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In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection

Gene Therapy volume 18, pages 945–952 (2011)Cite this article

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Abstract

The humoral branch of the immune response has an important role in acute and chronic allograft dysfunction. The CD40/CD40L costimulatory pathway is crucial in B- and T- alloresponse. Our group has developed a new small interfering RNA (siRNA) molecule against CD40 that effectively inhibits its expression. The aim of the present study was to prevent rejection in an acute vascular rejection model of kidney transplant by intra-graft gene silencing with anti-CD40 siRNA (siCD40), associated or not with sub-therapeutic rapamycin. Four groups were designed: unspecific siRNA as control; sub-therapeutic rapamycin; siCD40; and combination therapy. Long-surviving rats were found only in both siCD40-treated groups. The CD40 mRNA was overexpressed in control grafts but treatment with siCD40 decreased its expression. Recipient spleen CD40+ B-lymphocytes were reduced in both siCD40-treated groups. Moreover, CD40 silencing reduced donor-specific antibodies, graft complement deposition and immune-inflammatory mediators. The characteristic histological features of humoral rejection were not found in siCD40-treated grafts, which showed a more cellular histological pattern. Therefore, the intra-renal effective blockade of the CD40/CD40L signal reduces the graft inflammation as well as the incidence of humoral vascular acute rejection, finally changing the type of rejection from humoral to cellular.

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Acknowledgements

This study was supported by grants from Instituto de Salud Carlos III/FIS (PI03/0082, PI03/0516, PI06/0230, PS09/00107) and Fundación SENEFRO 2007. Immaculada Herrero-Fresneda and Josep M. Aran are researchers from ‘Programa Estabilización Investigadores’ financed by ISCIII and Dpt. Salut Generalitat Catalunya. Elia Ripoll is the recipient of a fellowship from IDIBELL. We thank Núria Bolaños and Esther Herrero and Serveis Científico-Tècnics (UB, Bellvitge) for technical support.

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Author notes

  1. R Pluvinet

    Present address: 4Current address: Institute of Predictive and Personalized Medicine of Cancer, Crta Can Ruti, Camí de les Escoles s/n 08916 Badalona, Barcelona, Spain.,

  2. E Ripoll and R Pluvinet: These authors contributed equally to this work.

  3. J M Grinyó and J M Aran: Shares credit for senior authorship.

Authors and Affiliations

  1. Experimental Renal Transplantation, Laboratory of Experimental Nephrology, IDIBELL. Hospital Universitari de Bellvitge, Laboratori 4122, 4a Pl. Pavelló Govern, Campus Bellvitge, Barcelona, Spain

    E Ripoll, J Torras, M Franquesa, L Cassis, J M Cruzado, O Bestard, J M Grinyó & I Herrero-Fresneda

  2. Medical and Molecular Genetics Center, IDIBELL, Hospital Duran i Reynals, Barcelona, Spain

    R Pluvinet, R Olivar & J M Aran

  3. Pathology Department, Hospital Universitari de Bellvitge, Feixa Llarga s/n, Barcelona, Spain

    A Vidal

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Correspondence to J M Aran or I Herrero-Fresneda.

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Ripoll, E., Pluvinet, R., Torras, J. et al. In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection. Gene Ther 18, 945–952 (2011). https://doi.org/10.1038/gt.2011.39

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