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Altered immune responses in interleukin 10 transgenic mice.

Hagenbaugh A, Sharma S, Dubinett SM, Wei SH, Aranda R, Cheroutre H, Fowell DJ, Binder S, Tsao B, Locksley RM, Moore KW, Kronenberg M - J. Exp. Med. (1997)

Bottom Line: Interleukin (IL)-10 is a pleiotropic cytokine which inhibits a broad array of immune parameters including T helper cell type 1 (Th1) cytokine production, antigen presentation, and antigen-specific T cell proliferation.Upon in vitro stimulation, spleen cells from unimmunized transgenic mice secrete higher levels of IL-10 and lower amounts of IFN-gamma than do controls, although no gross abnormalities were detected in lymphocyte populations or serum Ig levels.These results demonstrate that a single alteration in the T cell cytokine profile can lead to dramatic changes in immune responses in a manner that is stimulus dependent.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biology Institute, Department of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.

ABSTRACT
Interleukin (IL)-10 is a pleiotropic cytokine which inhibits a broad array of immune parameters including T helper cell type 1 (Th1) cytokine production, antigen presentation, and antigen-specific T cell proliferation. To understand the consequences of altered expression of IL-10 in immune models of autoimmune disease, the response to infectious agents, and the response to tumors, we developed transgenic mice expressing IL-10 under the control of the IL-2 promoter. Upon in vitro stimulation, spleen cells from unimmunized transgenic mice secrete higher levels of IL-10 and lower amounts of IFN-gamma than do controls, although no gross abnormalities were detected in lymphocyte populations or serum Ig levels. Transfer of normally pathogenic CD4(+) CD45RBhigh splenic T cells from IL-10 transgenic mice did not cause colitis in recipient severe combined immunodeficiency mice. Furthermore, co-transfer of these transgenic cells with CD4(+) CD45RBhigh T cells from control mice prevented disease. Transgenic mice retained their resistance to Leishmania major infection, indicating that their cell-mediated immune responses were not globally suppressed. Lastly, in comparison to controls, IL-10 transgenic mice were unable to limit the growth of immunogenic tumors. Administration of blocking IL-10 mAbs restored in vivo antitumor responses in the transgenic mice. These results demonstrate that a single alteration in the T cell cytokine profile can lead to dramatic changes in immune responses in a manner that is stimulus dependent. These mice will be useful in defining differences in inflammatory conditions and cellular immunity mediated by IL-10.

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Lack of intestinal inflammation in SCID recipients of CD4+ CD45RBhigh T cells from IL-10 transgenic mice. Tissues from the distal colon  were stained with hematoxylin and eosin and scored as described in Materials and Methods. (A) Section of distal colon from a SCID recipient injected  with control CD4+ CD45RBhigh T cells. Note the loss of goblet cells and disorganization of the epithelial cells. (B) Section of distal colon from a SCID  recipient injected with IL-10 transgenic, CD4+ CD45RBhigh T cells. Original magnification, ×78 for both sections.
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Figure 4: Lack of intestinal inflammation in SCID recipients of CD4+ CD45RBhigh T cells from IL-10 transgenic mice. Tissues from the distal colon were stained with hematoxylin and eosin and scored as described in Materials and Methods. (A) Section of distal colon from a SCID recipient injected with control CD4+ CD45RBhigh T cells. Note the loss of goblet cells and disorganization of the epithelial cells. (B) Section of distal colon from a SCID recipient injected with IL-10 transgenic, CD4+ CD45RBhigh T cells. Original magnification, ×78 for both sections.

Mentions: To determine the effect of altered IL-10 expression in the transgenic mice on Th1 cytokine synthesis during an in vivo immune response, we investigated a colitis model dependent upon the secretion of IFN-γ and TNF-α for pathogenesis. Transfer of CD4+ CD45RBhigh splenic T cells to SCID or RAG-2−/− immune-deficient recipients leads to a wasting disease that is characterized by Th1 cytokine release and inflammation of the large intestine, which might be similar to inflammatory bowel disease in humans (20–23). Recipients of control CD4+ CD45RBhigh splenic T cells followed a typical course of disease, losing weight at about 4 wk and remaining sick for the duration of the study (Fig. 3). These mice required killing by 9 wk after transfer, as they developed a hunched appearance and piloerection of the coat. By contrast, the recipients of CD4+ CD45RBhigh T cells from the IL-10 transgenic mice gained weight early on, and were able to maintain their weight for the entire experiment (Fig. 3). No other signs of illness were seen in recipients of T cells from the transgenic mice throughout the course of the study. Histological analysis indicates that the large intestines of recipients of CD4+ CD45RBhigh T cells from nontransgenic littermates have the typical hallmarks of inflammation of this model, consisting of lymphocyte infiltration, epithelial hyperplasia, and loss of goblet cells (Fig. 4 A). The recipients of IL-10 transgenic T lymphocytes have virtually normal large intestines (Fig. 4 B). The average histological scores were evaluated as described previously (12) and in Materials and Methods. For the distal colon of recipients of nontransgenic T cells, the score was 13.5 out of a possible 15 (n = 4). The score was 4.5 for the recipients of IL-10 transgenic T cells (n = 3), which is similar to that of normal mouse distal colon (12). Preparations of the small and large intestinal lamina propria lymphocytes and intraepithelial lymphocyte populations of the SCID recipients revealed numbers of IL-10 transgenic derived lymphocytes comparable to that after transfer of nontransgenic T cells (Hagenbaugh, A., data not shown). These data indicated that the CD4+ CD45RBhigh T cells from IL-10 transgenic mice were not impaired in their ability to colonize the SCID intestine.


Altered immune responses in interleukin 10 transgenic mice.

Hagenbaugh A, Sharma S, Dubinett SM, Wei SH, Aranda R, Cheroutre H, Fowell DJ, Binder S, Tsao B, Locksley RM, Moore KW, Kronenberg M - J. Exp. Med. (1997)

Lack of intestinal inflammation in SCID recipients of CD4+ CD45RBhigh T cells from IL-10 transgenic mice. Tissues from the distal colon  were stained with hematoxylin and eosin and scored as described in Materials and Methods. (A) Section of distal colon from a SCID recipient injected  with control CD4+ CD45RBhigh T cells. Note the loss of goblet cells and disorganization of the epithelial cells. (B) Section of distal colon from a SCID  recipient injected with IL-10 transgenic, CD4+ CD45RBhigh T cells. Original magnification, ×78 for both sections.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196349&req=5

Figure 4: Lack of intestinal inflammation in SCID recipients of CD4+ CD45RBhigh T cells from IL-10 transgenic mice. Tissues from the distal colon were stained with hematoxylin and eosin and scored as described in Materials and Methods. (A) Section of distal colon from a SCID recipient injected with control CD4+ CD45RBhigh T cells. Note the loss of goblet cells and disorganization of the epithelial cells. (B) Section of distal colon from a SCID recipient injected with IL-10 transgenic, CD4+ CD45RBhigh T cells. Original magnification, ×78 for both sections.
Mentions: To determine the effect of altered IL-10 expression in the transgenic mice on Th1 cytokine synthesis during an in vivo immune response, we investigated a colitis model dependent upon the secretion of IFN-γ and TNF-α for pathogenesis. Transfer of CD4+ CD45RBhigh splenic T cells to SCID or RAG-2−/− immune-deficient recipients leads to a wasting disease that is characterized by Th1 cytokine release and inflammation of the large intestine, which might be similar to inflammatory bowel disease in humans (20–23). Recipients of control CD4+ CD45RBhigh splenic T cells followed a typical course of disease, losing weight at about 4 wk and remaining sick for the duration of the study (Fig. 3). These mice required killing by 9 wk after transfer, as they developed a hunched appearance and piloerection of the coat. By contrast, the recipients of CD4+ CD45RBhigh T cells from the IL-10 transgenic mice gained weight early on, and were able to maintain their weight for the entire experiment (Fig. 3). No other signs of illness were seen in recipients of T cells from the transgenic mice throughout the course of the study. Histological analysis indicates that the large intestines of recipients of CD4+ CD45RBhigh T cells from nontransgenic littermates have the typical hallmarks of inflammation of this model, consisting of lymphocyte infiltration, epithelial hyperplasia, and loss of goblet cells (Fig. 4 A). The recipients of IL-10 transgenic T lymphocytes have virtually normal large intestines (Fig. 4 B). The average histological scores were evaluated as described previously (12) and in Materials and Methods. For the distal colon of recipients of nontransgenic T cells, the score was 13.5 out of a possible 15 (n = 4). The score was 4.5 for the recipients of IL-10 transgenic T cells (n = 3), which is similar to that of normal mouse distal colon (12). Preparations of the small and large intestinal lamina propria lymphocytes and intraepithelial lymphocyte populations of the SCID recipients revealed numbers of IL-10 transgenic derived lymphocytes comparable to that after transfer of nontransgenic T cells (Hagenbaugh, A., data not shown). These data indicated that the CD4+ CD45RBhigh T cells from IL-10 transgenic mice were not impaired in their ability to colonize the SCID intestine.

Bottom Line: Interleukin (IL)-10 is a pleiotropic cytokine which inhibits a broad array of immune parameters including T helper cell type 1 (Th1) cytokine production, antigen presentation, and antigen-specific T cell proliferation.Upon in vitro stimulation, spleen cells from unimmunized transgenic mice secrete higher levels of IL-10 and lower amounts of IFN-gamma than do controls, although no gross abnormalities were detected in lymphocyte populations or serum Ig levels.These results demonstrate that a single alteration in the T cell cytokine profile can lead to dramatic changes in immune responses in a manner that is stimulus dependent.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biology Institute, Department of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.

ABSTRACT
Interleukin (IL)-10 is a pleiotropic cytokine which inhibits a broad array of immune parameters including T helper cell type 1 (Th1) cytokine production, antigen presentation, and antigen-specific T cell proliferation. To understand the consequences of altered expression of IL-10 in immune models of autoimmune disease, the response to infectious agents, and the response to tumors, we developed transgenic mice expressing IL-10 under the control of the IL-2 promoter. Upon in vitro stimulation, spleen cells from unimmunized transgenic mice secrete higher levels of IL-10 and lower amounts of IFN-gamma than do controls, although no gross abnormalities were detected in lymphocyte populations or serum Ig levels. Transfer of normally pathogenic CD4(+) CD45RBhigh splenic T cells from IL-10 transgenic mice did not cause colitis in recipient severe combined immunodeficiency mice. Furthermore, co-transfer of these transgenic cells with CD4(+) CD45RBhigh T cells from control mice prevented disease. Transgenic mice retained their resistance to Leishmania major infection, indicating that their cell-mediated immune responses were not globally suppressed. Lastly, in comparison to controls, IL-10 transgenic mice were unable to limit the growth of immunogenic tumors. Administration of blocking IL-10 mAbs restored in vivo antitumor responses in the transgenic mice. These results demonstrate that a single alteration in the T cell cytokine profile can lead to dramatic changes in immune responses in a manner that is stimulus dependent. These mice will be useful in defining differences in inflammatory conditions and cellular immunity mediated by IL-10.

Show MeSH
Related in: MedlinePlus