Transfer of hematopoietic stem cells encoding autoantigen prevents autoimmune diabetes
Raymond J. Steptoe, … , Janine M. Ritchie, Leonard C. Harrison
Raymond J. Steptoe, … , Janine M. Ritchie, Leonard C. Harrison
Published May 1, 2003
Citation Information: J Clin Invest. 2003;111(9):1357-1363. https://doi.org/10.1172/JCI15995.
View: Text | PDF
Article Metabolism

Transfer of hematopoietic stem cells encoding autoantigen prevents autoimmune diabetes

Abstract

Bone marrow or hematopoietic stem cell transplantation is a potential treatment for autoimmune disease. The clinical application of this approach is, however, limited by the risks associated with allogeneic transplantation. In contrast, syngeneic transplantation would be safe and have wide clinical application. Because T cell tolerance can be induced by presenting antigen on resting antigen-presenting cells (APCs), we reasoned that hematopoietic stem cells engineered to express autoantigen in resting APCs could be used to prevent autoimmune disease. Proinsulin is a major autoantigen associated with pancreatic β cell destruction in humans with type 1 diabetes (T1D) and in autoimmune NOD mice. Here, we demonstrate that syngeneic transplantation of hematopoietic stem cells encoding proinsulin transgenically targeted to APCs totally prevents the development of spontaneous autoimmune diabetes in NOD mice. This antigen-specific immunotherapeutic strategy could be applied to prevent T1D and other autoimmune diseases in humans.

Authors

Raymond J. Steptoe, Janine M. Ritchie, Leonard C. Harrison

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
Transplantation of T cell–depleted NOD-PI BM prevents insulitis but not ...
Transplantation of T cell–depleted NOD-PI BM prevents insulitis but not sialitis. (a) Islets free of inflammatory infiltrate (insulitis) were common in recipients of NOD-PI BM, and infiltration was restricted to the periphery of islets (arrow). (b) Extensively infiltrated islets (indicated by asterisks) were common in recipients of NOD BM. (c) The insulitis score was significantly reduced (P = 0.008) in recipients of T cell–depleted NOD-PI BM cells (triangles, 1.0 ± 0.6) as compared with NOD BM cells (inverted triangles, 2.1 ± 0.8 [means ± SD]). Data for age-matched NOD mice (squares) and NOD-PI mice (diamonds) are included for comparison. (d) The number of submandibular gland inflammatory foci (sialitis score) did not differ between BMT and untreated mice. Individual mouse scores are pooled from two experiments in which BMT from NOD and NOD-PI mice was performed in parallel (horizontal bar indicates mean).