Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells

Chu

et al. 2009

Arthritis & Rheumatism

410

340

Section: Discussionmentioning

confidence: 66%

Th17 and natural Treg cell population dynamics in systemic lupus erythematosus

Chu

et al. 2009

Arthritis & Rheumatism

410

340

“…14,15 Some dendritic cells (DCs), such as immature DCs (imDCs) and plasmacytoid DCs, exhibit regulatory but not stimulatory functions on CD4 1 T cells. [16][17][18][19] Therefore, these DCs, especially monocyte-derived imDCs, have been used to induce antigen-specific CD4 1 Tregs from naive precursors.…”

mentioning

confidence: 99%

CD40-activated B cells are more potent than immature dendritic cells to induce and expand CD4+ regulatory T cells

et al. 2010

CD4 1 regulatory T cells (Tregs) play an important role in maintaining immune tolerance by suppressing pathologic immune responses. The generation of large numbers of antigen-specific Tregs ex vivo is critical for the development of clinical immunotherapy based on the adoptive transfer of Tregs. Both CD40-activated B cells (CD40-B) and immature dendritic cells (imDCs) have been used as professional antigen-presenting cells (APCs) to generate antigen-specific Tregs. However, the efficiencies of CD40-B and imDCs to generate CD4 1 Tregs have not been compared directly and the mechanism driving the generation of these Tregs remains largely unknown. In this study, we found that CD40-B exhibited mature phenotypes and were more able to induce and expand CD4 high CD25 1 Tregs than imDCs. Moreover, Tregs induced by CD40-B had greater suppressive capacity than those induced by imDCs. The generation of CD4 high CD25 1 Tregs by CD40-B and imDCs is cell-cell contact dependent and partially relies on the expression of human leukocyte antigen (HLA)-DR and CD80/86. Differences in CD4 high CD25 1 Treg generation efficiency were largely explained by the production of endogenous IL-2 by CD40-B. Our results suggest that CD40-B is better able to generate large numbers of antigen-specific Tregs than imDCs. Additionally, using CD40-B to generate Tregs may accelerate the clinical use of Treg-based immunotherapy in the treatment of allograft rejection, graft versus host disease (GVHD) and autoimmune diseases.

“…Whole cell lysates were prepared from fractionated spleen cell subsets or whole splenocytes. CD4 T cells (macrophages plus DCs) were purified from splenocytes using a technique as previously described (21,22). Western blotting was then carried out (15,16), and blots were probed with primary goat anti-COX-2 antibody (sc-1745; Santa Cruz Biotechnology, Santa Cruz, CA) overnight at 4°C in 5% nonfat dry milk in TBST (60 mmoles/liter Tris base, 120 mmoles/liter NaCl, 0.5% Tween 20), and then incubated with a horseradish peroxidase-conjugated secondary antibody (sc-2020; Santa Cruz Biotechnology) in 5% dry milk in TBST for 1 hour at RT.…”

Section: Quantitation Of Autoantibodiesmentioning

confidence: 99%

Hyperexpression of cyclooxygenase 2 in the lupus immune system and effect of cyclooxygenase 2 inhibitor diet therapy in a murine model of systemic lupus erythematosus

Zhang

Bertucci

Smith

et al. 2007

Arthritis & Rheumatism

Self Cite

Objective. To investigate the role of cyclooxygenase 2 (COX-2) in the functioning of different cell types involved in the lupus autoimmune response, and to examine the therapeutic effect of COX-2 inhibitors in mice prone to spontaneously develop systemic lupus erythematosus (SLE).Methods. Lupus-prone (SWR ؋ NZB)F 1 mice were fed with a diet containing different doses of the COX-2-specific inhibitor celecoxib or the nonspecific inhibitor aspirin, or a combination of both, and the effects of the therapy on autoantibody production, development of lupus nephritis, and mortality were determined. Expression of COX-2 by different cells of the lupus immune system and the effect of COX-2 inhibitors on the function of these cells in vitro and in vivo were assessed.Results. The immune cells of mice with SLE spontaneously hyperexpressed COX-2, and COX-2 inhibitors could cause cell apoptosis. Treatment with COX-2 inhibitors resulted in decreased autoantibody production and inhibition of the T cell response to the major lupus autoantigen, nucleosome, and its presentation by antigen-presenting cells. Surprisingly, a significant increase in survival occurred only in mice receiving intermittent therapy with the lowest dose of celecoxib (500 parts per million), approximating <100 mg of celecoxib/day in humans. A continuous diet, but not intermittent feeding, with the combination of celecoxib and aspirin delayed development of nephritis temporarily, but failed to prolong survival. Indeed, treatment with aspirin alone increased mortality.Conclusion. The contributions of the major players in the pathogenic autoimmune response, namely, T cells, B cells, dendritic cells, and macrophages that are abnormally hyperactive in lupus, depend on the increased expression and activity of COX-2, similar to inflammatory cells in target organs. Intermittent pulse therapy with low doses of select COX-2 inhibitors would be of value in the treatment of lupus.In systemic lupus erythematosus (SLE), hyperactivity of the immune system leads to activation of certain autoimmune T helper cells, which drive autoimmune B cells to produce somatically mutated IgG autoantibodies against apoptotic nuclear antigens (1-6). IgG immune complexes containing autoantigenic DNA and RNA bind Fc␥ receptors and Toll-like receptors (TLRs), which results in stimulation of type I interferon (IFN) production by hyperactive dendritic cells (DCs); moreover, autoimmune B cells bearing the T helper celldriven, high-affinity, somatically mutated B cell receptors are dually stimulated by TLRs (7-9). These events further amplify the ability of antigen-presenting cells (APCs) to present autoantigens to pathogenic T helper cells, which is an essential element of disease development (10-13).Normally, autoreactive T and B cells are eliminated by functional inactivation (anergy) and by activation-induced cell death (AICD; apoptosis), via Fas signaling (14). However, autoimmune T helper cells in human lupus resist AICD by up-regulating the expression of cyclooxygenase 2 (COX-2) and the anti...