DNA Fragments of the Human 60-kDa Heat Shock Protein (HSP60) Vaccinate Against Adjuvant Arthritis: Identification of a Regulatory HSP60 Peptide

Quintana, Francisco J.; Carmi, Pnina; Mor, Felix; Cohen, Irun R.

doi:10.4049/jimmunol.171.7.3533

Cited by 84 publications

(99 citation statements)

References 39 publications

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“…Here we describe NPs designed to coadminister a tissue specific antigen (i.e., MOG ) and an AhR ligand (i.e., ITE) to induce tolerogenic APCs that promote the differentiation of CNS-specific Tregs and suppress the development of EAE. Methods based on DNA vaccination (33,34), oral (35), nasal (36), and transdermal (37) tolerization, or administration of antigen coupled to red blood cells (38) have also been developed to expand antigen-specific Tregs, and their translational relevance is now being investigated in clinical trials. However, compared with other methods for antigen delivery, an advantage of NPs is their ability to codeliver target antigens in combination with well-defined tolerogenic small molecules to control APC activity.…”

Section: Discussionmentioning

confidence: 99%

Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis

Yeste

Nadeau²,

Burns³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The immune response is normally controlled by regulatory T cells (Tregs). However, Treg deficits are found in autoimmune diseases, and therefore the induction of functional Tregs is considered a potential therapeutic approach for autoimmune disorders. The activation of the ligand-activated transcription factor aryl hydrocarbon receptor by 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) or other ligands induces dendritic cells (DCs) that promote FoxP3 + Treg differentiation. Here we report the use of nanoparticles (NPs) to coadminister ITE and a T-cell epitope from myelin oligodendrocyte glycoprotein (MOG) M ultiple sclerosis (MS) is an autoimmune disease driven by an immune response directed against antigens in the CNS (1). The autoreactive components of the immune system are normally under the control of specialized regulatory T cells (Tregs); of particular importance are FoxP3 + (2) and IL-10 + Tregs (3). Treg deficits have been found in MS and other autoimmune diseases (4, 5). Conversely, Tregs have been shown to arrest the development of several experimental models of autoimmune disease (5). Thus, the induction of antigen-specific tolerance is considered a promising approach for the treatment of MS and other autoimmune disorders (6).As a result of our studies on immunoregulation in the zebrafish (7), we found that the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) controls the differentiation of FoxP3 + and IL-10 + Tregs and Th17 cells in mice and humans (8)(9)(10)(11)(12). AhR activation with the nontoxic mucosal ligand 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) expands Tregs and suppresses EAE (11). We (11) and others (13)(14)(15) showed that the generation of Tregs by AhR ligands involves the induction of tolerogenic dendritic cells (DCs). Indeed, the activation of AhR signaling in DCs by ITE or other ligands induces DCs that promote FoxP3 + Treg differentiation (11,(13)(14)(15). Nanoparticles (NPs) have unique features that prompted their use in medicine. For example, NPs have been used for in vivo tumor detection and targeting (16) and for the delivery of antiangiogenic compounds (17). NPs have also been used to induce pathogen-specific immunity in vaccination regimens (18,19). In the context of the therapeutic management of inflammation, NPs have been recently used to deliver siRNAs to silence ccr2 expression and prevent the accumulation of inflammatory monocytes at sites of inflammation (20). However, the use of NPs to induce antigen-specific tolerance and treat autoimmune disorders remains largely unexplored.In this work, we report the use of NPs to coadminister ITE and the T-cell epitope from myelin oligodendrocyte protein located between residues 35 and 55 to promote the generation of CNSspecific Tregs by DCs. NP-treated DCs displayed a tolerogenic phenotype and promoted the differentiation of Tregs. Moreover, NPs carrying ITE and a peptide corresponding to residues 35-55 of the myelin oligodendrocyte glycoprotein ) ex...

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Section: Discussionmentioning

confidence: 99%

Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis

Yeste

Nadeau²,

Burns³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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267

277

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“…It has been suggested that CD4 ϩ regulatory T cell responses may be induced through interaction with certain T cell markers loosely and collectively called ''ergotopes'' (7,11,12). There have been some indications that T cell activation molecules such as IL-2 receptor and heat-shock protein 60 may be among candidate ergotopes (11)(12)(13)(14). It has been a topic of great interest to characterize the nature and functional properties of human CD4 ϩ regulatory T cell responses induced by T cell vaccination in clinical trials because the findings would have direct implication in the understanding of the potential therapeutic role of T cell vaccination in human autoimmune conditions.…”

Section: Mmunization With Inactivated Autoreactive T Cells (T Cell mentioning

confidence: 99%

CD4⁺regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis

Hong

Zang²,

Nie³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Immunization with irradiated autologous T cells (T cell vaccination (3,6,8). CD8 ϩ antiidiotypic T cell response is thought to contribute directly to depletion of circulating autoreactive T cells (3,5,9). It was also evident in a number of studies that in addition to CD8 ϩ antiidiotypic T cells, T cell vaccination induces CD4 ϩ regulatory T cell responses in both experimental autoimmune encephalomyelitis and human MS (7, 10). CD4 ϩ regulatory T cell responses may represent an important immune regulatory component relevant to clinical effects of T cell vaccination (7, 9, 11). However, the nature and functional properties of these CD4 ϩ regulatory T cells are poorly understood. It has been suggested that CD4 ϩ regulatory T cell responses may be induced through interaction with certain T cell markers loosely and collectively called ''ergotopes'' (7, 11, 12). There have been some indications that T cell activation molecules such as IL-2 receptor and heat-shock protein 60 may be among candidate ergotopes (11)(12)(13)(14). It has been a topic of great interest to characterize the nature and functional properties of human CD4 ϩ regulatory T cell responses induced by T cell vaccination in clinical trials because the findings would have direct implication in the understanding of the potential therapeutic role of T cell vaccination in human autoimmune conditions. This study was undertaken to characterize CD4 ϩ regulatory T cell responses in patients with MS that received immunization through multiple s.c. injections with irradiated autologous myelin basic protein (MBP)-reactive T cell lines in a previous clinical trial (15). Substantial CD4 ϩ regulatory T cell responses were observed in all MS patients after three immunizations, which correlated with clinical improvement in some of the patients, with respect to disability score, rate of relapse, and brain lesions by magnetic resonance imaging (15). A panel of CD4 ϩ regulatory T cell lines was raised against autologous MBP-reactive T cells originally used for immunization. We first determined whether CD4 ϩ regulatory T cell responses induced by T cell vaccination represented heterogeneous populations of distinctive functional and phenotypic patterns. Experiments were designed to define whether a proportion of the resulting CD4 ϩ regulatory T cell lines expanded from the CD4 ϩ CD25 ϩ Foxp3 ϩ regulatory T cell pool, a hypothesis proposed in this study. Attempts were made to further address whether human CD4 ϩ regulatory T cells induced by T cell vaccination shared the features of antiergotypic T cells seen in experimental animal models in recognition of candidate ergotopes. The findings described here support the important role of CD4 ϩ regulatory T cell responses in T cell vaccination, which may have therapeutic relevance in MS. Results CD4 ؉ Regulatory T Cell Responses Induced by T Cell Vaccination inPatients with MS. Blood specimens were obtained from MS patients that received multiple s.c. injections of irradiated autologous MBPreactive T cells in a previous clinical tri...

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“…This proposition is further supported by the finding that the challenge of naive LEW rats with a low nonarthritogenic dose of DDA leads not only to protection against subsequent disease triggered by injection of a higher arthritogenic dose of DDA, but also to spontaneous induction of T cell response to one of the above-mentioned peptides of Rhsp65, peptide 213-227. However, considering that our pepscan consists of a limited number of Rhsp65 peptides, it is likely that other yet undefined epitopes within Rhsp65, which might be similar to that within human hsp60 (32,33), might also contribute to regulation of acute DIA. The above results are supported by the observations in the AA model (32,33,50) and those in patients with juvenile chronic arthritis (51) regarding the role of self mammalian hsp65 in regulation of arthritis.…”

Section: Discussionmentioning

confidence: 99%

“…However, considering that our pepscan consists of a limited number of Rhsp65 peptides, it is likely that other yet undefined epitopes within Rhsp65, which might be similar to that within human hsp60 (32,33), might also contribute to regulation of acute DIA. The above results are supported by the observations in the AA model (32,33,50) and those in patients with juvenile chronic arthritis (51) regarding the role of self mammalian hsp65 in regulation of arthritis. In addition, LEW rats with DIA develop an Ab response to Rhsp65.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, the mammalian homologues of Bhsp65, self (rat) hsp65 (Rhsp65), and human hsp60 have been shown to possess disease-regulating properties, as tested in the adjuvant arthritis (AA) model (32,33). Considering that DDA can induce an inflammatory reaction, we reasoned that Rhsp65, whose expression is up-regulated by inflammation, might serve as one of the endogenous Ags for priming of the T cell response in DIA.…”

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confidence: 99%

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Heat Shock Protein 65-Reactive T Cells Are Involved in the Pathogenesis of Non-Antigenic Dimethyl Dioctadecyl Ammonium Bromide-Induced Arthritis

Mia

Durai

Kim

et al. 2005

The Journal of Immunology

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Dimethyl dioctadecyl ammonium bromide (DDA) (C38H80NBr) is a nonantigenic lipoid material. DDA-induced arthritis (DIA) in the Lewis (LEW) (RT.1l) rat is a new experimental model for human rheumatoid arthritis (RA). DIA is a T cell-mediated autoimmune disease. However, the precise self/foreign Ags associated with the disease process in DIA are not yet known. We observed that LEW rats with DIA spontaneously raised a vigorous T cell response both to 65-kDa self (rat) heat shock protein (Rhsp65) and mycobacterial hsp65 (Bhsp65), but not to another arthritis-related Ag, bovine collagen type II. The T cell response to Rhsp65 was focused predominantly on determinant regions 120–134 and 213–227 of the self protein. Interestingly, pretreatment of adult LEW rats using either a mixture of peptides 120–134 and 213–227 of Rhsp65 or a low nonarthritogenic dose of DDA induced protection against subsequent DIA. Intriguingly, the protection induced by the latter was associated with spontaneous priming of T cells specific for peptide 213–227 of Rhsp65. Similarly, LEW rats neonatally tolerized against either Rhsp65 or Bhsp65 were significantly protected from subsequently induced DIA at adult stage, showing the disease-modulating attribute of the hsp65-specific T cells. Taken together, the above findings demonstrate that the hsp65-directed T cell repertoire is of significance in the pathogenesis of autoimmune arthritis induced by nonantigenic DDA. Like other animal models of RA involving hsp65, these first insights into the disease-associated Ags in the DIA model would pave the way for further understanding of the immunological aspects of induction and regulation of RA.

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DNA Fragments of the Human 60-kDa Heat Shock Protein (HSP60) Vaccinate Against Adjuvant Arthritis: Identification of a Regulatory HSP60 Peptide

Cited by 84 publications

References 39 publications

Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis

Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis

CD4⁺regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis

Heat Shock Protein 65-Reactive T Cells Are Involved in the Pathogenesis of Non-Antigenic Dimethyl Dioctadecyl Ammonium Bromide-Induced Arthritis

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DNA Fragments of the Human 60-kDa Heat Shock Protein (HSP60) Vaccinate Against Adjuvant Arthritis: Identification of a Regulatory HSP60 Peptide

Cited by 84 publications

References 39 publications

Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis

Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis

CD4+regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis

Heat Shock Protein 65-Reactive T Cells Are Involved in the Pathogenesis of Non-Antigenic Dimethyl Dioctadecyl Ammonium Bromide-Induced Arthritis

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CD4⁺regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis