Treatment of experimental autoimmune arthritis by nasal administration of a type II collagen-cholera toxoid conjugate vaccine

Self Cite

103

Oral administration of Ag coupled to cholera toxin B subunit (CTB) efficiently induces peripheral immunological tolerance. We investigated the extent to which this oral tolerance is mediated by CD25+CD4+ regulatory T cells (Treg). We found that total Treg, KJ1–26+ Treg and CTLA-4+ Treg were all increased in Peyer’s patches, mesenteric lymph nodes, and, to a lesser extent, in spleen of mice after intragastric administration of OVA/CTB conjugate, which also increased TGF-β in serum. This could be abolished by coadministering cholera toxin or by treatment with anti-TGF-β mAb. CD25+ Treg, but also CD25−CD4+ T cells from OVA/CTB-treated BALB/c or DO11.10 mice efficiently suppressed effector T cell proliferation and IL-2 production in vitro. Following adoptive transfer, both T cell populations also suppressed OVA-specific T cell and delayed-type hypersensitivity responses in vivo. Foxp3 was strongly expressed by CD25+ Treg from OVA/CTB-treated mice, and treatment also markedly expanded CD25+Foxp3+ Treg. Furthermore, in Rag1−/− mice that had adoptively received highly purified Foxp3−CD25−CD4+ OT-II T cells OVA/CTB feeding efficiently induced CD25+ Treg cells, which expressed Foxp3 more strongly than naturally developing Treg and also had stronger ability to suppress effector OT-II T cell proliferation. A remaining CD25− T cell population, which also became suppressive in response to OVA/CTB treatment, did not express Foxp3. Our results demonstrate that oral tolerance induced by CTB-conjugated Ag is associated with increase in TGF-β and in both the frequency and suppressive capacity of Foxp3+ and CTLA-4+ CD25+ Treg together with the generation of both Foxp3+ and Foxp3−CD25− CD4+ Treg.

Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Oral Tolerance Induction with Antigen Conjugated to Cholera Toxin B Subunit Generates Both Foxp3+CD25+ and Foxp3−CD25− CD4+ Regulatory T Cells

Sun

Raghavan

Sjöling

et al. 2006

Self Cite

103

“…It has been shown that in addition to functioning as a carrier for the cholera toxin A subunit to target adenylate cyclase, CTB can exert immune-modulating effects independent of the A subunit (30,31). CTB has been reported to suppress the onset of T cell-dependent autoimmune diseases and to potentiate tolerance of the adaptive immune response (32)(33)(34). Pretreatment of macrophages with CTB has been reported to suppress the LPS-induced production of TNF-␣ and IL-6 (30, 31).…”

Section: Mkp-1 Is Induced By the Immune-modulatory Agents Dexamethasomentioning

confidence: 99%

Restraint of Proinflammatory Cytokine Biosynthesis by Mitogen-Activated Protein Kinase Phosphatase-1 in Lipopolysaccharide-Stimulated Macrophages

Chen

Barnes

et al. 2002

267

315

Exposure of macrophages to LPS elicits the production of proinflammatory cytokines, such as TNF-α, through complex signaling mechanisms. Mitogen-activated protein (MAP) kinases play a critical role in this process. In the present study, we have addressed the role of MAP kinase phosphatase-1 (MKP-1) in regulating proinflammatory cytokine production using RAW264.7 macrophages. Analysis of MAP kinase activity revealed a transient activation of c-Jun N-terminal kinase (JNK) and p38 after LPS stimulation. Interestingly, MKP-1 was induced concurrently with the inactivation of JNK and p38, whereas blocking MKP-1 induction by triptolide prevented this inactivation. Ectopic expression of MKP-1 accelerated JNK and p38 inactivation and substantially inhibited the production of TNF-α and IL-6. Induction of MKP-1 by LPS was found to be extracellular signal-regulated kinase dependent and involved enhanced gene expression and increased protein stability. Finally, MKP-1 expression was also induced by glucocorticoids as well as cholera toxin B subunit, an agent capable of preventing autoimmune diseases in animal models. These findings highlight MKP-1 as a critical negative regulator of the macrophage inflammatory response, underscoring its premise as a potential target for developing novel anti-inflammatory drugs.

“…At present, T cell recognition of only a limited number of self-Ags has been described in RA, e.g., type II collagen (19,20), human cartilage glycoprotein 39 (HC gp-39) (21), hsp60 (22,23), chondrocyte Ag 65 (24), synovial fluid-derived p205 (25), and the endoplasmatic reticulum molecular chaperone BiP (26). In this study, we have identified several new targets for the immune system during the arthritis process.…”

Section: Discussionmentioning

confidence: 62%

Matrix Metalloproteinases as Targets for the Immune System during Experimental Arthritis

Bilsen

Wagenaar-Hilbers

Grosfeld-Stulemeijer

et al. 2004

Novel therapies for rheumatoid arthritis aiming at intervention in the inflammatory process by manipulation of autoreactive T and B lymphocytes receive major interest. However, the development of such therapies is largely hampered by the lack of knowledge of self-Ags recognized during the disease process. Recently, we predicted putative T cell self-epitopes based on a computer search profile. In the present study, the predicted self-epitopes were tested for T cell recognition in two experimental arthritis models, and their arthritogenic capacity was analyzed. Fourteen of n = 51 predicted self-epitopes were recognized during experimental arthritis of which six were able to actively induce arthritis. Interestingly, three of these six peptides were derived from matrix metalloproteinases (MMP), and only T cells responsive to MMP-derived epitopes were able to passively transfer arthritis to naive rats. Moreover, we demonstrate the presence of Abs to MMP-3 during the course of adjuvant arthritis. Together these data indicate that MMPs play a pivotal role as target for T and B cells during the development of inflammatory arthritis. This finding sheds new light on the pathophysiological role of MMPs during arthritis and opens novel possibilities for Ag-specific immunotherapy.