The in vitro anti-inflammatory effects of recombinant anti-CD25 immunotoxin on lamina propria T cells of patients with inflammatory bowel disease are not sufficient to cure experimental colitis in mice

Pfister, Kerstin; Wittig, B.; Jüngling, B.; Ecker, K. W.; Barth, Stefan; Hühn, Michael; Sasse, Stephanie; Engert, Andreas; Mueller-Molaian, Ina; Diehl, Volker; Zeitz, Martin; Stallmach, Andreas

doi:10.1007/s003840100336

Cited by 6 publications

(6 citation statements)

References 23 publications

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“…Therefore, targeting of the IL‐2R affects both effector and suppressor arms of the immune reaction. Various conjugates of IL‐2 display different activities, such as inefficient treatment of experimental colitis by a Pseudomonas exotoxin‐A chimeric molecule 56. The two cytotoxic molecules evaluated in this study had distinct effects on the immune profiles of healthy mice as well as at therapeutic doses that prevented TNBS‐induced mortality and DSS‐induced morbidity.…”

Section: Discussionmentioning

confidence: 95%

Targeted therapy to the IL‐2R using diphtheria toxin and caspase‐3 fusion proteins modulates Treg and ameliorates inflammatory colitis

Yarkoni

Sagiv²,

Kaminitz

et al. 2009

Eur J Immunol

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Pathogenic lymphocytes in the enteric wall of inflammatory bowel disease patients display various abnormalities, including reduced sensitivity to apoptosis. We evaluated a therapeutic approach to elimination of cytotoxic cells, using two IL-2 fusion proteins, a diphtheria toxin (IL2-DT) and a caspase-3 (IL2-cas) conjugate. In models of acute (dextran sodium sulfate and trinitrobenzene sulfonic acid) and chronic (dextran sodium sulfate) toxic colitis, therapeutic doses of the fusion proteins improved survival and prevented colon shortening. While both chimeric proteins eradicated CD41 CD251 Foxp3 1 T cells in mesenteric LN, IL2-DT caused severe lymphopenia. In contrast, IL2-cas was equally protective and increased fractional expression of Foxp3. Similar effects of the fusion proteins were observed in healthy mice: IL2-DT caused lymphopenia and IL2-cas increased fractional expression of FoxP3. The fusion proteins induced apoptosis in CD25 1T cells in vitro, with lower toxicity of IL2-cas to Foxp3 1 T cells. These data infer that targeted depletion of cells expressing the IL-2 receptor has therapeutic potential in models of inflammatory colitis, despite depletion of CD25 1 Treg. The IL2-cas fusion protein is particularly relevant to inflammatory bowel disease, as direct internalization of toxic moieties overcomes multiple pathways of resistance to apoptosis of colitogenic T cells.

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Section: Discussionmentioning

confidence: 95%

Targeted therapy to the IL‐2R using diphtheria toxin and caspase‐3 fusion proteins modulates Treg and ameliorates inflammatory colitis

Yarkoni

Sagiv²,

Kaminitz

et al. 2009

Eur J Immunol

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“…Another new interesting approach is the mechanical removal of leucocytes from patients’ peripheral blood using apheresis, in order to reduce the number of granulocytes, monocytes and lymphocytes, all of which can aggravate inflammation 32. Pfister et al 33 described the use of a recombinant anti-CD25 immunotoxin. This was found to be insufficient to cure experimental colitis in mice models, even though they demonstrated a killing effect in vitro on lamina propria T cells of patients with IBD.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic potency of IL2-caspase 3 targeted treatment in a murine experimental model of inflammatory bowel disease

Shteingart

Rapoport

Grodzovski

et al. 2008

Gut

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“…Furthermore, it remains to be explained why and how various fusion proteins that target the IL‐2 receptor but use different apoptotic moieties affect differentially autoimmunity. For example, anti–IL‐2 antibodies did not provide effective protection in patients suffering from ulcerative colitis 8 and a fusion protein composed of IL‐2 conjugated to Pseudomonas exotoxin‐A provided no protection in models of experimental colitis 39 . Another conjugate composed of diphtheria toxin showed specific toxicity to colitogenic cells in vitro ; 40 however, it ameliorated the course of DSS‐induced colitis at toxic doses that caused severe lymphodepletion (Sagiv, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

“…For example, anti-IL-2 antibodies did not provide effective protection in patients suffering from ulcerative colitis 8 and a fusion protein composed of IL-2 conjugated to Pseudomonas exotoxin-A provided no protection in models of experimental colitis. 39 Another conjugate composed of diphtheria toxin showed specific toxicity to colitogenic cells in vitro; 40 however, it ameliorated the course of DSS-induced colitis at toxic doses that caused severe lymphodepletion (Sagiv, unpublished data). IL2-cas has evolved as an additional prospective tool for treatment of IBD, as it has a wider therapeutic range with low toxicity.…”

Section: Discussionmentioning

confidence: 99%

A Fusion Protein Composed of IL‐2 and Caspase‐3 Ameliorates the Outcome of Experimental Inflammatory Colitis

Sagiv

Kaminitz

Lorberboum-Galski

et al. 2009

Annals of the New York Academy of Sciences

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Targeted depletion of immune cells expressing the interleukin-2 (IL-2) receptor can exacerbate inflammatory bowel disease (IBD) through elimination of regulatory T (Treg) cells, or ameliorate its course by depletion of cytotoxic cells. To answer this question we used a fusion protein composed of IL-2 and caspase-3 (IL2-cas) in an experimental model of DSS-induced toxic colitis. In a preventive setting, co-administration of DSS with a daily therapeutic dose of IL2-cas for seven days improved all disease parameters. Although CD4(+)CD25(+) T cells were depleted in the mesenteric lymph nodes, a fractional increase in CD4(+)FoxP3(+) T cells was observed in the spleen. Likewise, IL2-cas therapy improved the outcome of established disease in a chronic model of colitis. These data demonstrate that therapies that use IL-2 as a targeting moiety exert a protective effect over the colon under conditions of inflammation. The efficacy of IL-2-targeted therapy is attributed to reduced activity of reactive T cells, which ameliorates the secondary inflammatory infiltration. IL2-cas evolves as a potential therapeutic tool in IBD.

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The in vitro anti-inflammatory effects of recombinant anti-CD25 immunotoxin on lamina propria T cells of patients with inflammatory bowel disease are not sufficient to cure experimental colitis in mice

Cited by 6 publications

References 23 publications

Targeted therapy to the IL‐2R using diphtheria toxin and caspase‐3 fusion proteins modulates Treg and ameliorates inflammatory colitis

Targeted therapy to the IL‐2R using diphtheria toxin and caspase‐3 fusion proteins modulates Treg and ameliorates inflammatory colitis

Therapeutic potency of IL2-caspase 3 targeted treatment in a murine experimental model of inflammatory bowel disease

A Fusion Protein Composed of IL‐2 and Caspase‐3 Ameliorates the Outcome of Experimental Inflammatory Colitis

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