Targeting T cell costimulation in autoimmune disease

Abstract

Many factors contribute to the pathogenesis of autoimmune diseases. Targets for treating such debilitating diseases will become more apparent by understanding the nature of immune activation. This review examines the possibility of targeting costimulation and discusses the molecules found on the T cell and the antigen-presenting cell (APC) that participate in T cell activation. Although new molecules continue to be discovered, the functions of B7-1 (CD80), B7-2 (CD86), CD28, cytotoxic T lymphocyte antigen 4 (CTLA-4), inducible costimulator (ICOS), programmed death 1 (PD-1), OX 40 (CD134) and CD40 ligand (CD40L, CD154) are now sufficiently understood that immunologists are targeting them to manipulate T cells to slow the progression of autoimmune diseases or treat tumours through the increase in T cell activation. CD28, ICOS, OX 40 and CD40L are considered the costimulatory molecules that increase T cell activation. However, ICOS and OX 40 appear to act on memory cells while CD28 is predominantly a naive T cell activator. Most therapies in the treatment of autoimmunity that target these molecules work through blockade of their function with receptor specific immunoglobulin (Ig). CTLA-4 and PD-1 are considered to be the inhibitory T cell costimulators. While stimulating CTLA-4 has not been a widely used therapy, using soluble CTLA-4Ig to block B7 and disrupt the B7/CD28 pathway is fairly common. The majority of therapeutic use for PD-1 stems from targeting PD-1 with its natural ligand. It is hoped that therapies targeting costimulation may provide a means of conserving the patient's normal T cell repertoire and immune function whilst eliminating or suppressing autoreactive T cells and thus provide a more efficient means to treat autoimmune disease.

Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for immune-related molecules by central nervous system mixed glial cell cultures

“…As an example, Th2 cytokines downregulated the gene for CD152 (CTLA-4), a protein associated with T cells as a costimulatory molecule by interacting with B7.1 and B7.2 (CD80 and CD86 respectively), which are found on antigen-presenting cells [163]. Th1 and M/M cytokines both upregulated the gene for OX40 precursor, similar to human CD134, a T-cell activation and costimulation molecule associated with memory cells, and a member of TNRSF [164]. Whether the cytokines would mediate a similar effect on a paracrine basis on infiltrating T-cells when secreted by infiltrating inflammatory cells and/or resident glial cells needs further investigation as such effects could modulate lesion formation.…”

Recent Advances in the Treatment of Neurological Autoimmune Disorders

“…Other molecules like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) regulate negative co-stimulation. Hence, effective therapeutics targeting these molecules will have a significant impact in the autoimmune disease control (Racke & Stuart, 2002;Kanwar et al 2004). The auto reactive T-cells gain entry into the CNS by the pairing of cell surface molecules leukocyte function-associated antigen-1 (LFA-1) and very late antigen-4(VLA-4) with the cell adhesion molecules, intercellular cell adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) expressed on the brain capillary endothelium.…”

Altering immune tolerance therapeutically: the power of negative thinking

“…When T cells interact with the APCs in the process of antigen recognition, several pairs of molecules interact to stimulate a response. Most notably, this includes CD28/B7, ICOS/ B7RP-1, and CD40L/CD40 interactions [26,27]. Conversely, inhibitory signals are delivered through CTLA-4/B7 [28 -30], PD-1/PD-L1/L2 [31][32][33][34][35][36][37][38], and BTLA/B7x interactions [24].…”