The potential of Fas ligand (apoptosis-inducing molecule) as an unconventional therapeutic target in type 1 diabetes
- 1 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- 2 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- 3 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
The development of type 1 diabetes (T1D) is driven by autoreactive T cells that attack and destroy the insulin-producing β-cells in pancreatic islets, forcing patients to take multiple daily insulin injections. Insulin therapy, however, is not a cure and diabetic patients often develop serious long-term microvascular and cardiovascular complications. Therefore, intensive efforts are being directed toward developing safe immunotherapy for the disease that does not impair host defense and preserves β-cells, leading to better glycemic control than exogenous insulin therapy. Engineering therapies that differentially cripple or tolerate autoreactive diabetogenic T cells while sparing protective T cells necessary for maintaining a competent immune system has proven challenging. Instead, recent efforts have focused on modulating or resetting the immune system through global but transient deletion of T cells or B cells using anti-CD3 or anti-CD20 mAb, respectively. However, phase III clinical trials have shown promising but modest efficacy so far with these approaches. Therefore, there is a need to identify novel biological targets that do not fit the classic properties of being involved in adaptive immune cell activation. In this prospective, we provide preclinical evidence that targeting Fas ligand (FasL) may provide a unique opportunity to prevent or cure T1D and perhaps other organ-specific autoimmune diseases without causing immune suppression. Unlike conventional targets that are involved in T and B lymphocyte activation (such as CD3 and CD20, respectively), FasL is an apoptosis-inducing surface molecule that triggers cell death by binding to Fas (also known as CD95 Apo-1). Therefore, targeting FasL is not expected to cause immune suppression, the Achilles Heel of conventional approaches. We will discuss the hypothesis that targeting FasL has unique benefits that are not offered by current immunomodulatory approaches.
Keywords: autoimmune diabetes, Fas pathway, immunotherapy, immunosuppression, apoptosis, lymphoproliferative disorders
Citation: Hamad ARAR, Arcara K, Uddin S and Donner T (2012) The potential of Fas ligand (apoptosis-inducing molecule) as an unconventional therapeutic target in type 1 diabetes. Front. Immun. 3:196. doi: 10.3389/fimmu.2012.00196
Received: 10 April 2012; Accepted: 21 June 2012;
Published online: 12 July 2012.
Copyright: © 2012 Hamad, Arcara, Uddin and Donner. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Abdel Rahim A. R. Hamad, Department of Pathology, Johns Hopkins University School of Medicine, Ross Building, Room 664G, 720 Rutland Avenue, Baltimore, MD 21205, USA. e-mail: firstname.lastname@example.org