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Tolerance induction and autoimmune encephalomyelitis amelioration after administration of myelin basic protein-derived peptide.

Marusić S, Tonegawa S - J. Exp. Med. (1997)

Bottom Line: Subcutaneous injection of p17 (a peptide consisting of 17 NH2-terminal aminoacids of MBP) in complete Freund's adjuvant (CFA) causes paralysis.In addition, ongoing paralysis is ameliorated by subsequent intraperitoneal injection of p17 in IFA.Tolerance induction by p17 seems to be based on reduction in the responsiveness of anti-MBP T cells, as documented by lower overall antigen-induced lymphokine production and proliferation, as well as diminished upregulation of early activation marker CD69 by tolerized T cells.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

ABSTRACT
Experimental autoimmune encephalomyelitis (EAE), a demyelinating disease of the central nervous system, is an animal model of paralyzing human disease, multiple sclerosis. EAE is readily induced by immunization with myelin basic protein (MBP) in mice transgenic for an alphabeta T cell receptor (TCR) that is specific for MBP. Subcutaneous injection of p17 (a peptide consisting of 17 NH2-terminal aminoacids of MBP) in complete Freund's adjuvant (CFA) causes paralysis. Induction of paralysis is inhibited by prior intraperitoneal injection of the same peptide in incomplete Freund's adjuvant (IFA). In addition, ongoing paralysis is ameliorated by subsequent intraperitoneal injection of p17 in IFA. Tolerance induction is equally efficient in Fas-deficient and IL-4-deficient TCR-transgenic mice, suggesting that neither activation-induced cell death nor differentiation into Th2 type cells plays a role in the tolerance induction. Tolerance induction by p17 seems to be based on reduction in the responsiveness of anti-MBP T cells, as documented by lower overall antigen-induced lymphokine production and proliferation, as well as diminished upregulation of early activation marker CD69 by tolerized T cells. We propose that continuous encounters of MBP-specific T cells with p17 play a critical role in the induction and maintenance of tolerance.

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(A) A single intraperitoneal or five subcutaneous, but not a  single subcutaneous injection of p17 in IFA prevents EAE. On day −14,  mice were either left untreated (open squares) or injected with 500 μg of  p17 emulsified in IFA intraperitoneally (closed squares) or subcutaneously  (circles). The fourth group of mice (triangles) was injected subcutaneously  five times with 100 μg of p17/IFA, on days −14, −11, −8, −5, and −2.  (The total amount of p17 injected into these mice was 500 μg.) On day  0, all mice were injected subcutaneously with p17/CFA and intraperitoneally with pertussis toxin. Eleven mice in each group were scored daily  for signs of paralysis, as described in Fig. 1 A. (B) Intraperitoneal administration of p17 in CFA prevents EAE. TR+ mice were injected subcutaneously with p17/CFA and intraperitoneally with pertussis toxin. On day 6,  mice were injected intraperitoneally with either 100 μg of p17 (closed  squares) or PBS (open squares) emulsified in CFA. Mice were scored daily  for the level of EAE as described in Fig. 1 A. The results shown are representative of four similar experiments with five to eight mice per group.
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Figure 7: (A) A single intraperitoneal or five subcutaneous, but not a single subcutaneous injection of p17 in IFA prevents EAE. On day −14, mice were either left untreated (open squares) or injected with 500 μg of p17 emulsified in IFA intraperitoneally (closed squares) or subcutaneously (circles). The fourth group of mice (triangles) was injected subcutaneously five times with 100 μg of p17/IFA, on days −14, −11, −8, −5, and −2. (The total amount of p17 injected into these mice was 500 μg.) On day 0, all mice were injected subcutaneously with p17/CFA and intraperitoneally with pertussis toxin. Eleven mice in each group were scored daily for signs of paralysis, as described in Fig. 1 A. (B) Intraperitoneal administration of p17 in CFA prevents EAE. TR+ mice were injected subcutaneously with p17/CFA and intraperitoneally with pertussis toxin. On day 6, mice were injected intraperitoneally with either 100 μg of p17 (closed squares) or PBS (open squares) emulsified in CFA. Mice were scored daily for the level of EAE as described in Fig. 1 A. The results shown are representative of four similar experiments with five to eight mice per group.

Mentions: Several experiments were performed to define better the mode of antigen administration that is required for tolerance induction. In the above-described experiments p17 induced EAE when administered subcutaneously in CFA but prevented disease induction or reversed ongoing disease when administered intraperitoneally in IFA. To determine whether the different effects of p17 arose from the difference in the adjuvant or from differences in the routes of administration, or from both, we injected p17 in IFA subcutaneously rather than intraperitoneally into TR+ mice. 2 wk later, we tested whether these mice were resistant to EAE induction. Mice injected with p17/IFA subcutaneously developed paralysis after the challenge with p17/CFA and pertussis toxin (Fig. 7 A; data not shown). However, tolerance could be achieved if the mice were injected subcutaneously with p17 in IFA five times within 2 wk. The total dose of p17 was the same in the multiple- and in the single-injection protocol. Finally, we injected mice intraperitoneally with p17 in CFA rather than IFA 6 d after the subcutaneous injection of p17/CFA and pertussis toxin. In contrast with mice intraperitoneally injected with CFA, mice injected with p17/CFA did not develop paralysis (Fig. 7 B).


Tolerance induction and autoimmune encephalomyelitis amelioration after administration of myelin basic protein-derived peptide.

Marusić S, Tonegawa S - J. Exp. Med. (1997)

(A) A single intraperitoneal or five subcutaneous, but not a  single subcutaneous injection of p17 in IFA prevents EAE. On day −14,  mice were either left untreated (open squares) or injected with 500 μg of  p17 emulsified in IFA intraperitoneally (closed squares) or subcutaneously  (circles). The fourth group of mice (triangles) was injected subcutaneously  five times with 100 μg of p17/IFA, on days −14, −11, −8, −5, and −2.  (The total amount of p17 injected into these mice was 500 μg.) On day  0, all mice were injected subcutaneously with p17/CFA and intraperitoneally with pertussis toxin. Eleven mice in each group were scored daily  for signs of paralysis, as described in Fig. 1 A. (B) Intraperitoneal administration of p17 in CFA prevents EAE. TR+ mice were injected subcutaneously with p17/CFA and intraperitoneally with pertussis toxin. On day 6,  mice were injected intraperitoneally with either 100 μg of p17 (closed  squares) or PBS (open squares) emulsified in CFA. Mice were scored daily  for the level of EAE as described in Fig. 1 A. The results shown are representative of four similar experiments with five to eight mice per group.
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Related In: Results  -  Collection

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Figure 7: (A) A single intraperitoneal or five subcutaneous, but not a single subcutaneous injection of p17 in IFA prevents EAE. On day −14, mice were either left untreated (open squares) or injected with 500 μg of p17 emulsified in IFA intraperitoneally (closed squares) or subcutaneously (circles). The fourth group of mice (triangles) was injected subcutaneously five times with 100 μg of p17/IFA, on days −14, −11, −8, −5, and −2. (The total amount of p17 injected into these mice was 500 μg.) On day 0, all mice were injected subcutaneously with p17/CFA and intraperitoneally with pertussis toxin. Eleven mice in each group were scored daily for signs of paralysis, as described in Fig. 1 A. (B) Intraperitoneal administration of p17 in CFA prevents EAE. TR+ mice were injected subcutaneously with p17/CFA and intraperitoneally with pertussis toxin. On day 6, mice were injected intraperitoneally with either 100 μg of p17 (closed squares) or PBS (open squares) emulsified in CFA. Mice were scored daily for the level of EAE as described in Fig. 1 A. The results shown are representative of four similar experiments with five to eight mice per group.
Mentions: Several experiments were performed to define better the mode of antigen administration that is required for tolerance induction. In the above-described experiments p17 induced EAE when administered subcutaneously in CFA but prevented disease induction or reversed ongoing disease when administered intraperitoneally in IFA. To determine whether the different effects of p17 arose from the difference in the adjuvant or from differences in the routes of administration, or from both, we injected p17 in IFA subcutaneously rather than intraperitoneally into TR+ mice. 2 wk later, we tested whether these mice were resistant to EAE induction. Mice injected with p17/IFA subcutaneously developed paralysis after the challenge with p17/CFA and pertussis toxin (Fig. 7 A; data not shown). However, tolerance could be achieved if the mice were injected subcutaneously with p17 in IFA five times within 2 wk. The total dose of p17 was the same in the multiple- and in the single-injection protocol. Finally, we injected mice intraperitoneally with p17 in CFA rather than IFA 6 d after the subcutaneous injection of p17/CFA and pertussis toxin. In contrast with mice intraperitoneally injected with CFA, mice injected with p17/CFA did not develop paralysis (Fig. 7 B).

Bottom Line: Subcutaneous injection of p17 (a peptide consisting of 17 NH2-terminal aminoacids of MBP) in complete Freund's adjuvant (CFA) causes paralysis.In addition, ongoing paralysis is ameliorated by subsequent intraperitoneal injection of p17 in IFA.Tolerance induction by p17 seems to be based on reduction in the responsiveness of anti-MBP T cells, as documented by lower overall antigen-induced lymphokine production and proliferation, as well as diminished upregulation of early activation marker CD69 by tolerized T cells.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

ABSTRACT
Experimental autoimmune encephalomyelitis (EAE), a demyelinating disease of the central nervous system, is an animal model of paralyzing human disease, multiple sclerosis. EAE is readily induced by immunization with myelin basic protein (MBP) in mice transgenic for an alphabeta T cell receptor (TCR) that is specific for MBP. Subcutaneous injection of p17 (a peptide consisting of 17 NH2-terminal aminoacids of MBP) in complete Freund's adjuvant (CFA) causes paralysis. Induction of paralysis is inhibited by prior intraperitoneal injection of the same peptide in incomplete Freund's adjuvant (IFA). In addition, ongoing paralysis is ameliorated by subsequent intraperitoneal injection of p17 in IFA. Tolerance induction is equally efficient in Fas-deficient and IL-4-deficient TCR-transgenic mice, suggesting that neither activation-induced cell death nor differentiation into Th2 type cells plays a role in the tolerance induction. Tolerance induction by p17 seems to be based on reduction in the responsiveness of anti-MBP T cells, as documented by lower overall antigen-induced lymphokine production and proliferation, as well as diminished upregulation of early activation marker CD69 by tolerized T cells. We propose that continuous encounters of MBP-specific T cells with p17 play a critical role in the induction and maintenance of tolerance.

Show MeSH
Related in: MedlinePlus