Abstract
Regulation of immune responses is critical for ensuring pathogen clearance and for preventing reaction against self-antigens. Failure or breakdown of immunological tolerance results in autoimmunity. CD28 is an important co-stimulatory receptor expressed on T cells that, upon specific ligand binding, delivers signals essential for full T-cell activation and for the development and homeostasis of suppressive regulatory T cells. Many in vivo mouse models have been used for understanding the role of CD28 in the maintenance of immune homeostasis, thus leading to the development of CD28 signaling modulators that have been approved for the treatment of some autoimmune diseases. Despite all of this progress, a deeper understanding of the differences between the mouse and human receptor is required to allow a safe translation of pre-clinical studies in efficient therapies. In this review, we discuss the role of CD28 in tolerance and autoimmunity and the clinical efficacy of drugs that block or enhance CD28 signaling, by highlighting the success and failure of pre-clinical studies, when translated to humans.
Highlights
Shifting the balance toward restoration of immune tolerance could represent an important goal of the ongoing research in autoimmunity
Most of the data on the pivotal role of CD28 in regulating tolerance and susceptibility to autoimmunity derive from mouse models, which have been extensively used for clarifying the pathogenic mechanisms of several autoimmune diseases as well as for identifying molecular targets to translate in clinical trials
These efforts led to the development of soluble CTLA-4-binding domain linked to the Fc region of Ig (CTLA-4Ig) able to efficiently bind B7 molecules and to block CD28/B7 interaction through the removal of its ligands from antigen-presenting cells (APCs), a process known as trans-endocytosis, and by directly interfering with T/APC interaction[15]
Summary
Shifting the balance toward restoration of immune tolerance could represent an important goal of the ongoing research in autoimmunity. Most of the data on the pivotal role of CD28 in regulating tolerance and susceptibility to autoimmunity derive from mouse models, which have been extensively used for clarifying the pathogenic mechanisms of several autoimmune diseases as well as for identifying molecular targets to translate in clinical trials These efforts led to the development of soluble CTLA-4-binding domain linked to the Fc region of Ig (CTLA-4Ig) able to efficiently bind B7 molecules (with a 20-fold higher affinity compared with the CD28Ig) and to block CD28/B7 interaction through the removal of its ligands from APC, a process known as trans-endocytosis, and by directly interfering with T/APC interaction[15]. More recent data by Haanstra et al showing the reduction of both CNS inflammation and demyelination in human EAE in rhesus macaques following the administration of FR104 CD28 blocking Ab31 strongly support a crucial role for CD28 in regulating the expansion and inflammatory function of autoreactive T cells in MS. The non-physiologic activation by CD28SAbs fails to induce PD-1 on the cell surface, leading to the loss of a crucial negative feedback conferred by the PD-1/PD-L1 interaction[56] that represents a key checkpoint of immune response by effecting its negative regulation mainly on CD2857
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