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Nonlymphocyte-derived tumor necrosis factor is required for induction of colitis in recombination activating gene (RAG)2(-/-) mice upon transfer of CD4(+)CD45RB(hi) T cells.

Corazza N, Eichenberger S, Eugster HP, Mueller C - J. Exp. Med. (1999)

Bottom Line: In contrast, clinical signs of disease are completely absent in TNF(-/-)RAG2(-/-) recipients of TNF(-/-) CD4(+)CD45RB(hi) T cells, although elevated numbers of interferon-gamma-producing cells are present in the colonic mucosa.This protection from colitis is not a consequence of the absence of LT-alpha, as TNF-alpha(-/-)RAG2(-/-) recipients of TNF-alpha(-/-) CD4(+)CD45RB(hi) T cells are also protected from colitis induction.These results demonstrate the importance of TNF production by non-T cells of the colonic mucosa in the pathogenesis of colitis and provide direct evidence for a nonredundant role of TNF-alpha in this mouse model of colitis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, Division of Immunopathology, University of Bern, CH-3010 Bern, Switzerland.

ABSTRACT
In this study, we addressed the role of tumor necrosis factor (TNF)-alpha and lymphotoxin (LT)-alpha in the development of colitis and defined the cellular sources (T cells versus non-T cells) of TNF (TNF-alpha and LT-alpha) relevant to disease development. After adoptive transfer of TNF(+/+) CD4(+)CD45RB(hi) splenocytes into TNF(+/+) recombination activating gene (RAG)2(-/-) mice, the recipients develop massive inflammation of the large intestinal mucosa concurrent with massive weight loss. In contrast, clinical signs of disease are completely absent in TNF(-/-)RAG2(-/-) recipients of TNF(-/-) CD4(+)CD45RB(hi) T cells, although elevated numbers of interferon-gamma-producing cells are present in the colonic mucosa. Surprisingly, upon transfer of TNF(-/-)CD4(+)CD45RB(hi) T cells into TNF(+/+)RAG2(-/-) recipients, colitis develops with kinetics similar to those upon transfer of TNF(+/+)CD4(+)CD45RB(hi) donor cells. In contrast, no clinical signs of colitis are observed in TNF(-/-)RAG2(-/-) recipients of TNF(+/+)CD4(+)CD45RB(hi) T cells. This protection from colitis is not a consequence of the absence of LT-alpha, as TNF-alpha(-/-)RAG2(-/-) recipients of TNF-alpha(-/-) CD4(+)CD45RB(hi) T cells are also protected from colitis induction. These results demonstrate the importance of TNF production by non-T cells of the colonic mucosa in the pathogenesis of colitis and provide direct evidence for a nonredundant role of TNF-alpha in this mouse model of colitis.

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TNF-α/LT-α is essential to induce wasting disease. Reconstitution of RAG2−/− mice with 2 × 105 TNF+/+ CD4+CD45RBhi T cells induces colitis characterized by weight loss (A), whereas no weight loss is detected in TNF−/− recipients reconstituted with 2 × 105 TNF−/− CD4+CD45RBhi T cells (B). As negative controls, mice were injected with 2 × 105 CD4+CD45RBlo T cells. The change in weight is expressed as percentage of the weight at the time of cell transfer. Data represent the mean values ± SD of four to five mice per group. Experiments were repeated at least three times.
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Figure 1: TNF-α/LT-α is essential to induce wasting disease. Reconstitution of RAG2−/− mice with 2 × 105 TNF+/+ CD4+CD45RBhi T cells induces colitis characterized by weight loss (A), whereas no weight loss is detected in TNF−/− recipients reconstituted with 2 × 105 TNF−/− CD4+CD45RBhi T cells (B). As negative controls, mice were injected with 2 × 105 CD4+CD45RBlo T cells. The change in weight is expressed as percentage of the weight at the time of cell transfer. Data represent the mean values ± SD of four to five mice per group. Experiments were repeated at least three times.

Mentions: When 2 × 105 CD4+CD45RBhi T cells from B6 × 129 donor animals (TNF+/+) were transferred into sex-matched, 8–10-wk-old syngeneic RAG2−/− mice, the recipients rapidly started to lose weight 12–14 d after adoptive T cell transfer. This dramatic wasting disease led to an average weight loss of 25–30% 24 d after transfer and is associated with clinical signs of severe colitis, in particular, persistent diarrhea and occasionally also bloody stool and anal prolapses. RAG2−/− recipients of 2 × 105 CD4+CD45RBlo T cells did not, however, show weight loss, and clinical signs of colitis were completely absent throughout the entire observation period (Fig. 1 A).


Nonlymphocyte-derived tumor necrosis factor is required for induction of colitis in recombination activating gene (RAG)2(-/-) mice upon transfer of CD4(+)CD45RB(hi) T cells.

Corazza N, Eichenberger S, Eugster HP, Mueller C - J. Exp. Med. (1999)

TNF-α/LT-α is essential to induce wasting disease. Reconstitution of RAG2−/− mice with 2 × 105 TNF+/+ CD4+CD45RBhi T cells induces colitis characterized by weight loss (A), whereas no weight loss is detected in TNF−/− recipients reconstituted with 2 × 105 TNF−/− CD4+CD45RBhi T cells (B). As negative controls, mice were injected with 2 × 105 CD4+CD45RBlo T cells. The change in weight is expressed as percentage of the weight at the time of cell transfer. Data represent the mean values ± SD of four to five mice per group. Experiments were repeated at least three times.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195702&req=5

Figure 1: TNF-α/LT-α is essential to induce wasting disease. Reconstitution of RAG2−/− mice with 2 × 105 TNF+/+ CD4+CD45RBhi T cells induces colitis characterized by weight loss (A), whereas no weight loss is detected in TNF−/− recipients reconstituted with 2 × 105 TNF−/− CD4+CD45RBhi T cells (B). As negative controls, mice were injected with 2 × 105 CD4+CD45RBlo T cells. The change in weight is expressed as percentage of the weight at the time of cell transfer. Data represent the mean values ± SD of four to five mice per group. Experiments were repeated at least three times.
Mentions: When 2 × 105 CD4+CD45RBhi T cells from B6 × 129 donor animals (TNF+/+) were transferred into sex-matched, 8–10-wk-old syngeneic RAG2−/− mice, the recipients rapidly started to lose weight 12–14 d after adoptive T cell transfer. This dramatic wasting disease led to an average weight loss of 25–30% 24 d after transfer and is associated with clinical signs of severe colitis, in particular, persistent diarrhea and occasionally also bloody stool and anal prolapses. RAG2−/− recipients of 2 × 105 CD4+CD45RBlo T cells did not, however, show weight loss, and clinical signs of colitis were completely absent throughout the entire observation period (Fig. 1 A).

Bottom Line: In contrast, clinical signs of disease are completely absent in TNF(-/-)RAG2(-/-) recipients of TNF(-/-) CD4(+)CD45RB(hi) T cells, although elevated numbers of interferon-gamma-producing cells are present in the colonic mucosa.This protection from colitis is not a consequence of the absence of LT-alpha, as TNF-alpha(-/-)RAG2(-/-) recipients of TNF-alpha(-/-) CD4(+)CD45RB(hi) T cells are also protected from colitis induction.These results demonstrate the importance of TNF production by non-T cells of the colonic mucosa in the pathogenesis of colitis and provide direct evidence for a nonredundant role of TNF-alpha in this mouse model of colitis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, Division of Immunopathology, University of Bern, CH-3010 Bern, Switzerland.

ABSTRACT
In this study, we addressed the role of tumor necrosis factor (TNF)-alpha and lymphotoxin (LT)-alpha in the development of colitis and defined the cellular sources (T cells versus non-T cells) of TNF (TNF-alpha and LT-alpha) relevant to disease development. After adoptive transfer of TNF(+/+) CD4(+)CD45RB(hi) splenocytes into TNF(+/+) recombination activating gene (RAG)2(-/-) mice, the recipients develop massive inflammation of the large intestinal mucosa concurrent with massive weight loss. In contrast, clinical signs of disease are completely absent in TNF(-/-)RAG2(-/-) recipients of TNF(-/-) CD4(+)CD45RB(hi) T cells, although elevated numbers of interferon-gamma-producing cells are present in the colonic mucosa. Surprisingly, upon transfer of TNF(-/-)CD4(+)CD45RB(hi) T cells into TNF(+/+)RAG2(-/-) recipients, colitis develops with kinetics similar to those upon transfer of TNF(+/+)CD4(+)CD45RB(hi) donor cells. In contrast, no clinical signs of colitis are observed in TNF(-/-)RAG2(-/-) recipients of TNF(+/+)CD4(+)CD45RB(hi) T cells. This protection from colitis is not a consequence of the absence of LT-alpha, as TNF-alpha(-/-)RAG2(-/-) recipients of TNF-alpha(-/-) CD4(+)CD45RB(hi) T cells are also protected from colitis induction. These results demonstrate the importance of TNF production by non-T cells of the colonic mucosa in the pathogenesis of colitis and provide direct evidence for a nonredundant role of TNF-alpha in this mouse model of colitis.

Show MeSH
Related in: MedlinePlus