title: Costimulatory pathways in kidney transplantation: pathogenetic role, clinical significance and new therapeutic opportunities.
abstract: Costimulatory pathways play a key role in immunity, providing the second signal required for a full activation of adaptive immune response. Different costimulatory families (CD28, TNF-related, adhesion and TIM molecules), characterized by structural and functional analogies, have been described. Costimulatory molecules modulate T cell activation, B cell function, Ig production, cytokine release and many other processes, including atherosclerosis. Patients suffering from renal diseases present significant alterations of the costimulatory pathways, which might make them particularly liable to infections. These alterations are further pronounced in patients undergoing kidney transplantation. In these patients, different costimulatory patterns have been related to distinct clinical features. The importance that costimulation has gained during the last years has led to development of several pharmacological approaches to modulate this critical step in the immune activation. Different drugs, mainly monoclonal antibodies targeting various costimulatory molecules (i.e. anti-CD80, CTLA-4 fusion proteins, anti-CD154, anti-CD40, etc.) were designed and tested in both experimental and clinical studies. The results of these studies highlighted some criticisms, but also some promising findings and now costimulatory blockade is considered a suitable strategy, with belatacept (a CTLA-4 fusion protein) being approved as the first costimulatory blocker for use in renal transplantation. In this review, we summarize the current knowledge on costimulatory pathways in the setting of kidney transplantation. We describe the principal costimulatory molecule families, their role and clinical significance in patients undergoing renal transplantation and the new therapeutic approaches that have been developed to modulate the costimulatory pathways.
authors.affiliation: Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico S. Matteo and University of Pavia , Pavia , Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Esposito
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Grosjean
authors.forename: Teresa
authors.initials: T
authors.lastname: Rampino
authors.forename: Carmelo
authors.initials: C
authors.lastname: Libetta
authors.forename: Marilena
authors.initials: M
authors.lastname: Gregorini
authors.forename: Gianluca
authors.initials: G
authors.lastname: Fasoli
authors.forename: Gianluca
authors.initials: G
authors.lastname: Marchi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sileno
authors.forename: Francesca
authors.initials: F
authors.lastname: Montagna
authors.forename: Antonio
authors.initials: A
authors.lastname: Dal Canton
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D019138:Antibodies, Blocking / Q000276:immunology / Q000627:therapeutic use; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007674:Kidney Diseases / Q000276:immunology / Q000601:surgery; D016030:Kidney Transplantation / Q000009:adverse effects / Q000379:methods*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D061025:Costimulatory and Inhibitory T-Cell Receptors
keywords: CD28; CD40; belatacept; dialysis; drug development; graft rejection; kidney transplantation