title: In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection.
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.
authors.affiliation: Experimental Renal Transplantation, Laboratory of Experimental Nephrology, IDIBELL. Hospital Universitari de Bellvitge, Laboratori 4122, 4a Pl. Pavelló Govern, Campus Bellvitge, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Ripoll
authors.forename: R
authors.initials: R
authors.lastname: Pluvinet
authors.forename: J
authors.initials: J
authors.lastname: Torras
authors.forename: R
authors.initials: R
authors.lastname: Olivar
authors.forename: A
authors.initials: A
authors.lastname: Vidal
authors.forename: M
authors.initials: M
authors.lastname: Franquesa
authors.forename: L
authors.initials: L
authors.lastname: Cassis
authors.forename: J M
authors.initials: JM
authors.lastname: Cruzado
authors.forename: O
authors.initials: O
authors.lastname: Bestard
authors.forename: J M
authors.initials: JM
authors.lastname: Grinyó
authors.forename: J M
authors.initials: JM
authors.lastname: Aran
authors.forename: I
authors.initials: I
authors.lastname: Herrero-Fresneda
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood; D019013:CD40 Antigens / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004359:Drug Therapy, Combination; D020868:Gene Silencing; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D056724:Immunity, Humoral / Q000276:immunology*; D007150:Immunohistochemistry; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D014184:Transplantation, Homologous
chemical_list: D000906:Antibodies; D019013:CD40 Antigens; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D020123:Sirolimus