Targeting co-stimulatory pathways: transplantation and autoimmunity

• Published in: Nature reviews. Nephrology Vol. 10; no. 1; pp. 14 - 24
• Main Authors: Ford, Mandy L., Adams, Andrew B., Pearson, Thomas C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2014; Nature Publishing Group
• Subjects: 631/250/38; 692/699/1585/104/1586; 692/700/565/251; 692/700/565/545/576; Antigens; Autoimmunity - immunology; Cell death; Clinical outcomes; Cytotoxicity; Glycoproteins; Humans; Immunoglobulins; Immunology; Kidney Transplantation; Ligands; Lymphocyte Activation - immunology; Lymphocytes; Medicine & Public Health; Nephrology; review-article; Signal Transduction - immunology; T-Lymphocytes - immunology; Transplants & implants
• ISSN: 1759-5061; 1759-507X
• DOI: 10.1038/nrneph.2013.183

Key Points T-cell co-stimulatory signals, expressed either constitutively or upon activation, critically affect the magnitude and character of autoreactive or alloreactive T-cell responses Targeting T-cell co-stimulation pathways to reduce pathological T-cell responses has met with therapeutic success in many instances, but challenges remain Efficacy of co-stimulatory blockade with abatacept or belatacept could be further optimized to improve inhibition of alloreactive and autoreactive T-cell responses by leaving co-inhibitory signals intact Clinical application of CD154 pathway blockade has, thus far, been limited, but novel reagents in development might allow for therapeutic manipulation of this pathway to achieve immunological tolerance Several other T-cell co-stimulatory pathways also hold promise as therapeutic targets for the treatment of autoimmunity and transplant rejection Understanding the interplay between individual co-stimulatory and co-inhibitory pathways will lead to rational and targeted therapeutic interventions to manipulate T-cell responses and improve clinical outcomes Co-inhibitory and co-stimulatory signals that are expressed upon T-cell-activation influence both autoreactive and alloreactive T-cell responses. Here, the authors describe the functional importance of T-cell co-stimulatory molecules in transplantation, tolerance and autoimmunity, and how therapeutic blockade of these pathways might be harnessed to manipulate the immune response to prevent or attenuate pathological immune responses. The myriad of co-stimulatory signals expressed, or induced, upon T-cell activation suggests that these signalling pathways shape the character and magnitude of the resulting autoreactive or alloreactive T-cell responses during autoimmunity or transplantation, respectively. Reducing pathological T-cell responses by targeting T-cell co-stimulatory pathways has met with therapeutic success in many instances, but challenges remain. In this Review, we discuss the T-cell co-stimulatory molecules that are known to have critical roles during T-cell activation, expansion, and differentiation. We also outline the functional importance of T-cell co-stimulatory molecules in transplantation, tolerance and autoimmunity, and we describe how therapeutic blockade of these pathways might be harnessed to manipulate the immune response to prevent or attenuate pathological immune responses. Ultimately, understanding the interplay between individual co-stimulatory and co-inhibitory pathways engaged during T-cell activation and differentiation will lead to rational and targeted therapeutic interventions to manipulate T-cell responses and improve clinical outcomes.