Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Semin Arthritis Rheum. Author manuscript; available in PMC 2009 Dec 1.
Published in final edited form as:
PMCID: PMC2723747

Antigen-specific tolerogenic and immunomodulatory strategies for the treatment of autoimmune arthritis

Shailesh R. Satpute, M.B.B.S., Graduate student,1 Malarvizhi Durai, Ph.D., Postdoctoral fellow,2 and Kamal D. Moudgil, MD, PhD Associate Professor1,3



To review various antigen-specific tolerogenic and immunomodulatory approaches for arthritis in animal models and patients in regard to their efficacy, mechanisms of action and limitations.


We reviewed the published literature in Medline (PubMed) on the induction of antigen-specific tolerance and its effect on autoimmune arthritis, as well as the recent work on B cell-mediated tolerance from our laboratory. The prominent key words used in different combinations included arthritis, autoimmunity, immunotherapy, innate immunity, tolerance, treatment, and rheumatoid arthritis (RA). Although this search spanned the years 1975 to 2007, the majority of the short-listed articles belonged to the period 1990 to 2007. The relevant primary as well as cross-referenced articles were then collected from links within PubMed and reviewed.


Antigen-specific tolerance has been successful in the prevention and/or treatment of arthritis in animal models. The administration of soluble native antigen or an altered peptide ligand intravenously, orally, or nasally, and the delivery of the DNA encoding a particular antigen by gene therapy have been the mainstay of immunomodulation. Recently, the methods for in vitro-expansion of CD4+CD25+ regulatory T cells have been optimized. Furthermore, interleukin-17 has emerged as a promising new therapeutic target in arthritis. However, in RA patients, non-antigen-specific therapeutic approaches have been much more successful than antigen-specific tolerogenic regimens.


An antigen-specific treatment against autoimmune arthritis is still elusive. However, insights into newly emerging mechanisms of disease pathogenesis provide hope for the development of effective and safe immunotherapeutic strategies in the near future.


Rheumatoid arthritis (RA) is a multisystem autoimmune disorder affecting about 1% of the world’s population (1). Despite advances in immune-based therapies in recent years, a much-desired antigen-specific therapy for this debilitating disease has been elusive. The induction of antigen-specific T cell tolerance has been extensively tested in various experimental models of autoimmune diseases, and several mechanisms associated with tolerance to combat potentially harmful autoimmune processes have been elucidated (25). In addition, the role of antibodies (pathogenic versus protective) in the pathogenesis of T cell-mediated diseases is gradually being realized (68). Although, most of the antigen-specific tolerogenic approaches are successful in the prevention of autoimmune diseases, the efficacy of these approaches against the ongoing disease is variable. Therefore, there is a pressing need to develop novel immunomodulatory approaches that are effective in the treatment of established autoimmune diseases (913, 14). Nevertheless, significant advances have been made in this direction as discussed below.

Currently available therapeutic agents mainly treat the symptoms of autoimmune diseases and are only partially able to interfere with disease evolution, and thereby, fail to decrease the extent of physical impairment. Thus, the development of therapeutic strategies to limit tissue damage is imperative. Immunosuppressive drugs such as cyclosporine or steroids are widely used for inducing remission in the active phase of autoimmune diseases. While global immunosuppression may ameliorate an autoimmune disease, the immunocompromised state increases the susceptibility to infections. Thus, antigen-specific immunosuppression or tolerance induction is a highly desired goal for the treatment of autoimmune diseases.


In addition to the classical tolerance-associated parameters such as T cell ignorance (15, 16), anergy (17, 18) and the T helper 1- T helper 2 cytokine balance (immune deviation) (1921), the roles of the CD4+CD25+ T regulatory cells (Treg) (22, 23) and the indoleamine -2, 3 -dioxygenase (IDO)-tryptophan pathway (24, 25) in controlling autoimmunity have been elaborated in different animal models. Currently available methods for antigen-specific tolerance induction are listed in Tables 1 and and22.

Table 1
Immuno-specific tolerogenic approaches tested in animal models of autoimmune diseases
Table 2
Antigen-specific approaches for the prevention/treatment of autoimmune arthritis in animal models


I. Antigen-specific tolerance induction and immunomodulation in experimental models of autoimmunity

Systemic administration of soluble antigen has been shown to prevent diseases such as experimental autoimmune encephalomyelitis (EAE) (26) and Type 1 diabetes mellitus (T1D) (4, 27). Single or multiple intravenous or intraperitoneal injections of antigen in the absence of an adjuvant have been shown to induce antigen-specific immune tolerance. Fathman and colleagues showed that this tolerance was a result of induction of anergy in antigen-specific T cells (3). This anergic state resulted from T cell receptor (TCR) activation in the absence of a costimulatory signal that is generally provided by an adjuvant (28). Furthermore, it was shown that CD4+CD25+ regulatory T cells are generated after such a tolerization regimen (29). Although successful in animal models, the beneficial effects of systemic antigen administration in clinical settings are rather limited (3032).

Weiner et. al. have demonstrated that oral administration of antigen prevents the induction of autoimmune diseases (33, 34). The success of oral administration of the disease-related antigen in the control of the respective autoimmune disease has been shown for EAE, collagen-induced arthritis (CIA), adjuvant arthritis (AA), and T1D (33, 34). Several mechanisms mediating the effects of oral tolerance have been suggested, such as anergy/deletion of CD4 T cells and the induction of CD4+ regulatory T cells that produce interleukin-10 or transforming growth factor-β (35, 36). Furthermore, the induction of oral tolerance can be enhanced by interleukin-4, interleukin-10, anti IL-12 antibody, transforming growth factor-β, cholera toxin B subunit and anti-CD40 ligand (37). It has been shown that peripheral blood mononuclear cells (PBMC) of RA patients respond well in vitro to collagen Type II (CII) 256–271 epitope and its overlapping variants (38). Using the CIA model, the oral administration of this CII peptide suppressed and suppression of the associated antigen specific T cell/antibody responses (39). In another study, the oral administration of CII induced interleukin-10-producing CD4+CD25+ regulatory T cells (40). These Treg mediate anti-inflammatory effect by reducing the production of interferon-g by CII-specific effector T cells. The role of Treg in CIA is further validated by the observation that the depletion of Treg in vivo increased the severity of CIA (41). Interestingly, the DQ8- HLA-transgenic (humanized) mice developed normal number of functional Treg (42, 43). These results have implications in further understanding the pathogenesis of RA. Although the majority of animal studies have yielded positive results with oral tolerance regimen, under some circumstances, mucosal application of antigen may instead exacerbate the disease process (44).

An altered peptide ligand (APL) is a synthetic peptide similar to the pathogenic epitope of a self antigen, but with a change in 1 or 2 critical amino acids. Such a synthetic peptide has been shown to inhibit the activation of a T-cell clone (antagonistic activity) (45). APL administration prevents EAE in mice (46). Furthermore, a large variety of microbial agents might possess structural entities that mimic self epitopes, and thereby possess APL activity (47). The implication is that microbial immunity could modulate autoimmunity. This relationship between microbially-derived APL and autoimmunity could help understand the long-observed relationship between infection and triggering of autoimmunity or the relapse of ongoing autoimmunity. Another aspect of APL activity involves IDO, which is related to tolerance induction. Stimulation of myelin-reactive T cells with tolerogenic APL led to increased IDO transcription, which in turn induced suppression of both T cell proliferation and production of proinflammatory cytokines (48). Interestingly, the oral administration of a synthetic derivative of anthralinic acid (a tryptophan metabolite) reversed paralysis in mice with EAE, showing the significance of both APL and the tryptophan pathway in the treatment of autoimmunity (48).

The use of peptides/APL has been associated with a serious side effect, anaphylaxis. Attempts are being made to alter the solubility, dose, and route of administration of such peptides to minimize severe side effects. In this regard, one successful approach consisted of altering the isoelectric pH/point of the peptide by adding basic residues (arginine residues) to the carboxy-terminal of the peptide (49). This modification significantly reduced the side effect without affecting the disease modulating activity of the peptide.

II. Immunomodulatory approaches tested in the adjuvant arthritis model

AA is inducible in the Lewis (LEW) rat by injecting subcuteneously heat-inactivated Mycobacterium tuberculosis H37Ra (Mtb), and it shares several features with human RA (50, 51). Numerous immunologic approaches are effective in protection against AA (Table 2). In most of these approaches, attempts have been made to generate protective immunity against mycobacterial hsp65 (Bhsp65) and its self homolog, the rat hsp65 (Rhsp65). The administration of soluble recombinant Bhsp65 either intravenously/intraperitoneally (52) or orally (53, 54) prevents subsequently induced AA. Systemically administered Bhsp65 induces suppression of antigen-specific T cell proliferation. This hypoproliferative state of T cells is reversible by interleukin-2, indicating that these T cells are anergic in nature. Interestingly, the protection against AA is associated with reduced production of IL-17 but enhanced anti-Bhsp65 antibody response (55). The latter is protective against AA (7, 8). However, most of the soluble antigen-based approaches in AA are ineffective against the ongoing disease with the exception of oral tolerance to Bhsp65 (53) and of tolerance induced by Bhsp65-expressing B cells (52).

III. Tolerogenic gene therapy for arthritis

Somatic gene therapy involves the introduction of new genetic material into a cell in to modify the function of the cell or to alter the level of expression of the corresponding protein within the cell (5658). Although therapies based on the use of cytokine receptors, inhibitors, or antibodies are gaining widespread popularity in the treatment of autoimmune diseases, these treatment modalities suffer from limitations such as high expense, the need for repeated injections and unwanted side effects. Many of these limitations can be overcome by gene delivery (5659).

B cell-mediated gene therapy

In the past several years, Scott and colleagues have developed a novel gene therapy approach for the induction of antigen-specific tolerance using antigen-Ig fusion protein delivered via a retroviral vector in B cells (6064). In short, a fusion protein construct consisting of an immunodominant epitope or a full length antigen in-frame at the N-terminus of an IgG heavy chain was created. This fusion construct was then delivered into bone marrow-derived cells or lipopolysaccharide-stimulated B cell blasts via retroviral infection. The injection of these B cells into syngeneic recipients rendered them tolerant to a particular epitope or antigen (6064). So far, the B cell-mediated gene therapy approach was successful in disease models such as experimental autoimmune uveitis (EAU) (62), EAE [induced either by myelin basic protein (MBP) or by myelin oligodendrocyte glycoprotein (MOG)] (64), and the non-obese diabetic (NOD) mouse model of diabetes (64, 65). This approach has also been successful in inducing tolerance to factor VIII inhibitors in hemophilia A (66) and (in combination with BM transplantation) in the treatment of EAE (67). Our recent testing of the B cell-mediated gene therapy approach in the AA model (52) has not only extended the application of this therapeutic approach to a new model of autoimmune disease, arthritis, but also to another related species, the rat.

Adoptive cellular gene therapy of RA

Fathman and colleagues have developed the concept of adoptive cellular gene therapy of RA (68). In this approach, specific cell types (e.g., T cells or T cell hybridomas) that specifically migrate to the target organ in a particular autoimmune disease (e.g., the joints in arthritis) can be genetically modified to express a therapeutic product (e.g., interleukin-4) locally (69). Thus, the local delivery of an immunotherapeutic product is assured, which in turn limits the side effects inherent in the systemic delivery of cytokines and other biomolecules. This approach involving genetically engineered T cells expressing interleukin-4 was used successfully to prevent the development of CIA in mice (69). In addition to cytokines, agents that can prevent damage to cartilage and bone would constitute attractive molecules for targeted delivery. Other investigators have shown that direct local injection of the gene of interest (e.g., the tumor necrois factor-α receptor gene) in the paws can downmodulate arthritis in mice (70). Thus, an appropriately tailored adoptive cellular gene therapy approach using B cells, T cells, dendritic cells (DCs) and the desired gene can be applied for the treatment of multiple sclerosis (MS), RA, and insulin-dependent diabetes mellitus (IDDM or T1D).

Tolerizing DNA vaccines

Recently, the success of another gene therapy approach in arthritis was reported: the tolerizing DNA vaccine encoding CII leading to the downmodulation of established CIA (71). The reduced severity of CIA was associated with decreased pro-inflammatory cytokines as well as reduced spreading of the antibody response (the latter was tested by arthritis microarray analysis) (71). Interestingly, the effect of DNA vaccination was significantly increased by atorvastatin, one of the statin drugs previously shown to suppress the severity of EAE (71).

IV. Current status of the antigen-specific tolerogenic/immunomodulatory approaches in clinical practice

Extensive efforts have been made in the past several years to transfer the promising bench-tested therapeutic approaches to the bed-side (translational research). The outcome of this transition has been mixed, with significant success for some approaches, but unexpectedly poor outcomes for others. We describe below an overview of the clinical application of various tolerogenic and immunomodulatory approaches in arthritis as the primary example. However, we also have included examples of other rheumatic diseases (e.g., systemic lupus erythematosus; SLE) as well as additional autoimmune diseases (e.g., MS and T1D) for sharing a broader perspective on the treatment of autoimmune diseases. Considering the availability of a relatively sizable literature on the use of biologics (such as anti-tumor necrois factor-α agents (infliximab, etanercept and adalimumab), interleukin-1-receptor antagonist (anakinra), cytotoxic T lymphocyte-associated antigen-4-immunoglobulin heavy chain (CTLA-4)-Ig (abatacept)) and anti-CD3 antibody in the treatment of autoimmune diseases or transplantation, this aspect of immunotherapy will not be further discussed.

CD4+CD25+ regulatory T cells (Treg)

CD4+CD25+ T cells play an important role in mediating peripheral tolerance and controlling the activity of potentially self-reactive T cells (72, 73). Currently, several efforts are being made to induce and maintain tolerance by using therapeutic vaccination with CD4+CD25+ regulatory T cells, which can be done either directly or indirectly (through the use of anti CD3-antibody or antigen-directed immunotherapy) (72, 74, 75). Treg are functionally compromised in RA (76) and SLE (77) patients. In RA patients, anti-tumor necrosis factor-α treatment increases the number as well as the function of Treg (76). Thus, the reduced function of Treg can be reversed/restored by treatment with a biologic agent.

Peptide/APL and tolerogenic DC therapy

Current therapeutic strategies that are based on global immune suppression or blocking of inflammatory pathways do not induce long-term disease remission, and have serious side effects, including infections. Thus, there is a need to develop antigen-/epitope-specific immunotherapy. Several immunomodulatory peptides have been identified as promising candidates for immunotherapy in various autoimmune diseases. Examples are heat-shock protein (hsp) peptides for the treatment of RA and juvenile chronic arthritis (JCA), and peptides derived from anti-DNA antibodies for the treatment of SLE (74, 78, 79). The immune modulation with Hsp peptides was associated with the induction of Treg. In one pilot trial, immunization of RA patients with a peptide of a prokaryotic heat-shock protein led to the induction of Treg and disease improvement (75). Furthermore, small peptides that can interfere with cytokines or specific cell surface molecules have been developed, and can lead to the inhibition of autoimmune inflammatory reactions (80). Similarly, attempts have been made to block helper T cell responses by the use of competitor peptides whose in vivo efficacy had been increased by coupling to transferrin (81).

APLs are quite successful in controlling autoimmunity in animal models. However, the immune response to autoantigens in humans is polyclonal and a peptide that inhibits one clone may stimulate another. A clinical trial of an APL for the treatment of MS was halted because of disease exacerbation in a few patients (82). In 9% of the patients, the immune response deviated from T helper 1 type to a severe allergic (Th2) type (83).

DCs have been implicated in the induction of autoimmune diseases. These cells have been identified in lesions associated with several autoimmune inflammatory diseases, including RA (84). Unlike mature DC that are potent activators of naïve T cells, immature or semi-mature DC have the ability to tolerize T cells or prevent autoimmune reactions (85). Thus, current strategies exploiting the tolerogenic potential of DC or blocking their migration to the inflammatory site by chemokine-blocking antibodies are attractive approaches for the treatment of RA and other autoimmune diseases (8486).

Oral tolerance

Mucosal administration of antigen is an efficient way of tolerizing antigen-specific T cells. Oral tolerance has been tested in patients with RA, MS, uveitis, T1D, and allergies (35, 36, 8790). No significant beneficial effect was observed in phase III clinical trials of oral bovine/chicken CII treatment in RA patients (87, 88, 91), or of oral myelin and glatiramer acetate in MS patients (37). Oral insulin treatment delays the onset of diabetes in a high-risk population (37, 90). On the basis of animal studies, it has been suggested that the feasibility of the induction of oral tolerance to CII or other antigens in RA patients is high if prostaglandin levels are maintained normally in gut associated lymphoid tissue (92). Another report indicated that a cytotoxic T cell response could be induced by oral application of antigen, which could lead to the induction of an autoimmune disease (44). Thus, there is a possibility that oral tolerization may either have a beneficial effect or a detrimental effect, or no effect at all, depending on the dose, timing and other related conditions of testing (93).


The breakdown of self-tolerance results in autoreactivity, which if continued may result in autoimmune pathology. Several mechanisms have been described for the development of spontaneous autoimmunity. Genetic predisposition, especially the presence of a particular human leukocyte antigen (HLA) haplotype, plays an important role in susceptibility to arthritis and other autoimmune diseases (9498). In addition, the background (non-major histocompatibility complex; non-MHC) genes also contribute to the disease process. For example, inbred rats of the same MHC haplotype display differential susceptibility to autoimmune diseases (99, 100).

Deficiency in the number and/or function of CD4+CD25+ regulatory T cells (Treg) is associated with autoimmunity

Forkhead box p3 (Foxp3)-positive Treg have emerged as the central controllers of spontaneously-induced as well as experimentally-induced autoimmunity in a variety of animal models (22, 23, 101). Experimental cellular therapy using CD4+CD25+ T cells effectively delays and downmodulates the course of diabetes, colitis, gastritis, and graft-versus-host disease in animal models (22, 23, 101103). An important question that is raised in autoimmunity is whether a deficiency of Treg is an essential component of the disease process. There is a relative deficiency of Treg in the NOD mouse compared to that of other mouse strains (104). However, a difference in the frequency of Treg may not explain the differential susceptibility of rat strains to an autoimmune disease (Satpute & Moudgil, unpublished data). Furthermore, it has recently been shown that the frequency of Treg in MS patients is comparable to that of healthy controls; however, the Treg of these patients are significantly less efficient in mediating the suppression of pathogenic effector T cells compared to the Treg from controls (105). Similarly, Treg defects have been reported in RA as well as SLE (76, 77). Thus, both the frequency as well as the efficacy of suppression of Treg needs to be considered in evaluating an autoimmune state. Interestingly, the number and function of Treg can be altered significantly by treatment with appropriate immunomodulatory peptides (75, 106).

IL-17 plays a critical role in the pathogenesis of autoimmunity

IL-17 is a pro-inflammatory cytokine produced by effector T cells (T helper 17; Th17) distinct from T helper 1 cells (107, 108). Interleukin-6 and transforming growth factor-β are essential for the differentiation of naïve CD4 cells into Th17 effector cells (109, 110). Ironically, transforming growth factor-β alone is required for Foxp3 expression in Treg (109). Therefore, these new studies suggest that interleukin-6, which stimulates Th17 differentiation but inhibits Treg development, might act as a master switch that determines the induction of immune response versus its regulation (111). Recently, a number of reports have described a reciprocal interaction between T helper 1 (interferon-γ) and Th17 (IL-17) (112, 113), as well as the role of interleukin-2 and interleukin-27 in the inhibition of Th17 differentiation (114, 115). Interestingly, retinoid-related orphan receptor-gamma (RORγt), an orphan nuclear receptor, is a transcription factor required for the differentiation of Th17 lineage (116).

Studies involving the modulation of IL-17 or interleukin-23 have revealed that these cytokines are critical in EAE (117, 118), CIA (119, 120), inflammatory lung disease (113), and T1D (121, 122). Through these studies, it has been suggested that the IL-17/interleukin-23 axis is required to initiate tissue-specific autoimmune diseases. IL-17 has been associated with RA pathology, as IL-17 can be found in the synovium of RA patients, and acts in concert with interleukin-1 to stimulate interleukin-6 production by synovial fibroblasts (123).

Mechanisms underlying tolerance induction by B cell-mediated gene therapy

Immunoglobulins are efficient antigen-carriers for the induction of T- and B-cell tolerance, and B cells are among the most potent tolerogenic antigen-presenting cells (APCs) (6064). Gene therapy with DNA fragment encoding an antigen (in the absence of an IgG scaffold) produces hyporesponsiveness and affords protection against disease (124). However, the level of hyporesponsiveness induced is significantly higher when the antigen is expressed within the IgG scaffold. Moreover, such tolerance is maintained for a much longer duration compared to the transient tolerance offered by antigen/DNA alone (61). A recent study has demonstrated that the assembly of the IgG heterodimer may contribute to the efficacy of tolerance induction (125). The advantages of B cell-mediated gene therapy protocol over other methods include the following: the tolerance induced is antigen-specific, the effective tolerance is maintained for as long as 6 months (62), the tolerance can be induced not only in the peripheral lymphoid organs, but also in the target organ, and the tolerogenic regimen is capable of ameliorating the ongoing disease, simulating application in the clinical setting for patients (62, 64, 65).

The precise mechanisms of tolerance induction by B cell-delivered antigen are not fully defined. The question whether B-cell mediated tolerance occurs via the secretion of chimeric antibody molecules, or via B cells acting as APCs for the presentation of IgG-peptide, has been examined through studies based on specific gene knock-out mice (63, 64). B cells were critical APCs for this tolerance induction. MHC class II expression by the presenting B cells was essential for the tolerogenic effect, but the Fc receptors (FcRs) were not required (63). A high level of expression of B7, especially B7.2 costimulatory molecule, was required for the induction of tolerance by negative regulatory signaling through CTLA-4 (126). T helper 1/T helper 2 deviation was not observed following tolerance induction, and interleukin-10 was not required as the mediator for tolerance (64). However, the expression of Fas ligand (FasL) on the tolerogenic B cell was required for the induction of tolerance (64). Song et al have recently demonstrated that transforming growth factor-β was upregulated in long-term tolerant NOD mice treated with B cells expressing glutamic acid decarboxylase-IgG (65). Furthermore, the frequency of CD4+CD25+ T cells in the spleen of the experimental group of mice was significantly higher than that of the control mice, and these regulatory T cells suppressed the proliferative response of CD4+CD25 T cells in vitro (65). The role of Treg in B cell-mediated tolerance has been corroborated by subsequent studies in hemophilia (66) and in the NOD mouse model of T1D (127).

B cell tolerance and the protective effect of antibodies in arthritis

Most of the examples discussed above have focused on the tolerization of T cells. However, it is conceivable that the tolerization of B cells that are the potential source of arthritogenic antibodies would also serve a useful therapeutic purpose. In a recent study based on the K/BXN model of arthritis, it was shown that multiple mechanisms were operative in the tolerization of B cells depending on the affinity of the B cell receptor (BCR) for the ligand, glucose-6-phosphate isomerase (GPI) (128). The B cells bearing high affinity-BCR for GPI were negatively selected, with receptor editing contributing to this process. However, several B cells escaped tolerance induction through the expression of an additional light chain. Furthermore, B cells bearing low affinity-BCR for GPI were ‘ignored’ (immune ignorance) (128). Considering that anti-GPI antibodies serve as a good marker for extra-articular RA (129), the detailed understanding of the tolerization of B cells specific for GPI would contribute towards better understanding of the pathogenesis of RA as well as for designing novel antigen-specific therapeutic approaches for this disease.

Increasing evidence suggests that antibodies to certain disease-related antigens might be regulatory in nature (7, 8, 130, 131). We and others have shown that arthritic Lewis (LEW) rats develop antibodies to Bhsp65 during the peak and recovery phase of AA (7, 8). These antibody responses are seen early after Mtb immunization in AA-resistant rat strains such as the Wistar Kyoto rat (WKY) (7), the Fischer F344 rat and the Brown Norway (BN) rat (131). Interestingly, the transfer into naïve LEW rats of serum derived from the late phase arthritic LEW rats or the AA-resistant BN rats offered protection against subsequent AA in the recipient rats (7, 131). Furthermore, the Bhsp65 peptides 31–46, 211–226, and 349–364 represent the epitopes that were recognized by the late antibodies from both WKY and LEW rats (7).

The role in innate immune mechanisms in the pathogenesis of autoimmunity

Rapid advancements in the field of innate immunity have brought to focus the interactions between innate and adaptive immune effectors mechanisms in infection and host immune response (132136). It is increasingly being realized that the molecules and receptors that were initially assumed to be restricted to the microbial agents in regard to their origin or response are also capable of recognizing and responding to certain self components. This, along with the observations showing the involvement of the Toll-like receptors (TLRs) in the activation of macrophages, dendritic cells, T cells and B cells (132136), begin to provide one of the rationales for the long-observed association between infection and autoimmunity. Furthermore, mast cells that were typically viewed in the context of allergies, only are now coming to the forefront constituting one of the effector mechanisms of autoimmune inflammation (137, 138). Similarly, the perturbations of the complement pathway-components and their impact on self reactivity and autoimmune damage are gaining significance (139, 140).

Several recent studies have highlighted the role of various innate immune mechanisms in rheumatic diseases. The role of complement components and mast cells in effector mechanisms of arthritis is exemplified by studies in the K/BXN model of arthritis (128, 138, 140). In RA patients, synovial tissue expresses TLRs (e.g., TLR 2 and 4), which affect macrophage activation, cytokine production and chemokine expression (141143). In regard to antibody responses, TLRs (e.g., TLR 7 and 9) are involved in the production of autoantibodies in murine lupus (134, 144). Some of the innate immune pathways are also being targeted for therapeutic purposes. For example, in experimental models, arthritis can be suppressed by inhibitors of the innate pathways by using, for example, a tylophorine analog, anti-complement 5 antibodies, or a TLR 4-antagonist (145147).

Concluding remarks

Two major realizations that have emerged in experiments from animal models and in clinical trials in patients with autoimmune diseases are (2, 914, 148)-: a) Non-antigen-specific immunomodulatory approaches (e.g., biologics and costimulation blockade) have been far more successful than the antigen-specific tolerogenic approaches (9, 10). However, newer therapeutic strategies may have to harness the beneficial aspects of both approaches (9, 10); and b) There is increasing emphasis on restoring a functional balance across the immune system among the critical subsets of T/B cells involved in autoimmune processes, including the naïve, effector, memory, and regulatory cells (13, 14). Thus, newer therapies would be aimed at controlling or deleting effector cells, and at shifting the profile of the immune homeostasis of patients towards a healthy type (148).


This work was supported by grants from the National Institutes of Health (Bethesda, MD) (AI-47790 and AI-059623), Arthritis Foundation (Atlanta, GA), the Maryland Chapter of Arthritis Foundation, and the Maryland Arthritis Research Center (MARRC; Baltimore, MD).


The authors have no conflict of interest

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.


1. Lipsky PE. Rheumatoid arthritis. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, editors. Harrison’s principles of internal medicine. 16. McGraw-Hill; New York: 2005. pp. 1968–77.
2. Fontoura P, Garren H, Steinman L. Antigen-specific therapies in multiple sclerosis: going beyond proteins and peptides. Int Rev Immunol. 2005;24(5–6):415–46. [PubMed]
3. Gaur A, Wiers B, Liu A, Rothbard J, Fathman CG. Amelioration of autoimmune encephalomyelitis by myelin basic protein synthetic peptide-induced anergy. Science. 1992;258(5087):1491–4. [PubMed]
4. Tisch R, Wang B, Serreze DV. Induction of glutamic acid decarboxylase 65-specific Th2 cells and suppression of autoimmune diabetes at late stages of disease is epitope dependent. J Immunol. 1999;163(3):1178–87. [PubMed]
5. Rizzo LV, Caspi RR. Immunotolerance and prevention of ocular autoimmune disease. Curr Eye Res. 1995;14(9):857–64. [PubMed]
6. Wiik AS. The immune response to citrullinated proteins in patients with rheumatoid arthritis: genetic, clinical, technical, and epidemiological aspects. Clin Rev Allergy Immunol. 2007;32(1):13–22. [PubMed]
7. Kim HR, Kim EY, Cerny J, Moudgil KD. Antibody responses to mycobacterial and self heat shock protein 65 in autoimmune arthritis: epitope specificity and implication in pathogenesis. J Immunol. 2006;177(10):6634–41. [PubMed]
8. Ulmansky R, Cohen CJ, Szafer F, et al. Resistance to adjuvant arthritis is due to protective antibodies against heat shock protein surface epitopes and the induction of IL-10 secretion. J Immunol. 2002;168(12):6463–9. [PubMed]
9. Nepom GT. Therapy of autoimmune diseases: clinical trials and new biologics. Curr Opin Immunol. 2002;14(6):812–5. [PubMed]
10. Feldmann M, Steinman L. Design of effective immunotherapy for human autoimmunity. Nature. 2005;435(7042):612–9. [PubMed]
11. Sigal LH. Basic science for the clinician 26: Tolerance--mechanisms and manifestations. J Clin Rheumatol. 2005;11(2):113–7. [PubMed]
12. von Herrath MG, Nepom GT. Lost in translation: barriers to implementing clinical immunotherapeutics for autoimmunity. J Exp Med. 2005;202(9):1159–62. [PMC free article] [PubMed]
13. St Clair EW, Turka LA, Saxon A, et al. New reagents on the horizon for immune tolerance. Annu Rev Med. 2007;58:329–46. [PubMed]
14. Katsiari CG, Tsokos GC. Re-establishment of tolerance: the prospect of developing specific treatment for human lupus. Lupus. 2004;13(7):485–8. [PubMed]
15. Ohashi PS, Oehen S, Buerki K, et al. Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell. 1991;65(2):305–17. [PubMed]
16. Kurts C, Sutherland RM, Davey G, et al. CD8 T cell ignorance or tolerance to islet antigens depends on antigen dose. Proc Natl Acad Sci U S A. 1999;96(22):12703–7. [PMC free article] [PubMed]
17. Choi S, Schwartz RH. Molecular mechanisms for adaptive tolerance and other T cell anergy models. Semin Immunol. 2007;19(3):140–52. [PMC free article] [PubMed]
18. Schwartz RH. T cell anergy. Annu Rev Immunol. 2003;21:305–34. [PubMed]
19. Young DA, Lowe LD, Booth SS, et al. IL-4, IL-10, IL-13, and TGF-beta from an altered peptide ligand-specific Th2 cell clone down-regulate adoptive transfer of experimental autoimmune encephalomyelitis. J Immunol. 2000;164(7):3563–72. [PubMed]
20. Rocken M, Shevach EM. Immune deviation--the third dimension of nondeletional T cell tolerance. Immunol Rev. 1996;149:175–94. [PubMed]
21. Tian J, Clare-Salzler M, Herschenfeld A, et al. Modulating autoimmune responses to GAD inhibits disease progression and prolongs islet graft survival in diabetes-prone mice. Nat Med. 1996;2(12):1348–53. [PubMed]
22. Sakaguchi S, Ono M, Setoguchi R, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006;212:8–27. [PubMed]
23. Shevach EM, DiPaolo RA, Andersson J, Zhao DM, Stephens GL, Thornton AM. The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. Immunol Rev. 2006;212:60–73. [PubMed]
24. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 2004;4(10):762–74. [PubMed]
25. Fallarino F, Grohmann U, Hwang KW, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol. 2003;4(12):1206–12. [PubMed]
26. Levine S, Sowinski R, Kies MW. Treatment of experimental allergic encephalomyelitis with encephalitogenic basic proteins. Proc Soc Exp Biol Med. 1972;139(2):506–10. [PubMed]
27. Atkinson MA, Leiter EH. The NOD mouse model of type 1 diabetes: as good as it gets? Nat Med. 1999;5(6):601–4. [PubMed]
28. Boussiotis VA, Freeman GJ, Gray G, Gribben J, Nadler LM. B7 but not intercellular adhesion molecule-1 costimulation prevents the induction of human alloantigen-specific tolerance. J Exp Med. 1993;178(5):1753–63. [PMC free article] [PubMed]
29. Thorstenson KM, Khoruts A. Generation of anergic and potentially immunoregulatory CD25+CD4 T cells in vivo after induction of peripheral tolerance with intravenous or oral antigen. J Immunol. 2001;167(1):188–95. [PubMed]
30. Norman PS, Nicodemus CF, Creticos PS, et al. Clinical and immunologic effects of component peptides in Allervax Cat. Int Arch Allergy Immunol. 1997;113(1–3):224–6. [PubMed]
31. Bousquet J, Lockey R, Malling HJ, et al. Allergen immunotherapy: therapeutic vaccines for allergic diseases. World Health Organization. American academy of Allergy, Asthma and Immunology Ann Allergy Asthma Immunol. 1998;81(5 Pt 1):401–5. [PubMed]
32. Warren KG, Catz I, Wucherpfennig KW. Tolerance induction to myelin basic protein by intravenous synthetic peptides containing epitope P85 VVHFFKNIVTP96 in chronic progressive multiple sclerosis. J Neurol Sci. 1997;152(1):31–8. [PubMed]
33. Khoury SJ, Lider O, al-Sabbagh A, Weiner HL. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. III Synergistic effect of lipopolysaccharide. Cell Immunol. 1990;131(2):302–10. [PubMed]
34. Zhang ZJ, Davidson L, Eisenbarth G, Weiner HL. Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci U S A. 1991;88(22):10252–6. [PMC free article] [PubMed]
35. Mowat AM, Parker LA, Beacock-Sharp H, Millington OR, Chirdo F. Oral tolerance: overview and historical perspectives. Ann N Y Acad Sci. 2004;1029:1–8. [PubMed]
36. Meyer O. Oral immunomodulation therapy in rheumatoid arthritis. Joint Bone Spine. 2000;67(5):384–92. [PubMed]
37. Faria AM, Weiner HL. Oral tolerance. Immunol Rev. 2005;206:232–59. [PMC free article] [PubMed]
38. Ohnishi Y, Tsutsumi A, Sakamaki T, Sumida T. T cell epitopes of type II collagen in HLA-DRB1*0101 or DRB1*0405-positive Japanese patients with rheumatoid arthritis. Int J Mol Med. 2003;11(3):331–5. [PubMed]
39. Zhu P, Li XY, Wang HK, et al. Oral administration of type-II collagen peptide 250–270 suppresses specific cellular and humoral immune response in collagen-induced arthritis. Clin Immunol. 2007;122(1):75–84. [PubMed]
40. Min SY, Hwang SY, Park KS, et al. Induction of IL-10-producing CD4+CD25+ T cells in animal model of collagen-induced arthritis by oral administration of type II collagen. Arthritis Res Ther. 2004;6(3):R213–9. [PMC free article] [PubMed]
41. Morgan ME, Sutmuller RP, Witteveen HJ, et al. CD25+ cell depletion hastens the onset of severe disease in collagen-induced arthritis. Arthritis Rheum. 2003;48(5):1452–60. [PubMed]
42. Taneja V, Taneja N, Paisansinsup T, et al. CD4 and CD8 T cells in susceptibility/protection to collagen-induced arthritis in HLA-DQ8-transgenic mice: implications for rheumatoid arthritis. J Immunol. 2002;168(11):5867–75. [PubMed]
43. Morgan ME, Witteveen HJ, Sutmuller RP, de Vries RR, Toes RE. CD25+ regulatory cells from HLA-DQ8 transgenic mice are capable of modulating collagen-induced arthritis. Hum Immunol. 2004;65(11):1319–27. [PubMed]
44. Blanas E, Heath WR. Oral administration of antigen can lead to the onset of autoimmune disease. Int Rev Immunol. 1999;18(3):217–28. [PubMed]
45. Sloan-Lancaster J, Allen PM. Altered peptide ligand-induced partial T cell activation: molecular mechanisms and role in T cell biology. Annu Rev Immunol. 1996;14:1–27. [PubMed]
46. Franco A, Southwood S, Arrhenius T, et al. T cell receptor antagonist peptides are highly effective inhibitors of experimental allergic encephalomyelitis. Eur J Immunol. 1994;24(4):940–6. [PubMed]
47. Steinman L, Utz PJ, Robinson WH. Suppression of autoimmunity via microbial mimics of altered peptide ligands. Curr Top Microbiol Immunol. 2005;296:55–63. [PubMed]
48. Platten M, Ho PP, Youssef S, et al. Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science. 2005;310(5749):850–5. [PubMed]
49. Liu E, Moriyama H, Abiru N, et al. Preventing peptide-induced anaphylaxis: addition of C-terminal amino acids to produce a neutral isoelectric point. J Allergy Clin Immunol. 2004;114(3):607–13. [PubMed]
50. Pearson CM. Development of arthritis, periarthritis and periostitis in rats given adjuvants. Proc Soc Exp Biol Med. 1956;91(1):95–101. [PubMed]
51. Billingham M. Adjuvant arthritis: the first model. Mechanisms and Models of Rheumatoid Arthritis. 1995:389–409.
52. Satpute SR, Soukhareva N, Scott DW, Moudgil KD. Mycobacterial Hsp65-IgG-expressing tolerogenic B cells confer protection against adjuvant-induced arthritis in Lewis rats. Arthritis Rheum. 2007;56(5):1490–6. [PubMed]
53. Cobelens PM, Heijnen CJ, Nieuwenhuis EE, et al. Treatment of adjuvant-induced arthritis by oral administration of mycobacterial Hsp65 during disease. Arthritis Rheum. 2000;43(12):2694–702. [PubMed]
54. Haque MA, Yoshino S, Inada S, Nomaguchi H, Tokunaga O, Kohashi O. Suppression of adjuvant arthritis in rats by induction of oral tolerance to mycobacterial 65-kDa heat shock protein. Eur J Immunol. 1996;26(11):2650–6. [PubMed]
55. Satpute SR, Moudgil KD. Protection against autoimmune arthritis induced by hsp65-mediated tolerance involves enhanced production of both IFN-g and antigen-specific antibodies (abstract # 128.23). Immunology 2007; 94th Annual Meeting of The American Association of Immunologists; Miami Beach, Florida. 2007.
56. Ally BA, Hawley TS, McKall-Faienza KJ, et al. Prevention of autoimmune disease by retroviral-mediated gene therapy. J Immunol. 1995;155(11):5404–8. [PubMed]
57. Bagley J, Iacomini J. Gene therapy progress and prospects: gene therapy in organ transplantation. Gene Ther. 2003;10(8):605–11. [PubMed]
58. Siatskas C, Chan J, Field J, et al. Gene therapy strategies towards immune tolerance to treat the autoimmune diseases. Curr Gene Ther. 2006;6(1):45–58. [PubMed]
59. Chernajovsky Y, Gould DJ, Podhajcer OL. Gene therapy for autoimmune diseases: quo vadis? Nat Rev Immunol. 2004;4(10):800–11. [PubMed]
60. Zambidis ET, Scott DW. Epitope-specific tolerance induction with an engineered immunoglobulin. Proc Natl Acad Sci U S A. 1996;93(10):5019–24. [PMC free article] [PubMed]
61. Kang Y, Melo M, Deng E, Tisch R, El-Amine M, Scott DW. Induction of hyporesponsiveness to intact foreign protein via retroviral-mediated gene expression: the IgG scaffold is important for induction and maintenance of immune hyporesponsiveness. Proc Natl Acad Sci U S A. 1999;96(15):8609–14. [PMC free article] [PubMed]
62. Agarwal RK, Kang Y, Zambidis E, Scott DW, Chan CC, Caspi RR. Retroviral gene therapy with an immunoglobulin-antigen fusion construct protects from experimental autoimmune uveitis. J Clin Invest. 2000;106(2):245–52. [PMC free article] [PubMed]
63. El-Amine M, Hinshaw JA, Scott DW. In vivo induction of tolerance by an Ig peptide is not affected by the deletion of FcR or a mutated IgG Fc fragment. Int Immunol. 2002;14(7):761–6. [PubMed]
64. Melo ME, Qian J, El-Amine M, et al. Gene transfer of Ig-fusion proteins into B cells prevents and treats autoimmune diseases. J Immunol. 2002;168(9):4788–95. [PubMed]
65. Song L, Wang J, Wang R, et al. Retroviral delivery of GAD-IgG fusion construct induces tolerance and modulates diabetes: a role for CD4+ regulatory T cells and TGF-beta? Gene Ther. 2004;11(20):1487–96. [PubMed]
66. Lei TC, Scott DW. Induction of tolerance to factor VIII inhibitors by gene therapy with immunodominant A2 and C2 domains presented by B cells as Ig fusion proteins. Blood. 2005;105(12):4865–70. [PMC free article] [PubMed]
67. Xu B, Haviernik P, Wolfraim LA, Bunting KD, Scott DW. Bone marrow transplantation combined with gene therapy to induce antigen-specific tolerance and ameliorate EAE. Mol Ther. 2006;13(1):42–8. [PubMed]
68. Tarner IH, Neumann E, Gay S, Fathman CG, Muller-Ladner U. Developing the concept of adoptive cellular gene therapy of rheumatoid arthritis. Autoimmun Rev. 2006;5(2):148–52. [PubMed]
69. Tarner IH, Nakajima A, Seroogy CM, et al. Retroviral gene therapy of collagen-induced arthritis by local delivery of IL-4. Clin Immunol. 2002;105(3):304–14. [PubMed]
70. Mukherjee P, Wu B, Mayton L, Kim SH, Robbins PD, Wooley PH. TNF receptor gene therapy results in suppression of IgG2a anticollagen antibody in collagen induced arthritis. Ann Rheum Dis. 2003;62(8):707–14. [PMC free article] [PubMed]
71. Ho PP, Higgins JP, Kidd BA, et al. Tolerizing DNA vaccines for autoimmune arthritis. Autoimmunity. 2006;39(8):675–82. [PubMed]
72. Bluestone JA, Tang Q. Therapeutic vaccination using CD4+CD25+ antigen-specific regulatory T cells. Proc Natl Acad Sci U S A. 2004;101(Suppl 2):14622–6. [PMC free article] [PubMed]
73. Leipe J, Skapenko A, Lipsky PE, Schulze-Koops H. Regulatory T cells in rheumatoid arthritis. Arthritis Res Ther. 2005;7(3):93. [PMC free article] [PubMed]
74. Kamphuis S, Albani S, Prakken BJ. Heat-shock protein 60 as a tool for novel therapeutic strategies that target the induction of regulatory T cells in human arthritis. Expert Opin Biol Ther. 2006;6(6):579–89. [PubMed]
75. Prakken BJ, Samodal R, Le TD, et al. Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2004;101(12):4228–33. [PMC free article] [PubMed]
76. Ehrenstein MR, Evans JG, Singh A, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med. 2004;200(3):277–85. [PMC free article] [PubMed]
77. Valencia X, Yarboro C, Illei G, Lipsky PE. Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol. 2007;178(4):2579–88. [PubMed]
78. Prakken B, Kuis W, van Eden W, Albani S. Heat shock proteins in juvenile idiopathic arthritis: keys for understanding remitting arthritis and candidate antigens for immune therapy. Curr Rheumatol Rep. 2002;4(6):466–73. [PubMed]
79. Koffeman EC, Prakken B, Albani S. Recent developments in immunomodulatory peptides in juvenile rheumatic diseases: from trigger to dimmer? Curr Opin Rheumatol. 2005;17(5):600–5. [PubMed]
80. Vally M, Seenu S, Pillarisetti S. Emerging peptide therapeutics for inflammatory diseases. Curr Pharm Biotechnol. 2006;7(4):241–6. [PubMed]
81. Zaliauskiene L, Fazio RL, Kang S, et al. Inhibition of T cell responses by transferrin-coupled competitor peptides. Immunol Res. 2002;26(1–3):77–85. [PubMed]
82. Bielekova B, Goodwin B, Richert N, et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med. 2000;6(10):1167–75. [PubMed]
83. Kappos L, Comi G, Panitch H, et al. Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. The Altered Peptide Ligand in Relapsing MS Study Group. Nat Med. 2000;6(10):1176–82. [PubMed]
84. Cravens PD, Lipsky PE. Dendritic cells, chemokine receptors and autoimmune inflammatory diseases. Immunol Cell Biol. 2002;80(5):497–505. [PubMed]
85. van Duivenvoorde LM, van Mierlo GJ, Boonman ZF, Toes RE. Dendritic cells: vehicles for tolerance induction and prevention of autoimmune diseases. Immunobiology. 2006;211(6–8):627–32. [PubMed]
86. van Duivenvoorde LM, Louis-Plence P, Apparailly F, et al. Antigen-specific immunomodulation of collagen-induced arthritis with tumor necrosis factor-stimulated dendritic cells. Arthritis Rheum. 2004;50(10):3354–64. [PubMed]
87. Trentham DE, Dynesius-Trentham RA, Orav EJ, et al. Effects of oral administration of type II collagen on rheumatoid arthritis. Science. 1993;261(5129):1727–30. [PubMed]
88. McKown KM, Carbone LD, Kaplan SB, et al. Lack of efficacy of oral bovine type II collagen added to existing therapy in rheumatoid arthritis. Arthritis Rheum. 1999;42(6):1204–8. [PubMed]
89. Nussenblatt RB, Gery I, Weiner HL, et al. Treatment of uveitis by oral administration of retinal antigens: results of a phase I/II randomized masked trial. Am J Ophthalmol. 1997;123(5):583–92. [PubMed]
90. Chaillous L, Lefevre H, Thivolet C, et al. Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Diabete Insuline Orale group. Lancet. 2000;356(9229):545–9. [PubMed]
91. Staines NA, Derry CJ, Marinova-Mutafchieva L, Ali N, Davies DH, Murphy JJ. Constraints on the efficacy of mucosal tolerance in treatment of human and animal arthritic diseases. Ann N Y Acad Sci. 2004;1029:250–9. [PubMed]
92. Postlethwaite AE. Can we induce tolerance in rheumatoid arthritis? Curr Rheumatol Rep. 2001;3(1):64–9. [PubMed]
93. Trentham DE. Oral tolerization as a treatment of rheumatoid arthritis. Rheum Dis Clin North Am. 1998;24(3):525–36. [PubMed]
94. Buckner JH, Nepom GT. Genetics of rheumatoid arthritis: is there a scientific explanation for the human leukocyte antigen association? Curr Opin Rheumatol. 2002;14(3):254–9. [PubMed]
95. David CS, Taneja V. Role of major histocompatibility complex genes in murine collagen-induced arthritis: a model for human rheumatoid arthritis. Am J Med Sci. 2004;327(4):180–7. [PubMed]
96. Deighton C, Criswell LA. Recent advances in the genetics of rheumatoid arthritis. Curr Rheumatol Rep. 2006;8(5):394–400. [PubMed]
97. Klareskog L, Padyukov L, Ronnelid J, Alfredsson L. Genes, environment and immunity in the development of rheumatoid arthritis. Curr Opin Immunol. 2006;18(6):650–5. [PubMed]
98. van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Huizinga TW, Toes RE, de Vries RR. The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum. 2006;54(4):1117–21. [PubMed]
99. Moudgil KD, Chang TT, Eradat H, et al. Diversification of T cell responses to carboxy-terminal determinants within the 65-kD heat-shock protein is involved in regulation of autoimmune arthritis. J Exp Med. 1997;185(7):1307–16. [PMC free article] [PubMed]
100. Stevens DB, Gold DP, Sercarz EE, Moudgil KD. The Wistar Kyoto (RT1(l)) rat is resistant to myelin basic protein-induced experimental autoimmune encephalomyelitis: comparison with the susceptible Lewis (RT1(l)) strain with regard to the MBP-directed CD4+ T cell repertoire and its regulation. J Neuroimmunol. 2002;126(1–2):25–36. [PubMed]
101. Chatenoud L, Salomon B, Bluestone JA. Suppressor T cells—they’re back and critical for regulation of autoimmunity! Immunol Rev. 2001;182:149–63. [PubMed]
102. Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000;192(2):295–302. [PMC free article] [PubMed]
103. Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003;9(9):1144–50. [PubMed]
104. Wu AJ, Hua H, Munson SH, McDevitt HO. Tumor necrosis factor-alpha regulation of CD4+CD25+ T cell levels in NOD mice. Proc Natl Acad Sci U S A. 2002;99(19):12287–92. [PMC free article] [PubMed]
105. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199(7):971–9. [PMC free article] [PubMed]
106. Kang HK, Michaels MA, Berner BR, Datta SK. Very low-dose tolerance with nucleosomal peptides controls lupus and induces potent regulatory T cell subsets. J Immunol. 2005;174(6):3247–55. [PubMed]
107. Yao Z, Fanslow WC, Seldin MF, et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity. 1995;3(6):811–21. [PubMed]
108. Broxmeyer HE. Is interleukin 17, an inducible cytokine that stimulates production of other cytokines, merely a redundant player in a sea of other biomolecules? J Exp Med. 1996;183(6):2411–5. [PMC free article] [PubMed]
109. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–8. [PubMed]
110. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24(2):179–89. [PubMed]
111. Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8(4):345–50. [PubMed]
112. Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201(2):233–40. [PMC free article] [PubMed]
113. Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6(11):1133–41. [PMC free article] [PubMed]
114. Laurence A, Tato CM, Davidson TS, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity. 2007;26(3):371–81. [PubMed]
115. Amadi-Obi A, Yu CR, Liu X, et al. T(H)17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med. 2007 [PubMed]
116. Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126(6):1121–33. [PubMed]
117. Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744–8. [PubMed]
118. Hofstetter HH, Ibrahim SM, Koczan D, et al. Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell Immunol. 2005;237(2):123–30. [PubMed]
119. Lubberts E, Joosten LA, Oppers B, et al. IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J Immunol. 2001;167(2):1004–13. [PubMed]
120. Nakae S, Saijo S, Horai R, Sudo K, Mori S, Iwakura Y. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc Natl Acad Sci U S A. 2003;100(10):5986–90. [PMC free article] [PubMed]
121. Vukkadapu SS, Belli JM, Ishii K, et al. Dynamic interaction between T cell-mediated beta-cell damage and beta-cell repair in the run up to autoimmune diabetes of the NOD mouse. Physiol Genomics. 2005;21(2):201–11. [PubMed]
122. Mensah-Brown EP, Shahin A, Al-Shamisi M, Wei X, Lukic ML. IL-23 leads to diabetes induction after subdiabetogenic treatment with multiple low doses of streptozotocin. Eur J Immunol. 2006;36(1):216–23. [PubMed]
123. Chabaud M, Fossiez F, Taupin JL, Miossec P. Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. J Immunol. 1998;161(1):409–14. [PubMed]
124. Weiner LP, Louie KA, Atalla LR, et al. Gene therapy in a murine model for clinical application to multiple sclerosis. Ann Neurol. 2004;55(3):390–9. [PubMed]
125. Lei TC, Su Y, Scott DW. Tolerance induction via a B-cell delivered gene therapy-based protocol: optimization and role of the Ig scaffold. Cell Immunol. 2005;235(1):12–20. [PubMed]
126. Litzinger MT, Su Y, Lei TC, Soukhareva N, Scott DW. Mechanisms of gene therapy for tolerance: B7 signaling is required for peptide-IgG gene-transferred tolerance induction. J Immunol. 2005;175(2):780–7. [PubMed]
127. Soukhareva N, Jiang Y, Scott DW. Treatment of diabetes in NOD mice by gene transfer of Ig-fusion proteins into B cells: role of T regulatory cells. Cell Immunol. 2006;240(1):41–6. [PubMed]
128. Huang H, Kearney JF, Grusby MJ, Benoist C, Mathis D. Induction of tolerance in arthritogenic B cells with receptors of differing affinity for self-antigen. Proc Natl Acad Sci U S A. 2006;103(10):3734–9. [PMC free article] [PubMed]
129. van Gaalen FA, Toes RE, Ditzel HJ, et al. Association of autoantibodies to glucose-6-phosphate isomerase with extraarticular complications in rheumatoid arthritis. Arthritis Rheum. 2004;50(2):395–9. [PubMed]
130. Morris-Downes MM, Smith PA, Rundle JL, et al. Pathological and regulatory effects of anti-myelin antibodies in experimental allergic encephalomyelitis in mice. J Neuroimmunol. 2002;125(1–2):114–24. [PubMed]
131. Ulmansky R, Naparstek Y. Immunoglobulins from rats that are resistant to adjuvant arthritis suppress the disease in arthritis-susceptible rats. Eur J Immunol. 1995;25(4):952–7. [PubMed]
132. Kabelitz D. Expression and function of Toll-like receptors in T lymphocytes. Curr Opin Immunol. 2007;19(1):39–45. [PubMed]
133. Pasare C, Medzhitov R. Toll-dependent control mechanisms of CD4 T cell activation. Immunity. 2004;21(5):733–41. [PubMed]
134. Marshak-Rothstein A, Rifkin IR. Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease. Annu Rev Immunol. 2007;25:419–41. [PubMed]
135. Lanzavecchia A, Sallusto F. Toll-like receptors and innate immunity in B-cell activation and antibody responses. Curr Opin Immunol. 2007;19(3):268–74. [PubMed]
136. Medvedev AE, Sabroe I, Hasday JD, Vogel SN. Tolerance to microbial TLR ligands: molecular mechanisms and relevance to disease. J Endotoxin Res. 2006;12(3):133–50. [PubMed]
137. Metz M, Maurer M. Mast cells--key effector cells in immune responses. Trends Immunol. 2007;28(5):234–41. [PubMed]
138. Lee DM, Friend DS, Gurish MF, Benoist C, Mathis D, Brenner MB. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science. 2002;297(5587):1689–92. [PubMed]
139. Flierman R, Daha MR. The clearance of apoptotic cells by complement. Immunobiology. 2007;212(4–5):363–70. [PubMed]
140. Monach PA, Verschoor A, Jacobs JP, et al. Circulating C3 is necessary and sufficient for induction of autoantibody-mediated arthritis in a mouse model. Arthritis Rheum. 2007;56(9):2968–74. [PMC free article] [PubMed]
141. Huang Q, Ma Y, Adebayo A, Pope RM. Increased macrophage activation mediated through toll-like receptors in rheumatoid arthritis. Arthritis Rheum. 2007;56(7):2192–201. [PubMed]
142. Radstake TR, Roelofs MF, Jenniskens YM, et al. Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma. Arthritis Rheum. 2004;50(12):3856–65. [PubMed]
143. Sacre SM, Andreakos E, Kiriakidis S, et al. The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis. Am J Pathol. 2007;170(2):518–25. [PMC free article] [PubMed]
144. Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity. 2006;25(3):417–28. [PubMed]
145. You X, Pan M, Gao W, et al. Effects of a novel tylophorine analog on collagen-induced arthritis through inhibition of the innate immune response. Arthritis Rheum. 2006;54(3):877–86. [PubMed]
146. Banda NK, Kraus D, Vondracek A, et al. Mechanisms of effects of complement inhibition in murine collagen-induced arthritis. Arthritis Rheum. 2002;46(11):3065–75. [PubMed]
147. Abdollahi-Roodsaz S, Joosten LA, Roelofs MF, et al. Inhibition of toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. Arthritis Rheum. 2007;56(9):2957–67. [PubMed]
148. De Jager PL, Hafler DA. New therapeutic approaches for multiple sclerosis. Annu Rev Med. 2007;58:417–32. [PubMed]
149. Gumanovskaya ML, Myers LK, Rosloniec EF, Stuart JM, Kang AH. Intravenous tolerization with type II collagen induces interleukin-4-and interleukin-10-producing CD4+ T cells. Immunology. 1999;97(3):466–73. [PMC free article] [PubMed]
150. Yang XD, Gasser J, Riniker B, Feige U. Treatment of adjuvant arthritis in rats: vaccination potential of a synthetic nonapeptide from the 65 kDa heat shock protein of mycobacteria. J Autoimmun. 1990;3(1):11–23. [PubMed]
151. Turley DM, Miller SD. Peripheral tolerance induction using ethylenecarbodiimide-fixed APCs uses both direct and indirect mechanisms of antigen presentation for prevention of experimental autoimmune encephalomyelitis. J Immunol. 2007;178(4):2212–20. [PubMed]
152. Sriram S, Schwartz G, Steinman L. Administration of myelin basic protein-coupled spleen cells prevents experimental allergic encephalitis. Cell Immunol. 1983;75(2):378–82. [PubMed]
153. Durai M, Kim HR, Moudgil KD. The regulatory C-terminal determinants within mycobacterial heat shock protein 65 are cryptic and cross-reactive with the dominant self homologs: implications for the pathogenesis of autoimmune arthritis. J Immunol. 2004;173(1):181–8. [PubMed]
154. Golden HW, Maniglia CA, Ranges GE. A synthetic mycobacterial heat shock peptide prevents adjuvant arthritis but not proteoglycan-induced synovitis in the rat. Agents Actions. 1991;34(1–2):148–50. [PubMed]
155. Mia MY, Durai M, Kim HR, Moudgil KD. Heat shock protein 65-reactive T cells are involved in the pathogenesis of non-antigenic dimethyl dioctadecyl ammonium bromide-induced arthritis. J Immunol. 2005;175(1):219–27. [PubMed]
156. Ditzian-Kadanoff R. Testicular-associated immune deviation and prevention of adjuvant-induced arthritis by three tolerization methods. Scand J Immunol. 1999;50(2):150–8. [PubMed]
157. van Eden W, Thole JE, van der Zee R, et al. Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature. 1988;331(6152):171–3. [PubMed]
158. Kingston AE, Hicks CA, Colston MJ, Billingham ME. A 71-kD heat shock protein (hsp) from Mycobacterium tuberculosis has modulatory effects on experimental rat arthritis. Clin Exp Immunol. 1996;103(1):77–82. [PMC free article] [PubMed]
159. Agnello D, Scanziani E, Di GM, et al. Preventive administration of Mycobacterium tuberculosis 10-kDa heat shock protein (hsp10) suppresses adjuvant arthritis in Lewis rats. Int Immunopharmacol. 2002;2(4):463–74. [PubMed]
160. Ding CH, Li Q, Xiong ZY, Zhou AW, Jones G, Xu SY. Oral administration of type II collagen suppresses pro-inflammatory mediator production by synoviocytes in rats with adjuvant arthritis. Clin Exp Immunol. 2003;132(3):416–23. [PMC free article] [PubMed]
161. Beech JT, Siew LK, Ghoraishian M, Stasiuk LM, Elson CJ, Thompson SJ. CD4+ Th2 cells specific for mycobacterial 65–kilodalton heat shock protein protect against pristane-induced arthritis. J Immunol. 1997;159(8):3692–7. [PubMed]
162. Jorgensen C, Gedon E, Jaquet C, Sany J. Gastric administration of recombinant 65 kDa heat shock protein delays the severity of type II collagen induced arthritis in mice. J Rheumatol. 1998;25(4):763–7. [PubMed]
163. van den Broek MF, Hogervorst EJ, Van Bruggen MC, Van Eden W, van der Zee R, van den Berg WB. Protection against streptococcal cell wall-induced arthritis by pretreatment with the 65-kD mycobacterial heat shock protein. J Exp Med. 1989;170(2):449–66. [PMC free article] [PubMed]
164. Quintana FJ, Carmi P, Mor F, Cohen IR. DNA fragments of the human 60-kDa heat shock protein (HSP60) vaccinate against adjuvant arthritis: identification of a regulatory HSP60 peptide. J Immunol. 2003;171(7):3533–41. [PubMed]
165. Durai M, Gupta RS, Moudgil KD. The T cells specific for the carboxyl-terminal determinants of self (rat) heat-shock protein 65 escape tolerance induction and are involved in regulation of autoimmune arthritis. J Immunol. 2004;172(5):2795–802. [PubMed]
166. Anderton SM, van der Zee R, Noordzij A, van Eden W. Differential mycobacterial 65-kDa heat shock protein T cell epitope recognition after adjuvant arthritis-inducing or protective immunization protocols. J Immunol. 1994;152(7):3656–64. [PubMed]
167. Prakken BJ, van der Zee R, Anderton SM, van Kooten PJ, Kuis W, van Eden W. Peptide-induced nasal tolerance for a mycobacterial heat shock protein 60 T cell epitope in rats suppresses both adjuvant arthritis and nonmicrobially induced experimental arthritis. Proc Natl Acad Sci U S A. 1997;94(7):3284–9. [PMC free article] [PubMed]
168. Francis JN, Lamont AG, Thompson SJ. The route of administration of an immunodominant peptide derived from heat-shock protein 65 dramatically affects disease outcome in pristane-induced arthritis. Immunology. 2000;99(3):338–44. [PMC free article] [PubMed]
169. Thompson SJ, Francis JN, Siew LK, et al. An immunodominant epitope from mycobacterial 65-kDa heat shock protein protects against pristane-induced arthritis. J Immunol. 1998;160(9):4628–34. [PubMed]
170. Wauben MH, Boog CJ, van der Zee R, Joosten I, Schlief A, van Eden W. Disease inhibition by major histocompatibility complex binding peptide analogues of disease-associated epitopes: more than blocking alone. J Exp Med. 1992;176(3):667–77. [PMC free article] [PubMed]
171. Prakken BJ, Roord S, van Kooten PJ, et al. Inhibition of adjuvant-induced arthritis by interleukin-10-driven regulatory cells induced via nasal administration of a peptide analog of an arthritis-related heat-shock protein 60 T cell epitope. Arthritis Rheum. 2002;46(7):1937–46. [PubMed]
172. Sakurai Y, Brand DD, Tang B, et al. Analog peptides of type II collagen can suppress arthritis in HLA-DR4 (DRB1*0401) transgenic mice. Arthritis Res Ther. 2006;8(5):R150. [PMC free article] [PubMed]
173. Buzas EI, Hanyecz A, Murad Y, et al. Differential recognition of altered peptide ligands distinguishes two functionally discordant (arthritogenic and nonarthritogenic) autoreactive T cell hybridoma clones. J Immunol. 2003;171(6):3025–33. [PubMed]
174. Quintana FJ, Carmi P, Mor F, Cohen IR. Inhibition of adjuvant arthritis by a DNA vaccine encoding human heat shock protein 60. J Immunol. 2002;169(6):3422–8. [PubMed]
175. Hogervorst EJ, Schouls L, Wagenaar JP, et al. Modulation of experimental autoimmunity: treatment of adjuvant arthritis by immunization with a recombinant vaccinia virus. Infect Immun. 1991;59(6):2029–35. [PMC free article] [PubMed]
176. Lopez-Guerrero JA, Ortiz MA, Paez E, Bernabeu C, Lopez-Bote JP. Therapeutic effect of recombinant vaccinia virus expressing the 60-kd heat-shock protein on adjuvant arthritis. Arthritis Rheum. 1994;37(10):1462–7. [PubMed]
177. Esaguy N, Aguas AP. Prevention of adjuvant arthritis in Lewis rats by neonatal bacille Calmette-Guerin (BCG) infection. Clin Exp Immunol. 1996;104(1):103–7. [PMC free article] [PubMed]
178. Thompson SJ, Butcher PD, Patel VK, et al. Modulation of pristane-induced arthritis by mycobacterial antigens. Autoimmunity. 1991;11(1):35–43. [PubMed]
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...