In vivo effects of antibodies to immune response gene products: prevention of experimental allergic encephalitis.

Steinman, Lawrence; Rosenbaum, James T.; Subramaniam, Sriram; McDevitt, Hugh O.

doi:10.1073/pnas.78.11.7111

Cited by 196 publications

(88 citation statements)

References 26 publications

(12 reference statements)

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“…Several lines of evidence support our contention. Similar to this study using TLD-4A2 mAb, several earlier reports have demonstrated EAE inhibition using purified mAb against a series of immunologically important molecules including: MHC class II molecules (Sriram and Steinman, 1983;Steinman et al, 1981), the T cell receptor (Zaller et al, 1990), CD4, ICAM-1 (Archelos et al, 1993), VLA-4 (Baron et al, 1993;Kent et al, 1995;Yednock et al, 1992) CR3 (Huitinga et al, 1993), CD28 , and the CD40L (gp39) (Gerrotse et al, 1996). Yet all of these other molecules have molecular weights, cellular distributions, and flow cytometry profiles distinct from the 4A2 molecule.…”

Section: Williams Et Alsupporting

confidence: 76%

Inhibition of Experimental Allergic Encephalomyelitis with an Antibody that Recognizes a Novel Antigen Expressed on Lymphocytes, Endothelial Cells, and Microglia

Williams

Zhao

Politopoulou³

et al. 2000

Laboratory Investigation

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SUMMARY:Experimental allergic encephalomyelitis (EAE) is a frequently employed animal model of the human disease multiple sclerosis. EAE can be induced by adoptive transfer of CD4 ϩ T cells that are specific for central nervous system (CNS) antigens, typically myelin proteins. Although the pathogenic mechanism or mechanisms responsible for the clinical signs and histological changes in EAE and multiple sclerosis are not fully defined, the entry of T lymphocytes and antigen recognition within the CNS are required. The present study describes the participation of a novel cell surface molecule with properties suggesting a role in cell-cell adhesion or co-stimulation, or both, in the development of EAE in the rat. The molecule is defined by the unique monoclonal antibody (mAb) TLD-4A2. The TLD-4A2 antigen is present on resting and activated T lymphocytes, activated CNS endothelial cells, and microglia. The antigen is normally distributed in many tissues including lymph node, thymus, and spleen, as well as in the inflamed CNS. Both its pattern of tissue distribution and immunoprecipitation and immunoblotting studies suggest that the TLD-4A2 antigen is a novel molecule. Treatment of rats with the purified 4A2 mAb resulted in the inhibition of the clinical signs of EAE and also decreased the number T cells and macrophages accumulating in the CNS parenchyma. TLD-4A2 antibody did not seem to directly interfere with T cell viability in vivo, as demonstrated by the ability to recover and stimulate CD4 ϩ encephalitogenic T cells from cervical lymph nodes of 4A2-treated animals. In vitro, the antibody partially blocked T cell proliferation assays. These data suggest that the TLD-4A2 mAb recognizes a novel molecule expressed on lymphocytes, endothelial cells, and macrophages that may play a role in hematogenous cell traffic and the initiation of CNS inflammation. (Lab Invest 2000, 80:313-326).

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Section: Williams Et Alsupporting

confidence: 76%

Inhibition of Experimental Allergic Encephalomyelitis with an Antibody that Recognizes a Novel Antigen Expressed on Lymphocytes, Endothelial Cells, and Microglia

Williams

Zhao

Politopoulou³

et al. 2000

Laboratory Investigation

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“…antibodies to block immune responses strongly suggest that Ia antigens are the products of immune response (Ir) genes (3)(4)(5), but how a limited number of Ia molecules differentially regulate responses to a myriad of antigens is yet to be resolved. It seems likely that their role in the presentation of antigen to imtnunocompetent cells is of fundamental importance and that primary structural alterations in the a and (3 chains of the class II heterodimer result in a failure to present antigen in a configuration appropriate for recognition.…”

mentioning

confidence: 99%

Sequence analysis and structure-function correlations of murine q, k, u, s, and f haplotype I-A beta cDNA clones.

Estess¹,

Begovich²,

Koo³

et al. 1986

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

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100

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domain variability is clustered into three discrete regions, two of which divide the Ap chains into subgroups, suggesting an evolutionary history for the separation of alleles in inbred strains of mice. The amino acid sequences of these five chains are compared to each other and to previously published I-Ap chains. Correlations are made between the primary structural differences and the serologic and immune response characteristics mapping to the I-A subregion.The intimate relationship between I-region associated (Ia) antigens and immune responsiveness to a multitude of natural and synthetic antigens has been known for some time (1, 2).Recent studies using either anti-Ia antisera or monoclonal antibodies to block immune responses strongly suggest that Ia antigens are the products of immune response (Ir) genes (3-5), but how a limited number of Ia molecules differentially regulate responses to a myriad of antigens is yet to be resolved. It seems likely that their role in the presentation of antigen to imtnunocompetent cells is of fundamental importance and that primary structural alterations in the a and (3 chains of the class II heterodimer result in a failure to present antigen in a configuration appropriate for recognition. These alterations must also account for the multiple epitopes recognized by both anti-Ia antibodies and alloreactive T cells.In an effort to address the nature of primary structural differences among class II molecules and how these differences affect immune responses, we have undertaken the cloning and sequencing of cDNAs encoding I-Ap chains from several mouse haplotypes. This should facilitate the eventual assignment of particular serologic epitopes and restriction elements to specific amino acids in these chains. Such analysis is a first step in designing experiments in which immune responsiveness can be manipulated via structural alterations in Ia molecules and then, perhaps, understood. Clones hybridizing to the human DQp or the murine Al cDNA probes were tested for the presence of restriction enzyme sites consistent with AP but not Ed coding sequences (9). The longest such clones were subcloned into the EcoRI site ofpBR322 and from there into the EcoRI site of M13 mp8 for sequencing. Sequencing was performed by the dideoxysequencing method of Biggin et al. (10). All clones were sequenced using the M13 universal primer (UP) from the EcoRI ends, as shown in Fig. 1. In addition, five 18-bp synthetic oligonucleotide primers homologous to conserved regions of the known AP and DQO sequences (8,(11)(12)(13)(14) were constructed and used to obtain sequence information on portions of the clones inaccessible from the EcoRI ends (Fig. 1, B-H productive (8, 9, 11-17). MATERIALS AND METHODS

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“…In Lewis rats, the recognition of MBP 68-88 in the context of I-A by encephalitogenic clones is carried out by T cell receptors (TCRs) homologous to VJ3 8.2 and Va 2. Restriction in TCR usage in pathogenic clones provided a rationale for therapies that prevent and reverse EAE with MHC class II-specific, or V,3 specific monoclonal antibodies (6)(7)(8). The third complementarity determining region (CDR3) of TCR 1# chains expressed by these clones also show similarities, with conserved deduced amino acid motifs of DSGNTE, DSSNTE, or related sequences repeatedly observed in the rat clones responsive to MBP 68-88.…”

Section: Introductionmentioning

confidence: 90%

Homologies between T cell receptor junctional sequences unique to multiple sclerosis and T cells mediating experimental allergic encephalomyelitis.

et al. 1994

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In vivo effects of antibodies to immune response gene products: prevention of experimental allergic encephalitis.

Cited by 196 publications

References 26 publications

Inhibition of Experimental Allergic Encephalomyelitis with an Antibody that Recognizes a Novel Antigen Expressed on Lymphocytes, Endothelial Cells, and Microglia

Inhibition of Experimental Allergic Encephalomyelitis with an Antibody that Recognizes a Novel Antigen Expressed on Lymphocytes, Endothelial Cells, and Microglia

Sequence analysis and structure-function correlations of murine q, k, u, s, and f haplotype I-A beta cDNA clones.

Homologies between T cell receptor junctional sequences unique to multiple sclerosis and T cells mediating experimental allergic encephalomyelitis.

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