Immunosuppression in Xenotransplantation with Wf10

Kemp, K.; Dieperink, Hans; Hansen, Alastair; Horn, Thomas; Johansen, Allan; Jensen, Jørgen Steen; Kemp, Grethe; Larsen, Svend; Lillevang, Søren Thue; Svendsen, M.; Freilow, E.; Kuhlmann, I.‐L; Kemp, E

doi:10.1034/j.1600-0773.2002.900610.x

Cited by 4 publications

(4 citation statements)

References 7 publications

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“…In line with this hypothesis graft survival in a concordant xenograft model was significantly prolonged in the presence of WF-10. 41–43 Importantly, given that WF-10 has inhibitory effects on the late phase of T-cell activation, it also seems especially beneficial for patients with chronic inflammatory diseases. One example is T1D, in which CD8 + T-cell-mediated killing is involved in the pathogenesis (reviewed in Gravano and Hoyer, 11 Santamaria, 12 , 13 Walter and Santamaria, 14 and Liblau et al .…”

Section: Discussionmentioning

confidence: 99%

The pro-oxidative drug WF-10 inhibits serial killing by primary human cytotoxic T-cells

Wabnitz

Balta

Schindler

et al. 2016

Cell Death Discovery

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Cytotoxic T-cells (CTLs) play an important role in many immune-mediated inflammatory diseases. Targeting cytotoxicity of CTLs would allow to interfere with immune-mediated tissue destruction. Here we demonstrate that WF-10, a pro-oxidative compound, inhibits CTL-mediated cytotoxicity. WF-10 did not influence early steps of target-cell killing, but impaired the ability of CTLs to detach from the initial target cell and to move to a second target cell. This reduced serial killing was accompanied by stronger enrichment of the adhesion molecule LFA-1 in the cytolytic immune synapse. LFA-1 clustering requires activation of the actin-bundling protein L-plastin and was accordingly diminished in L-plastin knockdown cells. Interestingly, WF-10 likely acts through regulating L-plastin: (I) It induced L-plastin activation through phosphorylation leading to enhanced LFA-1-mediated cell adhesion, and, importantly, (II) WF-10 lost its influence on target-cell killing in L-plastin knockdown cells. Finally, we demonstrate that WF-10 can improve immunosuppression by conventional drugs. Thus, while cyclosporine A alone had no significant effect on cytotoxicity of CTLs, a combination of cyclosporine A and WF-10 blocked target-cell killing synergistically. Together, our findings suggest that WF-10 – either alone or in combination with conventional immunosuppressive drugs – may be efficient to control progression of diseases, in which CTLs are crucially involved.

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Section: Discussionmentioning

confidence: 99%

The pro-oxidative drug WF-10 inhibits serial killing by primary human cytotoxic T-cells

Wabnitz

Balta

Schindler

et al. 2016

Cell Death Discovery

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“…Indeed, WF10 entered clinical practise for treatment of chronic inflammatory disorders such as proctitis, cystitis, mucositis 8 or diabetic foot ulcer (DFU). 9 In our current work, we found that WF10 inhibits CTL-mediated target cell killing in a dose-dependent manner, 6 providing a potential explanation of why graft survival in a concordant xenograft model was significantly prolonged in the presence of WF10, 10 and why WF10 improves the clinical outcome of DFU. 9 …”

mentioning

confidence: 62%

Oxidative downmodulation of T cell-mediated cytotoxicity

Wabnitz

Samstag

2016

Cell Death Dis

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“…For pain relief donors were given pentobarbital and recipients were given a combination of hypnorm, stesolid and temgesic. The experiment ended as the transplanted heart stopped beating (7, 8).…”

Section: Methodsmentioning

confidence: 99%

The resistance of delayed xenograft rejection to α(1,3)‐galactosyltransferase gene inactivation and CD4 depletion in a mouse‐to‐rat model

Hansen

Kirkeby²,

Aasted³

et al. 2003

APMIS

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Critical to the prevention of xenograft loss is the prevention of delayed xenograft rejection (DXR), due to its resistance to conventional immunosuppression. The role of the carbohydrate galactose-alpha1,3-galactose (alpha1,3Gal) has been a matter of great debate and it has been proposed that the reaction between alpha1,3Gal epitopes on donor endothelial cells and recipient anti-alpha1,3Gal antibodies (Abs) may damage the graft during DXR. Recipient anti-alpha1,3Gal Abs are produced by CD4-dependent B cells. To test the above-mentioned hypothesis, hearts from alpha1,3Gal-free mice (GT-Ko mice), generated by alpha1,3-galacto-syltransferase gene disruption, were transplanted to anti-alpha1,3Gal antibody-free Lew/Mol rats. This model consists of an alpha1,3Gal/alpha1,3Gal-antibody-free environment, eliminating a possible influence of this specific system on DXR. A subgroup of recipients were furthermore CD4 depleted in order to inhibit CD4-dependent B-cell antibody production. Rejected hearts were evaluated by light- and immunofluorescence microscopy. Treatment effects on recipient T-cell subsets and cytokine expression were analyzed by flow cytometry, while antibody production was measured by ELISA. All recipients developed DXR with no differences among the groups. DXR was related to thrombosis with IgG and IgM desposition in vessel walls, as well as macrophage and granulocyte accumulation in the myocardium. No complement C3, CD4 cells or NK cells were found. Flow cytometric analysis confirmed peripheral blood CD4 depletion and IFN-gamma suppression in CD4 Ab-treated recipients. Finally, ELISA showed that specific anti-alpha1,3Gal Ab production was absent. However, Ab(s) against an unidentified Galalpha 1 were found among recipients. In our model, DXR is resistant to alpha1,3-galactosyltransferase gene inactivation and CD4 depletion. However, other Galalpha 1 epitopes and antibodies may play a role during DXR. Further studies are needed to elucidate the precise pathways leading to DXR.

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Immunosuppression in Xenotransplantation with Wf10

Cited by 4 publications

References 7 publications

The pro-oxidative drug WF-10 inhibits serial killing by primary human cytotoxic T-cells

The pro-oxidative drug WF-10 inhibits serial killing by primary human cytotoxic T-cells

Oxidative downmodulation of T cell-mediated cytotoxicity

The resistance of delayed xenograft rejection to α(1,3)‐galactosyltransferase gene inactivation and CD4 depletion in a mouse‐to‐rat model

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