Targeting T-cell integrins in autoimmune and inflammatory diseases

Abstract

The recruitment of T cells to tissues and their retention there are essential processes in the pathogenesis of many autoimmune and inflammatory diseases. The mechanisms regulating these processes have become better understood over the past three decades and are now recognized to involve temporally and spatially specific interactions between cell-adhesion molecules. These include integrins, which are heterodimeric molecules that mediate in-to-out and out-to-in signalling in T cells, other leukocytes, and most other cells of the body. Integrin signalling contributes to T-cell circulation through peripheral lymph nodes, immunological synapse stability and function, extravasation at the sites of inflammation, and T-cell retention at these sites. Greater understanding of the contribution of integrin signalling to the role of T cells in autoimmune and inflammatory diseases has focused much attention on the development of therapeutics that target T-cell integrins. This literature review describes the structure, activation, and function of integrins with respect to T cells, then discusses the use of integrin-targeting therapeutics in inflammatory bowel disease, multiple sclerosis, and psoriasis. Efficacy and safety data from clinical trials and post-marketing surveillance are presented for currently approved therapeutics, therapeutics that have been withdrawn from the market, and novel therapeutics currently in clinical trials. This literature review will inform the reader of the current means of targeting T-cell integrins in autoimmune and inflammatory diseases, as well as recent developments in the field.

Keywords: T cells; autoimmune; inflammatory bowel disease; integrins; multiple sclerosis; psoriasis.

Graphical Abstract

Figure 1.

Targeting T-cell integrins in inflammatory bowel disease. Vedolizumab and ontamalimab inhibit the binding of α4β7 to MAdCAM-1 by inhibiting each molecule, respectively. Natalizumab, abrilumab, etrolizumab, PN-943, AJM300, and PTG-100 inhibit the binding of α4β7 to MAdCAM-1 and VCAM-1 by inhibiting the integrin itself. Natalizumab and AJM300 also inhibit the binding of α4β1 and VCAM-1. Alicaforsen downregulates the expression of ICAM-1 to inhibit its binding to αLβ2 and αMβ2. The action of the aforementioned drugs is to inhibit extravasation of T cells in the gut. Etrolizumab also acts to reduce the retention of T cells in the intestinal lamina propria by inhibiting the binding of αEβ7 to E-cadherin, expressed by intestinal epithelial cells. Created with BioRender.com

Figure 2.

Targeting T-cell integrins in multiple sclerosis and psoriasis. A: Natalizumab inhibits the binding of α4β1 to VCAM-1 to inhibit extravasation of T cells across the blood-brain barrier (BBB). B: Efalizumab inhibits the binding of αLβ2 to ICAM-1 to inhibit the extravasation of T cells into skin. Created with BioRender.com