Immunomodulation of autoimmune diseases by high-dose intravenous immunoglobulins

Conclusion  IVIG represents a promising immunoregulatory agent which has the ability to control autoimmune disorders without subsequent predisposition to infectious complications. However, it is extremely expensive: the approximate average wholesale price is U.S. $1,800 per dose for a 70-kg patient. Further studies and controlled clinical trials will be necessary to prove the efficacy of this therapy for specific autoimmune disorders.     

Immunomodulation of autoimmune and inflammatory diseases with intravenous immunoglobulin

Abstract Intravenous immunoglobulin (IVIg) has been used in the treatment of primary and secondary antibody deficiencies for over two decades. Since the early 1980s, the therapeutic efficacy of IVIg has been established in idiopathic thrombocytopenic purpura, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, dermatomyositis and Kawasaki syndrome, and the prevention of graft versus host disease in recipients of allogeneic bone marrow transplants. Its use has also been reported in a large number of other autoimmune and systemic inflammatory conditions. In this review, we discuss the mechanisms by which IVIg exerts immunomodulatory effects in immune pathologies.     

Immunomodulation of experimental autoimmune encephalomyelitis by helminth ova immunization

Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS) characterized by chronic inflammatory demyelination of the central nervous system (CNS). The pathology of EAE involves autoimmune CD4(+) T(h)1 cells. There is a striking inverse correlation between the occurrence of parasitic and autoimmune diseases. We demonstrate that in mice with Schistosoma mansoni ova immunization, the severity of EAE is reduced as measured by decreased clinical scores and CNS cellular infiltrates. Disease suppression is associated with immune deviation in the periphery and the CNS, demonstrated by decreased IFN-gamma and increased IL-4, transforming growth factor-beta and IL-10 levels in the periphery, and increased frequency of IL-4 producing neuroantigen-specific T cells in the brain. S. mansoni helminth ova treatment influenced the course of EAE in wild-type mice, but not in STAT6-deficient animals. This indicates that STAT6 plays a critical role in regulating the ameliorating effect of S. mansoni ova treatment on the autoimmune response, and provides the direct link between helminth treatment, T(h)2 environment and improved EAE. As some intestinal helminthic infections induce minimal pathology, they might offer a safe and inexpensive therapy to prevent and/or ameliorate MS.     

Central tolerance and autoimmune diseases]

Central tolerance is established by the repertoire selection of immature T lymphocytes in the thymus, avoiding autoimmune responses to self-antigens. Differential ligand-TCR interactions that result in positive and negative selection initiate differential intracellular signals that, in turn, lead to the survival-or-death decision of immature thymocytes. TCR signal dysregulation due to the mutation of ZAP-70 or defective apoptosis of autoreactive thymocytes due to the deficiency of pro-apoptotic protein Bim impair tolerance and cause autoimmunity. Thymic repertoire selection also induces the development of CD25(+)CD4(+) regulatory T cells, which play important roles for maintaining peripheral tolerance. Furthermore, the establishment of central tolerance requires the development of thymic medulla that is mediated by the activation of NF-kappaB signaling pathway, promiscuous expression of tissue-specific self-antigens by medullary epithelial cells that is regulated by AIRE, and cortex-to-medulla migration of developing thymocytes that is regulated by CCR7-mediated chemokine signals.     

Immunomodulation by statins: mechanisms and potential impact on autoimmune diseases

Statins are inhibitors of the enzyme 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) and they are the most effective agents for lowering cholesterol in clinical practice for the treatment of cardiovascular diseases. However, it has become clear that statins also have pleiotropic immunomodulatory effects in addition to their lipid-lowering properties. As a result, much attention has been focused on their potential as therapeutic agents for the treatment of inflammatory autoimmune diseases. In this review the effect of statins on the expression and function of a variety of immune-relevant molecules will be discussed alongside the underlying mechanisms that contribute to the immunomodulatory effects of statins.     

Heterogeneity of oral tolerance defects in autoimmune mice

Three strains of mice, BXSB, MRL-lpr/lpr, and NZB, which spontaneously develop autoimmune syndromes, all fail to become tolerant to challenge with bovine gamma-globulin (BGG) in adjuvant by prior intraperitoneal (ip) injection of BGG in tolerogenic form. In the present study, these three strains were examined for the ability of a single enteric dose of BGG or ovalbumin (OVA) to tolerize to subsequent challenge with the corresponding antigen in adjuvant. In contrast to lack of ip tolerance to BGG, BXSB mice were tolerant to gastrointestinal (GI) BGG as well as to GI OVA, suggesting that ip and GI forms of tolerance to BGG operate through distinct mechanisms in these mice. MRL-lpr/lpr mice had normal tolerance to GI OVA but not GI BGG. The presence of enteric tolerance to one antigen but not another suggests that the responsible cellular defects vary from one antigen to another. NZB mice lacked tolerance to both GI BGG and GI OVA. Splenectomy of NZB mice allowed normal tolerance to enteric BGG; spleen cells administered to splenectomized NZB mice interfered with BGG tolerance. Congenic NZB.xid mice were tolerant only to OVA. These results suggest that in NZB mice Lyb 5+ cells interfere with tolerance to enteric OVA and Lyb 5- spleen cells interfere with tolerance to enteric BGG.     

Induction of low dose oral tolerance in IL-10 deficient mice with experimental autoimmune encephalomyelitis

IL-10 has been shown to be an important anti-inflammatory mediator that has both down-regulatory and immunomodulatory effects. Utilizing IL-10(-/-) mice we demonstrate the induction of low dose oral tolerance characterized by the up-regulation of TGF-beta and IL-4 and the suppression of Ag specific proliferation with little suppression of INF-gamma. More severe EAE was found in IL-10(-/-) mice than in wild type controls, however, feeding resulted in amelioration of disease severity in both groups. Orally tolerized IL-10(-/-) mice had greater disease severity compared to orally tolerized wild type mice. IL-4 was present in the GALT of IL-10(-/-) mice and up-regulation of TGF-beta was detected in the lamina propria of fed mice. These results demonstrate that IL-10 is not required for the induction of low dose oral tolerance but is required for the regulation of INF-gamma which affects severity of disease in tolerized mice.     

Induction of oral tolerance to S-antigen induced experimental autoimmune uveitis by a uveitogenic 20mer peptide

Experimental autoimmune uveitis (EAU) in Lewis rats is a T-cell dependent disease, which is induced by immunization with retinal S-Antigen (S-Ag) or its unveitogenic peptides. We have recently reported that the oral administration of S-Ag prior to the uveitogenic challenge results in suppression of the disease and of the cellular responses. We examined the effect of oral administration of a recently described uveitogenic peptide (Peptide 35) on the development of EAU induced with the whole protein. The severity of inflammation and retinal destruction, as well as the cellular proliferative responses, were suppressed compared to controls fed with Keyhole Limpet Hemocyanin (KLH). In addition, the levels of antigen-specific antibody isotypes in the serum of gavaged rats were determined. Although (IgA) levels were reduced in rats gavaged with S-Ag or the uveitogenic peptide, IgM and IgG levels were unaltered. Thus, the oral administration of Peptide 35 approaches the state of unresponsiveness seen in S-Ag feeding. In addition, the unresponsiveness can be demonstrated on both the cellular and humoral level.     

Oral tolerance: therapeutic implications for autoimmune diseases

Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-beta) regulatory T cells (Tregs) plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy.     

Treating autoimmune diseases through restoration of antigen-specific immune tolerance

The first line of treatment for many human autoimmune diseases involves the use of anti-inflammatory or immunosuppressive drugs such as prednisone or other steroids that not only suppress the underlying autoimmune disease, but lead to global suppression of the immune system. The sequelae of this approach include increased risk of infection, carcinogenesis, and osteoporosis. Moreover, such broad spectrum immunosuppression tends to have transient therapeutic benefit, as in many cases the disease becomes refractory to these drugs. There is a clear need for more specific means to restore immune tolerance to the specific autoantigens implicated in disease pathology. This review provides an overview of some of these newer, more specific therapeutic approaches to restoring immune tolerance to autoantigens, with an emphasis on those approaches that have been or will soon be tested in controlled clinical trials. Covered here are peptide- or protein-based therapeutics, oral tolerance, and cellular and gene therapy approaches to restoring antigen-specific immune tolerance.     

Oral tolerance in the treatment of inflammatory autoimmune diseases

Oral tolerance refers to the oral administration of protein antigens, which induces a state of systemic nonresponsiveness specific for the fed antigen. This method of inducing immune non-responsiveness has been applied to the prevention and treatment of experimental animal models of autoimmune disease. Extensive research in this area over the past ten years has led to the conclusion that two mechanisms are operative in the mediation of oral tolerance--active suppression and clonal anergy/deletion. A number of factors have been identified that determine which mechanism of tolerance is operative--antigen dose, antigen form, and the timing of antigen administration. Work from these animal models has recently been extended into human clinical trials of multiple sclerosis, rheumatoid arthritis, diabetes, uveitis, and allergy, with differing degrees of success. In this review, a discussion is provided of the animal model systems where oral tolerance has been applied and the clinical trials where an oral tolerization approach has been attempted. Moreover, recent mechanistic studies are reviewed and a model proposed for the induction of oral tolerance.     

Cytokine shifts and tolerance in experimental autoimmune encephalomyelitis

Cytokines play an important role in the pathogenesis of both multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Effective treatments for both diseases have been shown to alter cytokines in the central nervous system and in activated mononuclear cells. EAE is an animal model that mimics many aspects of multiple sclerosis, and has been widely used to study the mechanisms of disease and therapeutic approaches to multiple sclerosis. Cytokines play an important role in regulation of disease expression in EAE, and in tolerance to disease induction. In this review, we will summarize the current findings on the role of cytokine shifts in the induction of tolerance in EAE. In addition, we will discuss modulation of EAE by altered expression of members of the cytokine-regulated Jak/STAT intracellular signaling pathway.     

Experimental autoimmune uveitis: Molecular mimicry and oral tolerance

Intraocular inflammatory disease or uveitis, which affects the uveal tract and the retina of the eyes in human, is the major cause of visual impairment. Experimental autoimmune uveitis (EAU) is a T-cell-mediated autoimmune disease directed against retinal proteins and has been studied in several mammalian species including subhuman primates as a model for human posterior uveitis. Autoimmune responses provoked by molecular mimicry occur when the nonself and host determinants are similar enough to cross-react yet different enough to break immunological tolerance, and is one of the proposed mechanisms for induction of autoimmune diseases. Therapeutic immunomodulatory strategies have been used to induce antigen-specific peripheral immune tolerance in animal models of T-cell-mediated autoimmune diseases by oral administration of autoantigens. Oral tolerance leads to unique mechanisms of tissue and disease-specific immunosuppression, which would circumvent the immunotherapeutic problem of multiple target tissue autoreactivity. Several groups have investigated the effects of delivering autoantigens across gastric mucosal surfaces. This review briefly discusses molecular mimicry and the mechanism of induction of oral tolerance with respect to immunopathogenesis of T-cell-mediated autoimmune diseases in general and EAU in particular.     

Immunomodulation of liver injury by Ascaris suum extract in an experimental model of autoimmune hepatitis

Adult worm extract from Ascaris suum (Asc) has immunosuppressive activity and elicits Th2/IL-4/IL-10 response. This study evaluated the prophylactic and therapeutic effect of Asc in a murine model of concanavalin A (ConA)-induced autoimmune hepatitis (AIH). BALB/c mice received ConA, iv, (20 mg/kg), and three groups of animals were formed: (1) AIH, received only ConA; (2) AIH + Asc prophylactic, treated with Asc (1 mg/ml), ip, 30 min before of the AIH; and (3) AIH + Asc therapeutic, treated with Asc 2 h after the AIH. Plasma transaminase and immunoglobulins (measured at 8 and 24 h and 7 days after treatment) and cytokine production (IL-4, IL-10, IL-13, and IFN-γ) by splenocytes upon ConA and Asc stimulus were compared. The livers were weighed and examined histologically. In the AIH group, there was an increase in liver weight, transaminase levels, and total immunoglobulins. These parameters were reduced by 8–24 h and 7 days in the prophylactic group, but in the therapeutic group, only on day 7. The survival rate of mice in the AIH group was 38.5 %, compared to 67 % in the therapeutic Asc group. The survival rate of the animals with AIH that were prophylactically treated with Asc was 100 %. A decrease of cellular infiltration and high levels of IL-4, IL-10, and IL-13 were induced by Asc. An increase of liver fibrosis was also observed, but with less intensity with prophylactic treatment. Thus, the Ascaris components have an inhibitory effect on AIH, with an intense Th2 immune response.     

细胞因子在实验性自身免疫性脑脊髓炎耐受中的作用

细胞因子(CK)在实验性自身免疫性脑脊髓炎(EAE)的免疫机制中起着重要作用。Th细胞的不同转化决定EAE的发生、发展或抑制。由多种CK构成的免疫调节网络操纵着Th细胞的免疫应答。通过作用Th细胞使之向抑制EAE方向转化,从而寻找对EAE耐受的途径,是目前EAE研究的一个重要方面。以下就与EAE耐受相关的CK研究进行综述,探讨EAE免疫病理机制。     

Dendritic cells in tolerance induction for the treatment of autoimmune diseases

Autoimmune diseases are characterized by the loss of tolerance toward self‐antigens and the induction of destructive immune responses leading to tissue damage. Most patients with autoimmune diseases are treated with immunosuppressive drugs that suppress the immune response in a non‐specific fashion, which is inevitably accompanied by several side effects. Antigen‐specific immunomodulation and patient‐tailored therapies are likely to solve these issues and to elicit long‐term protection against disease flares. This Viewpoint analyzes the potential use of DC for induction of antigen‐specific tolerance in autoimmune disease settings.     

Antigen-specific tolerance as a therapy for experimental autoimmune encephalomyelitis.

The effects of neuroantigen-specific tolerance on the induction and effector stages of EAE were examined. Tolerance induced by the i.v. injection of syngeneic splenocytes coupled with purified neuroantigens or encephalitogenic peptides of MBP and PLP using ethylene carbodiimide was extremely effective in both prevention and treatment of acute and relapsing forms of EAE in Lewis rats and SJL/J mice. The unresponsiveness is rapidly-induced, dose-dependent, long-lasting, efficient, MHC class II-restricted, and exquisitely antigen-specific. This procedure targets only effector cells bearing clonotypic receptors specific for the autoantigen/autoepitope and thus does not depend upon the autoimmune response being dominated by a restricted T cell repertoire. Moreover, it does not require that the response to the autoantigen be dominated by recognition of a specific epitope(s) within a particular autoantigen, or even the identification of the specific autoantigen. The results also demonstrate the usefulness of peripheral tolerance induced by antigen-coupled syngeneic splenocytes for identifying the fine specificity of autoimmune T cell responses which appear to change during the progression of relapsing EAE. Thus, this technique offers major advantages over many other currently employed immunoregulatory strategies and is therefore relevant for establishment of therapeutic protocols for the antigen-specific treatment of human T cell-dependent autoimmune disorders.