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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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EAE can be prevented in IL-4–deficient mice transgenic for  the MBP-specific TCR. (A) IL-4–deficient, TR+ mice were injected intraperitoneally with p17 (closed squares) or PBS (open squares) on day −14,  as described in Fig. 1 A. On day 0, all mice were injected subcutaneously  with p17/CFA and intraperitoneally with pertussis toxin, and the level of  EAE was scored daily as described in Fig. 1. Similar results were obtained  in two independent experiments with 8 to 10 mice per group. (B) Intraperitoneally injected p17/IFA prevents EAE in IL-4–deficient TR+ mice  when administered during the course of EAE development. IL-4–deficient TR+ mice were injected subcutaneously with p17/CFA and intraperitoneally with pertussis toxin. On day 6, mice were injected intraperitoneally with either 500 μg of p17 (closed squares) or PBS (open squares)  emulsified in IFA. Eight mice in each group were scored daily for the  level of paralysis as described in Fig. 1 A.
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Figure 4: EAE can be prevented in IL-4–deficient mice transgenic for the MBP-specific TCR. (A) IL-4–deficient, TR+ mice were injected intraperitoneally with p17 (closed squares) or PBS (open squares) on day −14, as described in Fig. 1 A. On day 0, all mice were injected subcutaneously with p17/CFA and intraperitoneally with pertussis toxin, and the level of EAE was scored daily as described in Fig. 1. Similar results were obtained in two independent experiments with 8 to 10 mice per group. (B) Intraperitoneally injected p17/IFA prevents EAE in IL-4–deficient TR+ mice when administered during the course of EAE development. IL-4–deficient TR+ mice were injected subcutaneously with p17/CFA and intraperitoneally with pertussis toxin. On day 6, mice were injected intraperitoneally with either 500 μg of p17 (closed squares) or PBS (open squares) emulsified in IFA. Eight mice in each group were scored daily for the level of paralysis as described in Fig. 1 A.

Mentions: Because MBP-specific T cells are not deleted, antigen-induced functional changes must account for the prevention and/or reversal of tissue destruction and paralysis after p17/IFA administration. It has been suggested that tissue destruction is mediated by a Th1-type response, whereas a Th2-type response is nonpathological or even protective (26–30). Therefore, we attempted to prevent paralysis, using the p17/IFA tolerance induction protocol, in mice produced by a cross between TR+ mice and IL-4–deficient mice (20). IL-4 has been shown to be neccessary for Th2 responses in vitro as well as in vivo (20, 31–33). Intraperitoneal injection of p17 in IFA prevented paralysis in TR+, IL-4–deficient mice (Fig. 4 A). We could also show that the intraperitoneal injection of p17/IFA 6 d after the injection of p17/CFA and pertussis toxin prevented paralysis in TR+, IL-4–deficient mice (Fig. 4 B). Thus, IL-4 does not seem to play an essential role, neither in the induction of tolerance to prevent development of EAE nor in reversing the course of develop- ing EAE.


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

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

EAE can be prevented in IL-4–deficient mice transgenic for  the MBP-specific TCR. (A) IL-4–deficient, TR+ mice were injected intraperitoneally with p17 (closed squares) or PBS (open squares) on day −14,  as described in Fig. 1 A. On day 0, all mice were injected subcutaneously  with p17/CFA and intraperitoneally with pertussis toxin, and the level of  EAE was scored daily as described in Fig. 1. Similar results were obtained  in two independent experiments with 8 to 10 mice per group. (B) Intraperitoneally injected p17/IFA prevents EAE in IL-4–deficient TR+ mice  when administered during the course of EAE development. IL-4–deficient TR+ mice were injected subcutaneously with p17/CFA and intraperitoneally with pertussis toxin. On day 6, mice were injected intraperitoneally with either 500 μg of p17 (closed squares) or PBS (open squares)  emulsified in IFA. Eight mice in each group were scored daily for the  level of paralysis as described in Fig. 1 A.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199028&req=5

Figure 4: EAE can be prevented in IL-4–deficient mice transgenic for the MBP-specific TCR. (A) IL-4–deficient, TR+ mice were injected intraperitoneally with p17 (closed squares) or PBS (open squares) on day −14, as described in Fig. 1 A. On day 0, all mice were injected subcutaneously with p17/CFA and intraperitoneally with pertussis toxin, and the level of EAE was scored daily as described in Fig. 1. Similar results were obtained in two independent experiments with 8 to 10 mice per group. (B) Intraperitoneally injected p17/IFA prevents EAE in IL-4–deficient TR+ mice when administered during the course of EAE development. IL-4–deficient TR+ mice were injected subcutaneously with p17/CFA and intraperitoneally with pertussis toxin. On day 6, mice were injected intraperitoneally with either 500 μg of p17 (closed squares) or PBS (open squares) emulsified in IFA. Eight mice in each group were scored daily for the level of paralysis as described in Fig. 1 A.
Mentions: Because MBP-specific T cells are not deleted, antigen-induced functional changes must account for the prevention and/or reversal of tissue destruction and paralysis after p17/IFA administration. It has been suggested that tissue destruction is mediated by a Th1-type response, whereas a Th2-type response is nonpathological or even protective (26–30). Therefore, we attempted to prevent paralysis, using the p17/IFA tolerance induction protocol, in mice produced by a cross between TR+ mice and IL-4–deficient mice (20). IL-4 has been shown to be neccessary for Th2 responses in vitro as well as in vivo (20, 31–33). Intraperitoneal injection of p17 in IFA prevented paralysis in TR+, IL-4–deficient mice (Fig. 4 A). We could also show that the intraperitoneal injection of p17/IFA 6 d after the injection of p17/CFA and pertussis toxin prevented paralysis in TR+, IL-4–deficient mice (Fig. 4 B). Thus, IL-4 does not seem to play an essential role, neither in the induction of tolerance to prevent development of EAE nor in reversing the course of develop- ing EAE.

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