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A T helper cell 2 (Th2) immune response against non-self antigens modifies the cytokine profile of autoimmune T cells and protects against experimental allergic encephalomyelitis.

Falcone M, Bloom BR - J. Exp. Med. (1997)

Bottom Line: This interpretation is supported by the observation that the protective effect of preimmunization with KLH was overcome by rm-IL-12, which inhibited the production of IL-4 by the Th1 cells and biased the autoimmune response to a predominantly Th1 type.Since IL-4 mRNA could not be detected by reverse transcriptase PCR in the CNS, the protective effect was inferred to be mediated by Th2 cells in the lymphoid system, and not the target organ.We conclude that exogenous, nonself antigens that can induce Th2 responses, can modify the cytokine environment sufficiently to alter the cytokine phenotype of inflammatory, autoreactive T cell clones, and ultimately, to provide significant protection against EAE and possibly other T cell-mediated autoimmune diseases.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

ABSTRACT
Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system (CNS), and the most commonly used experimental model for multiple sclerosis. It is mediated by autoreactive T cell clones exhibiting a T helper cell (Th) 1 cytokine profile. Nonencephalitogenic T lymphocytes specific for self or exogenous antigens have been found to suppress encephalitogenic T cell responses and to protect against autoimmune disease. The mechanisms by which exogenous antigens modulate autoimmunity are not fully understood. In this study, we tested the hypothesis that a Th2-type immune response against an exogenous, nonself antigen, keyhole limpet hemocyanin (KLH), by releasing IL-4 in the microenvironment, could shift the cytokine profile of encephalitogenic T cells from an inflammatory Th1 to a protective Th2 type. SJL/J mice were preimmunized with the KLH in incomplete Freund's adjuvant to induce a population of Th2 memory cells that would be expected to release Th2 cytokines when activated by the specific antigen at the time of EAE induction. Four weeks later, mice received an encephalitogenic challenge containing guinea pig myelin in complete Freund's adjuvant with or without KLH. All KLH primed animals not receiving the exogenous antigen at the time of EAE induction developed a severe clinical disease indistinguishable from control mice not KLH primed. In contrast, animals preimmunized and challenged with the encephalitogenic inoculum containing KLH showed either no, or markedly reduced, clinical signs. Enzyme-linked immunospot analysis demonstrated that KLH-specific T cells in the primed mice were producing IL-4 characteristic of Th2 cells. In the KLH-primed and restimulated mice, the cytokine profile of the autoreactive, myelin basic protein-specific T cells was shifted from an inflammatory Th1 towards a protective Th2 type. We infer that the presence of IL-4 secreted by KLH-specific memory Th2 cells in the lymphoid system microenvironment in which the autoreactive T cells were engaged by the encephalitogenic stimulus were able to bias their cytokine profile towards a protective Th2 phenotype. This interpretation is supported by the observation that the protective effect of preimmunization with KLH was overcome by rm-IL-12, which inhibited the production of IL-4 by the Th1 cells and biased the autoimmune response to a predominantly Th1 type. Since IL-4 mRNA could not be detected by reverse transcriptase PCR in the CNS, the protective effect was inferred to be mediated by Th2 cells in the lymphoid system, and not the target organ. We conclude that exogenous, nonself antigens that can induce Th2 responses, can modify the cytokine environment sufficiently to alter the cytokine phenotype of inflammatory, autoreactive T cell clones, and ultimately, to provide significant protection against EAE and possibly other T cell-mediated autoimmune diseases.

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Effect of the KLH preimmunization and challenge at the  time of EAE induction on the incidence and clinical score of the disease.  Two groups of SJL/J mice were injected intraperitoneally with an emulsion of KLH in IFA. One control group was injected with PBS. After  4 wk, EAE was induced by immunizing the animals with guinea pig myelin in CFA. One of the two groups of mice pretreated with KLH received the foreign antigen with the encephalitogenic inoculum. This group  of mice was almost completely protected (filled circles) against EAE. The  control group that was not preimmunized with KLH (open circles) or the  group that was primed, but not challenged a second time with KLH (open  squares) both showed high incidences and clinical scores for the disease.
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Figure 1: Effect of the KLH preimmunization and challenge at the time of EAE induction on the incidence and clinical score of the disease. Two groups of SJL/J mice were injected intraperitoneally with an emulsion of KLH in IFA. One control group was injected with PBS. After 4 wk, EAE was induced by immunizing the animals with guinea pig myelin in CFA. One of the two groups of mice pretreated with KLH received the foreign antigen with the encephalitogenic inoculum. This group of mice was almost completely protected (filled circles) against EAE. The control group that was not preimmunized with KLH (open circles) or the group that was primed, but not challenged a second time with KLH (open squares) both showed high incidences and clinical scores for the disease.

Mentions: To test the hypothesis that T cells specific for a foreign antigen could alter the course of EAE in SJL/J mice, two groups of mice were primed intraperitoneally with KLH in IFA. A control group received PBS at the same time. After 4 wk all mice received an encephalitogenic inoculum containing guinea pig myelin in CFA, and one of the two groups of mice previously primed with KLH received the KLH antigen at this time. EAE was fully developed after 10–14 d in the animals that were not primed, or that received the KLH in IFA 4 wk before but were not given the foreign antigen at the time of the encephalitogenic immunization. In contrast, when the KLH-specific T cells were reactivated at the time of EAE induction by a second antigenic challenge, the KLHprimed mice were almost completely protected. In this group of mice, both the incidence and the mean clinical score were significantly reduced compared to controls (Fig. 1). These results indicated that stimulating primed mice with the nonself antigen at the time of activation of autoimmune T cell clones could alter the course of the autoimmune disease.


A T helper cell 2 (Th2) immune response against non-self antigens modifies the cytokine profile of autoimmune T cells and protects against experimental allergic encephalomyelitis.

Falcone M, Bloom BR - J. Exp. Med. (1997)

Effect of the KLH preimmunization and challenge at the  time of EAE induction on the incidence and clinical score of the disease.  Two groups of SJL/J mice were injected intraperitoneally with an emulsion of KLH in IFA. One control group was injected with PBS. After  4 wk, EAE was induced by immunizing the animals with guinea pig myelin in CFA. One of the two groups of mice pretreated with KLH received the foreign antigen with the encephalitogenic inoculum. This group  of mice was almost completely protected (filled circles) against EAE. The  control group that was not preimmunized with KLH (open circles) or the  group that was primed, but not challenged a second time with KLH (open  squares) both showed high incidences and clinical scores for the disease.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196156&req=5

Figure 1: Effect of the KLH preimmunization and challenge at the time of EAE induction on the incidence and clinical score of the disease. Two groups of SJL/J mice were injected intraperitoneally with an emulsion of KLH in IFA. One control group was injected with PBS. After 4 wk, EAE was induced by immunizing the animals with guinea pig myelin in CFA. One of the two groups of mice pretreated with KLH received the foreign antigen with the encephalitogenic inoculum. This group of mice was almost completely protected (filled circles) against EAE. The control group that was not preimmunized with KLH (open circles) or the group that was primed, but not challenged a second time with KLH (open squares) both showed high incidences and clinical scores for the disease.
Mentions: To test the hypothesis that T cells specific for a foreign antigen could alter the course of EAE in SJL/J mice, two groups of mice were primed intraperitoneally with KLH in IFA. A control group received PBS at the same time. After 4 wk all mice received an encephalitogenic inoculum containing guinea pig myelin in CFA, and one of the two groups of mice previously primed with KLH received the KLH antigen at this time. EAE was fully developed after 10–14 d in the animals that were not primed, or that received the KLH in IFA 4 wk before but were not given the foreign antigen at the time of the encephalitogenic immunization. In contrast, when the KLH-specific T cells were reactivated at the time of EAE induction by a second antigenic challenge, the KLHprimed mice were almost completely protected. In this group of mice, both the incidence and the mean clinical score were significantly reduced compared to controls (Fig. 1). These results indicated that stimulating primed mice with the nonself antigen at the time of activation of autoimmune T cell clones could alter the course of the autoimmune disease.

Bottom Line: This interpretation is supported by the observation that the protective effect of preimmunization with KLH was overcome by rm-IL-12, which inhibited the production of IL-4 by the Th1 cells and biased the autoimmune response to a predominantly Th1 type.Since IL-4 mRNA could not be detected by reverse transcriptase PCR in the CNS, the protective effect was inferred to be mediated by Th2 cells in the lymphoid system, and not the target organ.We conclude that exogenous, nonself antigens that can induce Th2 responses, can modify the cytokine environment sufficiently to alter the cytokine phenotype of inflammatory, autoreactive T cell clones, and ultimately, to provide significant protection against EAE and possibly other T cell-mediated autoimmune diseases.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

ABSTRACT
Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system (CNS), and the most commonly used experimental model for multiple sclerosis. It is mediated by autoreactive T cell clones exhibiting a T helper cell (Th) 1 cytokine profile. Nonencephalitogenic T lymphocytes specific for self or exogenous antigens have been found to suppress encephalitogenic T cell responses and to protect against autoimmune disease. The mechanisms by which exogenous antigens modulate autoimmunity are not fully understood. In this study, we tested the hypothesis that a Th2-type immune response against an exogenous, nonself antigen, keyhole limpet hemocyanin (KLH), by releasing IL-4 in the microenvironment, could shift the cytokine profile of encephalitogenic T cells from an inflammatory Th1 to a protective Th2 type. SJL/J mice were preimmunized with the KLH in incomplete Freund's adjuvant to induce a population of Th2 memory cells that would be expected to release Th2 cytokines when activated by the specific antigen at the time of EAE induction. Four weeks later, mice received an encephalitogenic challenge containing guinea pig myelin in complete Freund's adjuvant with or without KLH. All KLH primed animals not receiving the exogenous antigen at the time of EAE induction developed a severe clinical disease indistinguishable from control mice not KLH primed. In contrast, animals preimmunized and challenged with the encephalitogenic inoculum containing KLH showed either no, or markedly reduced, clinical signs. Enzyme-linked immunospot analysis demonstrated that KLH-specific T cells in the primed mice were producing IL-4 characteristic of Th2 cells. In the KLH-primed and restimulated mice, the cytokine profile of the autoreactive, myelin basic protein-specific T cells was shifted from an inflammatory Th1 towards a protective Th2 type. We infer that the presence of IL-4 secreted by KLH-specific memory Th2 cells in the lymphoid system microenvironment in which the autoreactive T cells were engaged by the encephalitogenic stimulus were able to bias their cytokine profile towards a protective Th2 phenotype. This interpretation is supported by the observation that the protective effect of preimmunization with KLH was overcome by rm-IL-12, which inhibited the production of IL-4 by the Th1 cells and biased the autoimmune response to a predominantly Th1 type. Since IL-4 mRNA could not be detected by reverse transcriptase PCR in the CNS, the protective effect was inferred to be mediated by Th2 cells in the lymphoid system, and not the target organ. We conclude that exogenous, nonself antigens that can induce Th2 responses, can modify the cytokine environment sufficiently to alter the cytokine phenotype of inflammatory, autoreactive T cell clones, and ultimately, to provide significant protection against EAE and possibly other T cell-mediated autoimmune diseases.

Show MeSH
Related in: MedlinePlus