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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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Determination of cytokine profiles of KLH (a) and MBP (b) specific short-term T cell lines. Two mice of each group were killed at day 10  p.i. and lymph node cells stimulated in vitro with KLH or MBP for 6 d. The number of IL-4 (crosshatched bars) and IFN-γ (solid bars) was determined by  ELISPOT analysis. The KLH-specific lymph node T cells of mice immunized with the antigen in IFA showed a Th2 cytokine profile. When the mice  were treated with rmIL-12, the number of IL-4–producing cells was decreased. In control mice receiving only PBS, the primary antigenic stimulation in  vitro with KLH induced a Th1 phenotype. The MBP-specific T cells showed a Th1 inflammatory profile in nonprotected controls (not pretreated with,  or not restimulated with KLH) while in KLH-protected mice, the cytokine profile was shifted to a Th2 type. Treatment with rmIL-12 for only 3 d was  sufficient to modify the phenotype of the MBP-specific T cells in the KLH/IFA-treated mice from Th2 from Th1.
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Figure 3: Determination of cytokine profiles of KLH (a) and MBP (b) specific short-term T cell lines. Two mice of each group were killed at day 10 p.i. and lymph node cells stimulated in vitro with KLH or MBP for 6 d. The number of IL-4 (crosshatched bars) and IFN-γ (solid bars) was determined by ELISPOT analysis. The KLH-specific lymph node T cells of mice immunized with the antigen in IFA showed a Th2 cytokine profile. When the mice were treated with rmIL-12, the number of IL-4–producing cells was decreased. In control mice receiving only PBS, the primary antigenic stimulation in vitro with KLH induced a Th1 phenotype. The MBP-specific T cells showed a Th1 inflammatory profile in nonprotected controls (not pretreated with, or not restimulated with KLH) while in KLH-protected mice, the cytokine profile was shifted to a Th2 type. Treatment with rmIL-12 for only 3 d was sufficient to modify the phenotype of the MBP-specific T cells in the KLH/IFA-treated mice from Th2 from Th1.

Mentions: To verify our hypothesis that KLH administered in IFA induces the Th2 response that alters the nature of autoimmune T cells, we examined the cytokine profiles of both KLH- and MBP-specific T cell lines in these mice. T cells were isolated from lymph nodes from the three groups of animals at 10 d p.i. and stimulated in vitro with KLH or MBP, the predominant autoantigen in EAE. After 6 d, the cytokine profiles of these short-term lines directly obtained from the animals were determined by ELISPOT. As expected, the KLH-specific T cells from animals preimmunized intraperitoneally with KLH in IFA showed a predominantly Th2 phenotype. In contrast, when the KLH-primed mice were treated with rmIL-12, both IFN-γ– and IL-4–producing cells were found among the KLH-specific T cells, but the number of IL-4 secreting T cells was consistently decreased (Fig. 3 a). In control mice not primed with KLH, the KLH-specific T cells receiving the first antigenic stimulus in vitro, expressed a Th1 profile. This indicated that primary antigenic stimulation of naive T cells with KLH in vitro leads to a predominantly Th1 phenotype.


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)

Determination of cytokine profiles of KLH (a) and MBP (b) specific short-term T cell lines. Two mice of each group were killed at day 10  p.i. and lymph node cells stimulated in vitro with KLH or MBP for 6 d. The number of IL-4 (crosshatched bars) and IFN-γ (solid bars) was determined by  ELISPOT analysis. The KLH-specific lymph node T cells of mice immunized with the antigen in IFA showed a Th2 cytokine profile. When the mice  were treated with rmIL-12, the number of IL-4–producing cells was decreased. In control mice receiving only PBS, the primary antigenic stimulation in  vitro with KLH induced a Th1 phenotype. The MBP-specific T cells showed a Th1 inflammatory profile in nonprotected controls (not pretreated with,  or not restimulated with KLH) while in KLH-protected mice, the cytokine profile was shifted to a Th2 type. Treatment with rmIL-12 for only 3 d was  sufficient to modify the phenotype of the MBP-specific T cells in the KLH/IFA-treated mice from Th2 from Th1.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Determination of cytokine profiles of KLH (a) and MBP (b) specific short-term T cell lines. Two mice of each group were killed at day 10 p.i. and lymph node cells stimulated in vitro with KLH or MBP for 6 d. The number of IL-4 (crosshatched bars) and IFN-γ (solid bars) was determined by ELISPOT analysis. The KLH-specific lymph node T cells of mice immunized with the antigen in IFA showed a Th2 cytokine profile. When the mice were treated with rmIL-12, the number of IL-4–producing cells was decreased. In control mice receiving only PBS, the primary antigenic stimulation in vitro with KLH induced a Th1 phenotype. The MBP-specific T cells showed a Th1 inflammatory profile in nonprotected controls (not pretreated with, or not restimulated with KLH) while in KLH-protected mice, the cytokine profile was shifted to a Th2 type. Treatment with rmIL-12 for only 3 d was sufficient to modify the phenotype of the MBP-specific T cells in the KLH/IFA-treated mice from Th2 from Th1.
Mentions: To verify our hypothesis that KLH administered in IFA induces the Th2 response that alters the nature of autoimmune T cells, we examined the cytokine profiles of both KLH- and MBP-specific T cell lines in these mice. T cells were isolated from lymph nodes from the three groups of animals at 10 d p.i. and stimulated in vitro with KLH or MBP, the predominant autoantigen in EAE. After 6 d, the cytokine profiles of these short-term lines directly obtained from the animals were determined by ELISPOT. As expected, the KLH-specific T cells from animals preimmunized intraperitoneally with KLH in IFA showed a predominantly Th2 phenotype. In contrast, when the KLH-primed mice were treated with rmIL-12, both IFN-γ– and IL-4–producing cells were found among the KLH-specific T cells, but the number of IL-4 secreting T cells was consistently decreased (Fig. 3 a). In control mice not primed with KLH, the KLH-specific T cells receiving the first antigenic stimulus in vitro, expressed a Th1 profile. This indicated that primary antigenic stimulation of naive T cells with KLH in vitro leads to a predominantly Th1 phenotype.

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