Recombinant TCR Ligand Induces Tolerance to Myelin Oligodendrocyte Glycoprotein 35-55 Peptide and Reverses Clinical and Histological Signs of Chronic Experimental Autoimmune Encephalomyelitis in HLA-DR2 Transgenic Mice

Vandenbark, Arthur A.; Rich, Cathleen; Mooney, Jeff; Zamora, Alex; Wang, Chunhe; Huan, Jianya; Fugger, Lars; Offner, Halina; Jones, Richard E.; Burrows, Gregory G.

doi:10.4049/jimmunol.171.1.127

Cited by 84 publications

(111 citation statements)

References 36 publications

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“…Moreover, the cumulative disease index that monitors the severity of the disease throughout the course of disease showed that there was a significant difference between RTL2001MII treated group vs the control group (data not shown). These results strongly suggest that only the cognate peptide/MHC complex but not the MHC moiety alone could modulate arthritogenic T cell responses, consistent with our previous studies (40,41,44).…”

Section: Rtl2001mii Treatment Reduced the Incidence And Clinical Signsupporting

confidence: 81%

“…In our previous studies, we demonstrated that both monomeric DR2-derived and I-A s -derived RTLs could protect and treat the clinical and histological signs of EAE in DR2 Tg mice (39,41) and SJL mice (40), respectively. In the current study, we used a similar approach, constructing monomeric I-A q -derived RTLs covalently linked with bCII257-270 peptide (RTL2001) (US patent no.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, we designed MHC class II derived recombinant TCR ligands (RTLs), which consist of only the minimal Ag/TCR interface in which ␣1 and ␤1 domains of MHC class II molecules were genetically linked into a single polypeptide chain (36 -39). Our previous studies showed that RTLs containing a single chain two-domain murine I-A s or HLA-DR2 class II moiety covalently linked to the immunodominant peptides of proteolipid protein (PLP139 -151) or myelin oligodendrocyte glycoprotein (MOG35-55), respectively, could reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS), and induce long-term tolerance in SJL mice (40) and HLA-DR2 Tg mice (41). In the current study, we produced a monomeric murine I-A q -derived RTL containing a single chain two-domain I-A q MHC class II molecule covalently linked to the immunogenic peptides of bCII257-270.…”

Section: R Heumatoid Arthritis (Ra)mentioning

confidence: 99%

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MHC Class II Derived Recombinant T Cell Receptor Ligands Protect DBA/1LacJ Mice from Collagen-Induced Arthritis

Huan¹,

Kaler²,

Mooney³

et al. 2008

The Journal of Immunology

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We previously demonstrated the therapeutic effects of MHC class II derived recombinant T cell receptor ligands (RTL), single-chain two domain complexes of the α1 and β1 domains of MHC class II molecules genetically linked with an immunodominant peptide, in experimental autoimmune encephalomyelitis. In the current study, we produced a monomeric murine I-Aq-derived RTL construct covalently linked with bovine collagen type II peptide (bCII257–270) suitable for use in DBA/1LacJ mice that develop collagen-induced arthritis (CIA), an animal model of human rheumatoid arthritis, after immunization with bCII protein in CFA. In this study, we demonstrate that the I-Aq-derived RTLs reduced the incidence of the disease, suppressed the clinical and histological signs of CIA and induced long-term modulation of T cells specific for arthritogenic Ags. Our results showed that the I-Aq/bCII257–270 molecule could systemically reduce proinflammatory IL-17 and IFN-γ production and significantly increase anti-inflammatory IL-10, IL-13, and FoxP3 gene expression in splenocytes. Moreover, I-Aq/bCII257–270 molecule could also selectively inhibit IL-1β, IL-6, and IL-23 expression in local joint tissue. This is the first report demonstrating effective prevention of joint inflammation and clinical signs of CIA with an I-Aq-derived RTL, thus supporting the possible clinical use of this approach for treating rheumatoid arthritis in humans.

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Section: Rtl2001mii Treatment Reduced the Incidence And Clinical Signsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: R Heumatoid Arthritis (Ra)mentioning

confidence: 99%

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MHC Class II Derived Recombinant T Cell Receptor Ligands Protect DBA/1LacJ Mice from Collagen-Induced Arthritis

Huan¹,

Kaler²,

Mooney³

et al. 2008

The Journal of Immunology

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“…WNV T-cell ligand sequences were identified by use of HLA transgenic mice, a leading animal model system for analysis of HLA-restricted T-cell responses to human pathogens (4,12,25,40,41,43,49,63,65), as follows: H-2 class II deficient, HLA-DR2 (DRB1*1501) (68), HLA-DR3 (DRB1*0301) (29,64), and HLA-DR4 (DRB1*0401)/human CD4 (huCD4) (6,10); and H-2 class I deficient, HLA-A2.1 (A*0201) (HHD monochain) (44), HLA-A24 (A*2402)/huCD8␣ (F. Lemonnier unpublished data), and HLA-B7 (B*0702) (51). HLA-DR2 transgenic mice express chimeric molecules, with ␣1 and ␤1 domains encoded by the HLA-DRA1*0101 and -DRB1*1501 sequences and the other domains encoded by I-E␣ and I-E␤ sequences from the I-E promoters (68). HLA-DR3 transgenic mice express the full-length HLA-DRA1*0101 and -DRB1*0301 sequences (29,64).…”

Section: Methodsmentioning

confidence: 99%

West Nile Virus T-Cell Ligand Sequences Shared with Other Flaviviruses: a Multitude of Variant Sequences as Potential Altered Peptide Ligands

Jung

Khan

Tan

et al. 2012

J Virol

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West Nile virus (WNV), a member of the genus Flavivirus, is a mosquito-borne RNA pathogen closely related to numerous other flaviviruses of the Japanese encephalitis (JE) group, and to a lesser degree to Dengue virus (DENV), Yellow fever virus (YFV), and several other flaviviruses of about 70 different species (5, 18). The genome is a positive-sense, single-stranded RNA of approximately 10,293 nucleotides encoding a polyprotein of approximately 3,430 amino acids (aa) that is cleaved to produce three structural proteins, capsid (C), precursor membrane (prM), and envelope (E), and seven nonstructural (NS) proteins, NS1, 2a, 2b,3, 4a, 4b, and 5 (24,37). Originally isolated in Africa in 1937 (62), WNV has become an increasingly important human pathogen widely endemic in Africa, Asia, Europe, and North America and a significant agent of viral encephalitis (28,38,45). WNV and several of the major human pathogen flaviviruses are known to cocirculate (28, 71); for example, WNV and St. Louis encephalitis virus (LEV) in North America; WNV, DENV, and Japanese encephalitis virus (JEV) around the Indian subcontinent and portions of Southeast Asia (SEA); and WNV, DENV, JEV, and Murray Valley encephalitis virus (MVE) in neighboring pockets of SEA and Australasia.The widespread colocalization of WNV with other flaviviruses calls for a greater understanding of the phylogenetic relatedness and possible pathophysiologic associations of flaviviruses. We previously reported a large-scale analysis of the conservation and variability of overlapping nonamers, the typical length of human leukocyte antigen (HLA) class I or class II binding cores of T-cell epitopes (47), of the 2,746 WNV protein sequences collected from the NCBI Entrez Protein Database (17). Notably, of the 88 completely conserved sequence fragments identified, representing 34% of the WNV proteome, 67 were also present in many other flaviviruses with identities of nine or more amino acids. These sequence homologies called attention to a broad inter-Flavivirus risk of altered peptide ligands (APL) (58), T-cell epitopes with one or more amino acid differences, that possibly would result in modified immune responses in the event of exposure to multiple Flavivirus pathogens.This study focused on analyses of the diversity and presence in

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“…HLA-DR2b transgenic mice bearing chimeric MHC class II molecules consisting of the a1 and h1 sequences of HLA-DRA1*0101 and HLA-DRB1*1501 and the a2 and h2 domains of IEa and IEb, respectively, were developed as previously described (12,13 [171][172][173][174][175][176][177][178][179][180][181][182][183][184][185][186][187][188][189][190] presented by autologous DC. CD4 T-cell lines were generated from PBMC of granulomatous prostatitis patients by multiple stimulations with peptide PSA [171][172][173][174][175][176][177][178][179][180][181][182][183][184][185][186][187][188][189][190] in the presence of irradiated autologous PBMC.…”

Section: Methodsmentioning

confidence: 99%

Identification of HLA-DRB1*1501–Restricted T-cell Epitopes from Prostate-Specific Antigen

Klyushnenkova

Link

Oberle

et al. 2005

Clinical Cancer Research

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The development of immunotherapy for prostate cancer based on the induction of autoimmunity to prostate tissue is very attractive because prostate is not a vital organ beyond the reproductive years. CD4 Tcells play an important role in the development of antitumor immune responses, yet the identification of naturally processed MHC Class II^restricted epitopes derived from prostate differentiation antigens has not been described. To facilitate the search for prostate-specific antigen (PSA)^derived MHC class II^restricted peptides, we immunized mice transgenic for HLA-DRB1*1501 with human PSA and showed a robust dose-dependent immune response to the antigen. Screening a library of overlapping 20-mer peptides that span the entire PSA sequence identified two 20-mer peptides, PSA [171][172][173][174][175][176][177][178][179][180][181][182][183][184][185][186][187][188][189][190] and PSA 221-240 , which were responsible for this reactivity. Immunization of DR2b transgenic mice with these peptides induced specific responses to the peptide and whole PSA. Identified peptides were used to stimulate CD4 T cells from HLA-DRB1*1501+ patients with a rare condition, granulomatous prostatitis, and who seem to have a preexisting immune response directed against the prostate gland. We previously showed a linkage of granulomatous prostatitis to HLA-DRB1*1501, suggesting that this disease may have an autoimmune etiology. Peptide-specific CD4 T-cell lines were generated from the peripheral blood of these patients as well as one patient with prostate cancer. These lines also recognized whole, processed PSA in the context of HLA-DRB1*1501. This study will be instrumental in understanding the interaction between circulating self-reactive T cells, organ-specific autoimmunity, and antitumor immune response. The use of these peptides for the immunotherapy of prostate cancer is under investigation.

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Recombinant TCR Ligand Induces Tolerance to Myelin Oligodendrocyte Glycoprotein 35-55 Peptide and Reverses Clinical and Histological Signs of Chronic Experimental Autoimmune Encephalomyelitis in HLA-DR2 Transgenic Mice

Cited by 84 publications

References 36 publications

MHC Class II Derived Recombinant T Cell Receptor Ligands Protect DBA/1LacJ Mice from Collagen-Induced Arthritis

MHC Class II Derived Recombinant T Cell Receptor Ligands Protect DBA/1LacJ Mice from Collagen-Induced Arthritis

West Nile Virus T-Cell Ligand Sequences Shared with Other Flaviviruses: a Multitude of Variant Sequences as Potential Altered Peptide Ligands

Identification of HLA-DRB1*1501–Restricted T-cell Epitopes from Prostate-Specific Antigen

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