF and LT are crucial for normal peripheral, but not central lymphoid organ development [ABSTRACT FROM PUBLISHER]