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 collagenspecific 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.

Objective. CD4؉,CD25؉ T regulatory cells may offer opportunities to intervene in the course of autoimmune disease. We wished to evaluate their potential for influencing systemic and chronic joint inflammation by investigating their involvement in collagen-induced arthritis (CIA).Methods. We depleted DBA/1 mice of CD25؉ regulatory cells by injection of a depleting monoclonal antibody specific for CD25 14 days before a single immunization with type II collagen (CII) in Freund's complete adjuvant. CD4؉,CD25؉ T cells were adoptively transferred to some groups of mice during immunization. Mice were then scored for signs of arthritis, and blood was taken periodically to measure the amounts of CII-specific antibodies. Splenocytes of treated mice were examined in vitro to determine the effects of depletion on proliferation to CII and control antigens.Results. CD25؉ cell-depleted DBA/1 mice had significantly more severe disease than control mice following collagen immunization. The magnified severity was also accompanied by higher antibody titers against collagen, and in vitro tests showed increased proliferation of collagen-specific T cells. Adoptively transferring CD4؉,CD25؉ T cells into depleted mice was shown to reverse the heightened severity. Control mice, which were depleted and immunized with the neoantigen keyhole limpet hemocyanin (KLH), had neither an increased antibody response toward KLH nor an augmented proliferative response, indicating that CD25؉ cell depletion preferentially affects immunity against self antigen.Conclusion. These results establish a link between CD4؉,CD25؉ regulatory cells and CIA and provide a rationale for investigating CD4؉,CD25؉ T regulatory cells in the treatment and prevention of arthritis.

Systemic autoimmune disease (AID) can be controlled with conventional therapies in most patients. However, relapses are common, leading to progressive disability and premature death. Nonmyeloablative conditioning and allogeneic bone marrow transplantation (BMT) could be an effective treatment for severe AID, because of mild toxicity of the conditioning and the potential benefits of donor chimerism. We examined the effects of this treatment in experimental autoimmune arthritis. Our results demonstrate the induction of complete donor chimerism and significant suppression of disease activity. No clinical graft-versushost disease (GVHD) was observed. The beneficial effects were most likely caused by the elimination of plasma cells producing pathogenic autoantibodies, because these antibodies disappeared rapidly after BMT. Although this type of treatment was effective in organ-specific T-cellmediated AID, the present study provides convincing evidence that nonmyeloablative conditioning and allogeneic BMT can effectively treat severe B-cell-mediated AID with a systemic inflammatory component. ( IntroductionSystemic autoimmune disease (AID) is characterized by immune dysregulation in which T or B cells play a pivotal role. 1 Preclinical studies and case reports indicate that myeloablative chemoradiotherapy plus allogeneic bone marrow transplantation (BMT) may be an effective treatment for systemic AID in humans. [2][3][4][5][6] The application of this treatment, however, is limited because of the risk for graft-versus-host disease (GVHD) and the toxicity of myeloablative therapy. Recently, preclinical protocols have been developed based on nonmyeloablative conditioning to achieve allogeneic donor chimerism without clinical GVHD. [7][8][9] Preliminary results indicate that this treatment modality may be effective in treating human AID. 1,10 The present study aimed to investigate the clinical and immunologic effects of allogeneic BMT after nonmyeloablation on experimental arthritis in mice, a systemic inflammatory B-cell-mediated autoimmune disease. More specifically, we wanted to study whether stable, long-term, and multilineage donor chimerism could be induced safely in mice with established polyarthritis and whether this treatment would result in the reduction of disease activity and serum levels of pathogenic autoantibodies produced by host plasma cells. Study design AnimalsMale DBA/1 and BALB/c mice (8-12 weeks of age) were obtained, housed, and fed as described earlier. 11,12 Induction and clinical assessment of arthritis Collagen-induced arthritis (CIA) was induced and evaluated as described by Morgan et al. 12 Mice with maximum scores of 12 were humanely killed. Bone marrow transplantationBMT was performed when more than 50% of the mice developed CIA. Mice were subjected to sublethal total body irradiation (TBI) of 6.0 Gy, and each received a single injection of anti-CD40 ligand (CD40L) monoclonal antibody (mAb) (MR1, 0.5 mg intraperitoneally) before BMT with 1.0 ϫ 10 7 total bone marrow (BM) cells intravenousl...

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