Visualization of Myelin Basic Protein (Mbp) T Cell Epitopes in Multiple Sclerosis Lesions Using a Monoclonal Antibody Specific for the Human Histocompatibility Leukocyte Antigen (Hla)-Dr2–Mbp 85–99 Complex

Krogsgaard, Michelle; Wucherpfennig, Kai W.; Canella, Barbara; Hansen, Bo Moelholm; Svejgaard, A.; Pyrdol, Jason W.; Ditzel, Henrik J.; Raine, Cedric S.; Engberg, Jan; Fugger, Lars

doi:10.1084/jem.191.8.1395

Cited by 181 publications

(138 citation statements)

References 70 publications

(97 reference statements)

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“…Their antigen presentation in vivo has been demonstrated both in the normal brain and inflammatory conditions caused by LPS injection, neuronal damage or MS lesions (Andersson et al, 1992;Shrikant and Benveniste, 1996;Krogsgaard et al, 2000). To fully activate T-cells, microglia are required to express HLA/MHC with members of the B7 and/or CD40 families, the co-stimulatory molecules.…”

Section: Antigen Presentation By Microgliamentioning

confidence: 99%

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Kim

Joh²

2006

Exp Mol Med

586

458

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Inflammation, a self-defensive reaction against various pathogenic stimuli, may become harmful self-damaging process. Increasing evidence has linked chronic inflammation to a number of neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis. In the central nervous system, microglia, the resident innate immune cells play major role in the inflammatory process. Although they form the first line of defense for the neural parenchyma, uncontrolled activation of microglia may directly toxic to neurons by releasing various substances such as inflammatory cytokines (IL-1β, TNF-α, IL-6), NO, PGE2, and superoxide. Moreover, our recent study demonstrated that activated microglia phagocytose not only damaged cell debris but also neighboring intact cells. It further supports their active participation in self-perpetuating neuronal damaging cycles. In the following review, we discuss microglial responses to damaging neurons, known activators released from injured neurons and how microglia cause neuronal degeneration. In the last part, microglial activation and their role in PD are discussed in depth.

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Section: Antigen Presentation By Microgliamentioning

confidence: 99%

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Kim

Joh²

2006

Exp Mol Med

586

458

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“…Antibodies that specifically recognize class I MHC-peptide complexes have already been used in murine systems to study antigen presentation, to localize and quantify APCs displaying a T cell epitope, or as a targeting tool (16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Here, we have isolated a large panel of high-affinity human recombinant Fab antibodies endowed with the antigen-specific, MHC-restricted specificity of T cells.…”

mentioning

confidence: 99%

Direct visualization of distinct T cell epitopes derived from a melanoma tumor-associated antigen by using human recombinant antibodies with MHC- restricted T cell receptor-like specificity

Denkberg

Cohen

Lev

et al. 2002

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

123

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Specificity in the cellular immune system is controlled and regulated by the T cell antigen receptor (TCR), which specifically recognizes peptide͞major histocompatibility complex (MHC) molecules. In recent years many cancer-associated MHC-restricted peptides have been isolated and because of their highly restricted fine specificity, they are desirable targets for novel approaches in immunotherapy. Antibodies that would recognize tumor-associated MHC-peptide complexes with the same specificity as the TCR would be valuable reagents for studying antigen presentation by tumor cells, for visualizing MHCpeptide complexes on cells, and eventually for monitoring the expression of specific complexes during immunotherapy. To generate molecules with such a unique fine specificity, we selected a large nonimmune repertoire of phage Fab antibodies on recombinant HLA-A2 complexed with three common antigenic T cell, HLA-A2-restricted epitopes derived from the melanoma differentiation antigen gp100. We were able to isolate a surprisingly large panel of human recombinant Fab antibodies that exhibit a characteristic TCRlike binding specificity to each of the three gp100-derived epitopes, yet unlike TCRs, they did so with an affinity in the nanomolar range. These TCR-like antibodies recognize the native MHC-peptide complex expressed on the surface of antigen-presenting cells. Moreover, they can detect the specific MHC-peptide complexes on the surface of melanoma tumor cells. These results demonstrate the ability to isolate high-affinity human recombinant antibodies with the antigenspecific, MHC-restricted specificity of T cells, and this ability was demonstrated for three different epitopes of the same melanomaderived antigen.

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“…There were several instances in which such molecules were isolated by hybridoma technology to murine MHCpeptide complexes [46][47][48][49][50] but not against human complexes.…”

Section: Discussionmentioning

confidence: 99%

Targeting TARP, a novel breast and prostate tumor‐associated antigen, with T cell receptor‐like human recombinant antibodies

et al. 2008

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MHC class I molecules are important components of immune surveillance. There are no available methods to directly visualize and determine the quantity and distribution of MHC/ peptide complexes on individual cells or to detect such complexes on antigen-presenting cells in tissues. MHC-restricted recombinant antibodies with the same specificity of T cell receptors (TCR) may become a valuable tool to address these questions. They may also serve as valuable targeting molecules that mimic the specificity of cytotoxic T cells. We isolated by phage display a panel of human recombinant Fab antibodies with peptidespecific, MHC-restricted TCR-like reactivity directed toward HLA-A2-restricted T cell epitopes derived from a novel antigen termed TCRc alternative reading frame protein (TARP) which is expressed on prostate and breast cancer cells. We have characterized one of these recombinant antibodies and demonstrated its capacity to directly detect specific HLA-A2/ TARP T cell epitopes on antigen-presenting cells that have complexes formed by naturally occurring active intracellular processing of the antigen, as well as on the surface of tumor cells. Moreover, by genetic fusion we armed the TCR-like antibody with a potent toxin and demonstrated that it can serve as a targeting moiety killing tumor cells in a peptide-specific, MHC-restricted manner similar to cytotoxic T lymphocytes. Key words: Immunotoxin Á MHC Á Recombinant antibody Á T-cell receptor IntroductionMost patients with metastatic prostate and breast cancers are provided with the limited benefits from standard chemo-and hormone-based therapies. During the recent years, much effort has been invested in developing new approaches, such as immunotherapy, to improve the therapeutic abilities, by combining the tumor specificity of cell-mediated immunity with the freedom from toxic chemotherapies.Recent immunotherapy approaches employ the principle that CD8 + CTL recognize and kill tumor cells that display peptides from tumor-associated antigens presented by MHC class I molecules. Several tumor antigens and HLA allele-specific peptides from prostate cancer-associated antigens have been identified as CD8 + T cell epitopes, including HLA-A2-binding peptides derived from prostate-specific antigen (PSA) [1,2], prostate-specific membrane antigen (PSMA) [3], prostate stem cell antigen (PSCA) [4,5], and prostate acid phosphatase 6, which are all now components of current vaccine trials [5][6][7][8][9][10][11].Identification of new tumor-specific antigens is an essential step for the successful development of immunotherapy ap- [12][13][14]. One of these, T cell receptor gamma alternate reading frame protein (TARP), is expressed on breast and prostate cancer cells [15,16]. It was shown that TARP was expressed on >90% of cancer specimens examined [9,15]. In order to define new breast and prostate CD8 + T cell tumor antigens, two wild-type HLA-A2 epitopes from TARP were identified [17]. The wild-type sequences were also improved by sequence modifications to produce epitopeenha...

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Visualization of Myelin Basic Protein (Mbp) T Cell Epitopes in Multiple Sclerosis Lesions Using a Monoclonal Antibody Specific for the Human Histocompatibility Leukocyte Antigen (Hla)-Dr2–Mbp 85–99 Complex

Cited by 181 publications

References 70 publications

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Direct visualization of distinct T cell epitopes derived from a melanoma tumor-associated antigen by using human recombinant antibodies with MHC- restricted T cell receptor-like specificity

Targeting TARP, a novel breast and prostate tumor‐associated antigen, with T cell receptor‐like human recombinant antibodies

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