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Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis.

Bettelli E, Pagany M, Weiner HL, Linington C, Sobel RA, Kuchroo VK - J. Exp. Med. (2003)

Bottom Line: Multiple sclerosis (MS) is considered to be an autoimmune disease of the central nervous system (CNS) that in many patients first presents clinically as optic neuritis.MOG-specific transgenic T cells are not deleted nor tolerized and are functionally competent.These results demonstrate that clinical manifestations of CNS autoimmune disease will vary depending on the identity of the target autoantigen and that MOG-specific T cell responses are involved in the genesis of isolated optic neuritis.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT
Multiple sclerosis (MS) is considered to be an autoimmune disease of the central nervous system (CNS) that in many patients first presents clinically as optic neuritis. The relationship of optic neuritis to MS is not well understood. We have generated novel T cell receptor (TCR) transgenic mice specific for myelin oligodendrocyte glycoprotein (MOG). MOG-specific transgenic T cells are not deleted nor tolerized and are functionally competent. A large proportion (>30%) of MOG-specific TCR transgenic mice spontaneously develop isolated optic neuritis without any clinical nor histological evidence of experimental autoimmune encephalomyelitis (EAE). Optic neuritis without EAE could also be induced in these mice by sensitization with suboptimal doses of MOG. The predilection of these mice to develop optic neuritis is associated with higher expression of MOG in the optic nerve than in the spinal cord. These results demonstrate that clinical manifestations of CNS autoimmune disease will vary depending on the identity of the target autoantigen and that MOG-specific T cell responses are involved in the genesis of isolated optic neuritis.

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Response of transgenic T cells to MOG 35–55 and MOG protein. Splenocytes from unimmunized mice were cultured with indicated concentrations of MOG 35–55 peptide (A) or recombinant protein MOG (B). T cell proliferation was determined by [3H]thymidine incorporation in triplicate wells in a 72-h proliferation assay. The mean cpm's in the presence of 50 μg/ml OVA 323–336 control peptide were 12,401 for TCR transgenic mice and 14,278 for the control littermates. Splenocytes produce IFN-γ in response to indicated concentrations of peptide MOG 35–55 (C). IFN-γ was measured on supernatants harvested 48 h after activation by ELISA. 2D2 Tg, 2D2 transgenic; NT, nontransgenic.
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fig2: Response of transgenic T cells to MOG 35–55 and MOG protein. Splenocytes from unimmunized mice were cultured with indicated concentrations of MOG 35–55 peptide (A) or recombinant protein MOG (B). T cell proliferation was determined by [3H]thymidine incorporation in triplicate wells in a 72-h proliferation assay. The mean cpm's in the presence of 50 μg/ml OVA 323–336 control peptide were 12,401 for TCR transgenic mice and 14,278 for the control littermates. Splenocytes produce IFN-γ in response to indicated concentrations of peptide MOG 35–55 (C). IFN-γ was measured on supernatants harvested 48 h after activation by ELISA. 2D2 Tg, 2D2 transgenic; NT, nontransgenic.

Mentions: To determine if the T cells were specific and responsive to MOG antigen in the peripheral lymphoid organs, we tested the proliferative response of spleen cells with the peptide MOG 35–55 and whole MOG protein. As shown in Fig. 2, A and B , spleen cells from naive 2D2 TCR transgenic mice with no sign of CNS autoimmune disease show a strong proliferative response to the peptide MOG 35–55 and to the MOG protein. However, they do not proliferate to a control peptide OVA 323–336. We also tested the production of various cytokines (IFN-γ, IL-4, IL-10, and IL-5) from these transgenic T cells in response to the encephalitogenic peptide. Spleen cells from unimmunized 2D2 TCR transgenic mice produce high levels of IFN-γ but no other cytokines were detected in the supernatant in response to the peptide MOG 35–55 (Fig. 2 C). The source of the IFN-γ appears to be from memory/primed T cells because production of IFN-γ was considerably reduced when sorted naive CD4+ CD62Lhigh transgenic T cells were activated in vitro with the MOG 35–55 peptide (unpublished data). Memory/primed transgenic T cells (Vα3.2+ CD4+ CD62Llow) represent ∼10% of the CD4+ transgenic T cell population. This percentage increases as the animals age. These results show that T cells from 2D2 TCR transgenic mice are able to respond to MOG antigen (peptide and protein) and that they are not tolerized in vivo. Furthermore, the data suggest that transgenic T cells have a tendency to develop into a Th1 phenotype.


Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis.

Bettelli E, Pagany M, Weiner HL, Linington C, Sobel RA, Kuchroo VK - J. Exp. Med. (2003)

Response of transgenic T cells to MOG 35–55 and MOG protein. Splenocytes from unimmunized mice were cultured with indicated concentrations of MOG 35–55 peptide (A) or recombinant protein MOG (B). T cell proliferation was determined by [3H]thymidine incorporation in triplicate wells in a 72-h proliferation assay. The mean cpm's in the presence of 50 μg/ml OVA 323–336 control peptide were 12,401 for TCR transgenic mice and 14,278 for the control littermates. Splenocytes produce IFN-γ in response to indicated concentrations of peptide MOG 35–55 (C). IFN-γ was measured on supernatants harvested 48 h after activation by ELISA. 2D2 Tg, 2D2 transgenic; NT, nontransgenic.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193967&req=5

fig2: Response of transgenic T cells to MOG 35–55 and MOG protein. Splenocytes from unimmunized mice were cultured with indicated concentrations of MOG 35–55 peptide (A) or recombinant protein MOG (B). T cell proliferation was determined by [3H]thymidine incorporation in triplicate wells in a 72-h proliferation assay. The mean cpm's in the presence of 50 μg/ml OVA 323–336 control peptide were 12,401 for TCR transgenic mice and 14,278 for the control littermates. Splenocytes produce IFN-γ in response to indicated concentrations of peptide MOG 35–55 (C). IFN-γ was measured on supernatants harvested 48 h after activation by ELISA. 2D2 Tg, 2D2 transgenic; NT, nontransgenic.
Mentions: To determine if the T cells were specific and responsive to MOG antigen in the peripheral lymphoid organs, we tested the proliferative response of spleen cells with the peptide MOG 35–55 and whole MOG protein. As shown in Fig. 2, A and B , spleen cells from naive 2D2 TCR transgenic mice with no sign of CNS autoimmune disease show a strong proliferative response to the peptide MOG 35–55 and to the MOG protein. However, they do not proliferate to a control peptide OVA 323–336. We also tested the production of various cytokines (IFN-γ, IL-4, IL-10, and IL-5) from these transgenic T cells in response to the encephalitogenic peptide. Spleen cells from unimmunized 2D2 TCR transgenic mice produce high levels of IFN-γ but no other cytokines were detected in the supernatant in response to the peptide MOG 35–55 (Fig. 2 C). The source of the IFN-γ appears to be from memory/primed T cells because production of IFN-γ was considerably reduced when sorted naive CD4+ CD62Lhigh transgenic T cells were activated in vitro with the MOG 35–55 peptide (unpublished data). Memory/primed transgenic T cells (Vα3.2+ CD4+ CD62Llow) represent ∼10% of the CD4+ transgenic T cell population. This percentage increases as the animals age. These results show that T cells from 2D2 TCR transgenic mice are able to respond to MOG antigen (peptide and protein) and that they are not tolerized in vivo. Furthermore, the data suggest that transgenic T cells have a tendency to develop into a Th1 phenotype.

Bottom Line: Multiple sclerosis (MS) is considered to be an autoimmune disease of the central nervous system (CNS) that in many patients first presents clinically as optic neuritis.MOG-specific transgenic T cells are not deleted nor tolerized and are functionally competent.These results demonstrate that clinical manifestations of CNS autoimmune disease will vary depending on the identity of the target autoantigen and that MOG-specific T cell responses are involved in the genesis of isolated optic neuritis.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT
Multiple sclerosis (MS) is considered to be an autoimmune disease of the central nervous system (CNS) that in many patients first presents clinically as optic neuritis. The relationship of optic neuritis to MS is not well understood. We have generated novel T cell receptor (TCR) transgenic mice specific for myelin oligodendrocyte glycoprotein (MOG). MOG-specific transgenic T cells are not deleted nor tolerized and are functionally competent. A large proportion (>30%) of MOG-specific TCR transgenic mice spontaneously develop isolated optic neuritis without any clinical nor histological evidence of experimental autoimmune encephalomyelitis (EAE). Optic neuritis without EAE could also be induced in these mice by sensitization with suboptimal doses of MOG. The predilection of these mice to develop optic neuritis is associated with higher expression of MOG in the optic nerve than in the spinal cord. These results demonstrate that clinical manifestations of CNS autoimmune disease will vary depending on the identity of the target autoantigen and that MOG-specific T cell responses are involved in the genesis of isolated optic neuritis.

Show MeSH
Related in: MedlinePlus