Proteoglycan‐induced polyarthritis and spondylitis adoptively transferred to naive (nonimmunized) BALB/c mice

Abstract

Mononuclear cells from BALB/c mice with progressive polyarthritis and spondylitis induced by injection of fetal human articular cartilage proteoglycan (PG) were used to transfer arthritis by intravenous injection into irradiated, nonimmunized syngeneic mice. Successful transfer of arthritis to BALB/c mice required the injection of lymphocytes from mice with arthritis, along with 50 m̈g of human fetal PG, or lymphocytes stimulated in vitro with either fetal human PG or with mouse cartilage PG. In addition, interleukin‐2 or immune sera from animals with arthritis significantly reduced the time to onset of transferred disease. The onset of adoptively transferred arthritis, using cells and antigen, from the time of the first injection (38.2 ± 18.2 days, mean ± SD) was shortened if lymphocytes from mice with transferred arthritis were reinjected (retransferred) into other, irradiated syngeneic mice (6.1 ± 2.6 days). The appearance of autoreactive antibodies to mouse cartilage PG in the sera of mice with adoptively transferred arthritis (secondary or tertiary) preceded the appearance of the first clinical symptoms by a few days. The transfer of arthritis was blocked by pretreatment of donor (arthritic) lymphocytes with either anti‐T cell or anti‐B cell antibodies and complement. Exposure of mononuclear cells from mice with arthritis to PG, and its removal prior to transfer, also resulted in transfer of the arthritis. PG‐induced arthritis was not transferred to nonirradiated mice, nor to irradiated mice injected with lymphocytes from animals with primary arthritis without chondroitinase ABC‐digested fetal human PG. Arthritis never developed after injection of immune sera from mice with arthritis (without cells), nor when cells of nonarthritic animals were used with chondroitinase ABC‐digested fetal human PG, with or without interleukin‐2.

Migration and homing of lymphocytes to lymphoid and synovial tissues in proteoglycan–induced murine arthritis

“…Lymphocytes transferred frvm nonarthritic mice (even those immunized with nonarthritogenic PGs) or immune sera without lymphocytes from ar-thritic animals never induce arthritis. Moreover, the successful transfer of arthritis requires that the donor cell population contain both B and T lymphocytes (11,16). In this study, using a stable cell membranelabeling technique (17), we demonstrated that the migration and homing profiles of lymphocytes obtained from arthritic donors are different from those of lymphocytes from nonarthritic donors, as judged by the localization of these cells in the lymphoid and synovial tissues of host animals.…”

“…High buoyant density PG (aggrecan) from canine articular cartilage was used to induce arthritis in female BALB/c mice (Charles River, Portage, MI) as described previously for human fetal cartilage PG (10, 11,13,14). Briefly, mice were primed by intraperitoneal injection of 100 pg of chondroitinase ABC-digested PG (measured as protein) in an emulsion of 100 pl of phosphate buffered saline (PBS), pH 7.4, and 100 pl of Freund's complete adjuvant.…”

“…The development of inflammatory joint disease in both the primarily induced and the passively transferred forms of arthritis depends upon the expression of cell-mediated and humoral immunities to the antigen used for immunization and to mouse (self) cartilage PG (11,(13)(14)(15). The crucial role of antigen (PG)-specific lymphocytes in the induction of arthritis has been shown by their ability to transfer the disease when stimulated in vivo (injecting cells with arthritogenic PGs) or in vitro in the presence of arthritogenic PGs (1 1).…”

Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis?

“…After injection of the emulsion, strong B cell and T cell responses develop (44) (45). It is proposed that subsequently produced antibodies form immune complexes with proteoglycan in mouse cartilage locally in the joint, resulting in complement deposition and further immune cell activation as well as cytokine and chemokine production (39).…”

Effector T cells in rheumatoid arthritis: Lessons from animal models

“…Conversely, the spontaneous development of disease in K/BÂN mice improved within 5 days of CD8 depletion [165]. In PGIA, depletion of CD8 + cells prevented disease transfer into irradiated recipient mice prevented disease [59]. On the other hand, the depletion of CD8 + cells in immunised mice exacerbated arthritis progression [60].…”