Limits...
Induction and suppression of an autoimmune disease by oligomerized T cell epitopes: enhanced in vivo potency of encephalitogenic peptides.

Falk K, Rötzschke O, Santambrogio L, Dorf ME, Brosnan C, Strominger JL - J. Exp. Med. (2000)

Bottom Line: In this study, we show that the encephalitogenic effect of these epitopes when injected subcutaneously in complete Freund's adjuvant was significantly enhanced if administered to the animal in a multimerized form as a T cell epitope oligomer (i.e., as multiple repeats of the peptide epitope, such as 16-mers).Importantly, the specific suppressive effect of oligomer treatment was also evident if EAE was induced with spinal cord homogenate instead of the single peptide antigen.By contrast, the PLP139-151 peptide accelerated rather than retarded the progression of disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

ABSTRACT
T cell epitope peptides derived from proteolipid protein (PLP139-151) or myelin basic protein (MBP86-100) induce experimental autoimmune encephalomyelitis (EAE) in "susceptible" strains of mice (e.g., SJL/J). In this study, we show that the encephalitogenic effect of these epitopes when injected subcutaneously in complete Freund's adjuvant was significantly enhanced if administered to the animal in a multimerized form as a T cell epitope oligomer (i.e., as multiple repeats of the peptide epitope, such as 16-mers). Oligomer-treated SJL/J mice developed EAE faster and showed a more severe progression of the disease than animals treated with peptide alone. In addition, haplotype-matched B10.S mice, "resistant" to EAE induction by peptide, on injection of 16-mers developed a severe form of EAE. Even more striking, however, was the dramatic suppression of incidence and severity of the disease, seen after single intravenous injections of only 50 microg of the PLP139-151 16-mer, administered to SJL/J mice 7 d after the induction of the disease. Although relapse occurred at about day 45, an additional injection several days before that maintained the suppression. Importantly, the specific suppressive effect of oligomer treatment was also evident if EAE was induced with spinal cord homogenate instead of the single peptide antigen. By contrast, the PLP139-151 peptide accelerated rather than retarded the progression of disease.

Show MeSH

Related in: MedlinePlus

Specificity of EAE suppression by intravenous injections of PLP139–151(C140S) 16-mers. SJL/J mice received intravenous injections of 50 μg PLP139–151(C140S) peptide or PLP139–151(C140S) 16-mer 7 d after the induction of the disease by the subcutaneous injection of 50 μg PLP178–191(C183S) (top) or PLP139–151(C140S) peptide (bottom). Groups of six mice were used for the experiment. The incidence rates were determined as 6/6 (peptide) and 6/6 (16-mer) for the groups immunized with the PLP178–191(C183S) peptide and as 6/6 (peptide) and 4/6 (16-mer) for the groups immunized with the PLP139–151(C140S) peptide.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2195838&req=5

Figure 7: Specificity of EAE suppression by intravenous injections of PLP139–151(C140S) 16-mers. SJL/J mice received intravenous injections of 50 μg PLP139–151(C140S) peptide or PLP139–151(C140S) 16-mer 7 d after the induction of the disease by the subcutaneous injection of 50 μg PLP178–191(C183S) (top) or PLP139–151(C140S) peptide (bottom). Groups of six mice were used for the experiment. The incidence rates were determined as 6/6 (peptide) and 6/6 (16-mer) for the groups immunized with the PLP178–191(C183S) peptide and as 6/6 (peptide) and 4/6 (16-mer) for the groups immunized with the PLP139–151(C140S) peptide.

Mentions: The effect of peptide treatment on enhancing instead of suppressing the disease progression could not be overcome by an increase in dosage. Even when 250 μg was administered to the animals, no reverse in the trend was apparent (data not shown). On the other hand, with the 16-mer a single injection of 50 μg on day 7 was found to be sufficient to produce a strong suppression (Fig. 7, bottom). At this time point, only very little submeningeal, perivascular infiltration was evident in brain sections taken from SJL/J mice immunized with the peptide (data not shown). However, the effect of the 16-mer was found to be highly specific, and no suppression was evident if the disease was induced with the PLP178–191 peptide (Fig. 7, top) instead of the PLP139–151 peptide (Fig. 7, bottom). Similar results were also obtained with MBP antigens containing the epitopes MBP86–100 and MBP86–101 (Fig. 8). Only a relatively modest suppression was observed after an injection of 100 μg of MBP86–100 16-mer on days 3 and 7 (triangles, top). The effect was greatly enhanced after using a 16-mer containing the more antigenic epitope MBP86–101 at an increased dosage (200 μg) on days 8 and 12. Also in the MBP system, the intravenous treatment with peptides had little or no effect (filled circles).


Induction and suppression of an autoimmune disease by oligomerized T cell epitopes: enhanced in vivo potency of encephalitogenic peptides.

Falk K, Rötzschke O, Santambrogio L, Dorf ME, Brosnan C, Strominger JL - J. Exp. Med. (2000)

Specificity of EAE suppression by intravenous injections of PLP139–151(C140S) 16-mers. SJL/J mice received intravenous injections of 50 μg PLP139–151(C140S) peptide or PLP139–151(C140S) 16-mer 7 d after the induction of the disease by the subcutaneous injection of 50 μg PLP178–191(C183S) (top) or PLP139–151(C140S) peptide (bottom). Groups of six mice were used for the experiment. The incidence rates were determined as 6/6 (peptide) and 6/6 (16-mer) for the groups immunized with the PLP178–191(C183S) peptide and as 6/6 (peptide) and 4/6 (16-mer) for the groups immunized with the PLP139–151(C140S) peptide.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195838&req=5

Figure 7: Specificity of EAE suppression by intravenous injections of PLP139–151(C140S) 16-mers. SJL/J mice received intravenous injections of 50 μg PLP139–151(C140S) peptide or PLP139–151(C140S) 16-mer 7 d after the induction of the disease by the subcutaneous injection of 50 μg PLP178–191(C183S) (top) or PLP139–151(C140S) peptide (bottom). Groups of six mice were used for the experiment. The incidence rates were determined as 6/6 (peptide) and 6/6 (16-mer) for the groups immunized with the PLP178–191(C183S) peptide and as 6/6 (peptide) and 4/6 (16-mer) for the groups immunized with the PLP139–151(C140S) peptide.
Mentions: The effect of peptide treatment on enhancing instead of suppressing the disease progression could not be overcome by an increase in dosage. Even when 250 μg was administered to the animals, no reverse in the trend was apparent (data not shown). On the other hand, with the 16-mer a single injection of 50 μg on day 7 was found to be sufficient to produce a strong suppression (Fig. 7, bottom). At this time point, only very little submeningeal, perivascular infiltration was evident in brain sections taken from SJL/J mice immunized with the peptide (data not shown). However, the effect of the 16-mer was found to be highly specific, and no suppression was evident if the disease was induced with the PLP178–191 peptide (Fig. 7, top) instead of the PLP139–151 peptide (Fig. 7, bottom). Similar results were also obtained with MBP antigens containing the epitopes MBP86–100 and MBP86–101 (Fig. 8). Only a relatively modest suppression was observed after an injection of 100 μg of MBP86–100 16-mer on days 3 and 7 (triangles, top). The effect was greatly enhanced after using a 16-mer containing the more antigenic epitope MBP86–101 at an increased dosage (200 μg) on days 8 and 12. Also in the MBP system, the intravenous treatment with peptides had little or no effect (filled circles).

Bottom Line: In this study, we show that the encephalitogenic effect of these epitopes when injected subcutaneously in complete Freund's adjuvant was significantly enhanced if administered to the animal in a multimerized form as a T cell epitope oligomer (i.e., as multiple repeats of the peptide epitope, such as 16-mers).Importantly, the specific suppressive effect of oligomer treatment was also evident if EAE was induced with spinal cord homogenate instead of the single peptide antigen.By contrast, the PLP139-151 peptide accelerated rather than retarded the progression of disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

ABSTRACT
T cell epitope peptides derived from proteolipid protein (PLP139-151) or myelin basic protein (MBP86-100) induce experimental autoimmune encephalomyelitis (EAE) in "susceptible" strains of mice (e.g., SJL/J). In this study, we show that the encephalitogenic effect of these epitopes when injected subcutaneously in complete Freund's adjuvant was significantly enhanced if administered to the animal in a multimerized form as a T cell epitope oligomer (i.e., as multiple repeats of the peptide epitope, such as 16-mers). Oligomer-treated SJL/J mice developed EAE faster and showed a more severe progression of the disease than animals treated with peptide alone. In addition, haplotype-matched B10.S mice, "resistant" to EAE induction by peptide, on injection of 16-mers developed a severe form of EAE. Even more striking, however, was the dramatic suppression of incidence and severity of the disease, seen after single intravenous injections of only 50 microg of the PLP139-151 16-mer, administered to SJL/J mice 7 d after the induction of the disease. Although relapse occurred at about day 45, an additional injection several days before that maintained the suppression. Importantly, the specific suppressive effect of oligomer treatment was also evident if EAE was induced with spinal cord homogenate instead of the single peptide antigen. By contrast, the PLP139-151 peptide accelerated rather than retarded the progression of disease.

Show MeSH
Related in: MedlinePlus