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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: 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.We propose that continuous encounters of MBP-specific T cells with p17 play a critical role in the induction and maintenance of tolerance.

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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Tolerized cells regain encephalitogenicity upon transfer into  tolerogen-free host. TR− mice were injected intraperitoneally with either  PBS/IFA or 500 μg p17/IFA. 3 wk later, spleen cells from either p17- or  PBS-pretreated mice, containing 3 × 106 Vβ8+CD4+ T cells, were injected intravenously into lethally irradiated (900 rads), RAG-1–deficient  bone marrow–reconstituted PL/J mice. 1 d after the spleen cell transfer,  EAE was induced as described in Fig. 1. Half of the mice that received the  cells from p17/IFA-pretreated donors also received 500 μg p17/IFA, intraperitoneally, 5 d after EAE induction. Similar results were obtained in  two independent experiments with five to eight mice per group.
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Figure 6: Tolerized cells regain encephalitogenicity upon transfer into tolerogen-free host. TR− mice were injected intraperitoneally with either PBS/IFA or 500 μg p17/IFA. 3 wk later, spleen cells from either p17- or PBS-pretreated mice, containing 3 × 106 Vβ8+CD4+ T cells, were injected intravenously into lethally irradiated (900 rads), RAG-1–deficient bone marrow–reconstituted PL/J mice. 1 d after the spleen cell transfer, EAE was induced as described in Fig. 1. Half of the mice that received the cells from p17/IFA-pretreated donors also received 500 μg p17/IFA, intraperitoneally, 5 d after EAE induction. Similar results were obtained in two independent experiments with five to eight mice per group.

Mentions: To test whether T cells from tolerized mice remain unable to induce EAE in the absence of p17, we transferred them into tolerogen-free hosts. As recipients, we used either RAG-1–deficient (H-2u) mice or PL/J mice that had been lethally irradiated and reconstituted with RAG-1–deficient (H-2u) bone marrow. When 3 × 106 p17-specific T cells from tolerized or nontolerized TR− mice were transferred into the p17-free recipients, all mice developed lethal EAE (Fig. 6). Mice that received T cells from tolerized donors developed EAE with a delay of 2–3 d, in comparison with the mice that received T cells from nontolerized donors. However, the severity of EAE was the same in both groups of mice. Next, we determined whether the tolerant state of the transferred T cells could be maintained if the host was treated with p17. Mice that received cells from tolerized mice were injected intraperitoneally with p17/IFA (500 μg per mouse), 5 d after EAE induction. Although all mice receiving tolerized cells only developed EAE, mice that received tolerized cells and p17/IFA remained healthy (Fig. 6). These results indicate that the continuous presence of p17 was necessary for the maintanence of tolerance.


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

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

Tolerized cells regain encephalitogenicity upon transfer into  tolerogen-free host. TR− mice were injected intraperitoneally with either  PBS/IFA or 500 μg p17/IFA. 3 wk later, spleen cells from either p17- or  PBS-pretreated mice, containing 3 × 106 Vβ8+CD4+ T cells, were injected intravenously into lethally irradiated (900 rads), RAG-1–deficient  bone marrow–reconstituted PL/J mice. 1 d after the spleen cell transfer,  EAE was induced as described in Fig. 1. Half of the mice that received the  cells from p17/IFA-pretreated donors also received 500 μg p17/IFA, intraperitoneally, 5 d after EAE induction. Similar results were obtained in  two independent experiments with five to eight mice per group.
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Related In: Results  -  Collection

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Figure 6: Tolerized cells regain encephalitogenicity upon transfer into tolerogen-free host. TR− mice were injected intraperitoneally with either PBS/IFA or 500 μg p17/IFA. 3 wk later, spleen cells from either p17- or PBS-pretreated mice, containing 3 × 106 Vβ8+CD4+ T cells, were injected intravenously into lethally irradiated (900 rads), RAG-1–deficient bone marrow–reconstituted PL/J mice. 1 d after the spleen cell transfer, EAE was induced as described in Fig. 1. Half of the mice that received the cells from p17/IFA-pretreated donors also received 500 μg p17/IFA, intraperitoneally, 5 d after EAE induction. Similar results were obtained in two independent experiments with five to eight mice per group.
Mentions: To test whether T cells from tolerized mice remain unable to induce EAE in the absence of p17, we transferred them into tolerogen-free hosts. As recipients, we used either RAG-1–deficient (H-2u) mice or PL/J mice that had been lethally irradiated and reconstituted with RAG-1–deficient (H-2u) bone marrow. When 3 × 106 p17-specific T cells from tolerized or nontolerized TR− mice were transferred into the p17-free recipients, all mice developed lethal EAE (Fig. 6). Mice that received T cells from tolerized donors developed EAE with a delay of 2–3 d, in comparison with the mice that received T cells from nontolerized donors. However, the severity of EAE was the same in both groups of mice. Next, we determined whether the tolerant state of the transferred T cells could be maintained if the host was treated with p17. Mice that received cells from tolerized mice were injected intraperitoneally with p17/IFA (500 μg per mouse), 5 d after EAE induction. Although all mice receiving tolerized cells only developed EAE, mice that received tolerized cells and p17/IFA remained healthy (Fig. 6). These results indicate that the continuous presence of p17 was necessary for the maintanence of tolerance.

Bottom Line: 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.We propose that continuous encounters of MBP-specific T cells with p17 play a critical role in the induction and maintenance of tolerance.

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