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Blood, 1 July 2007, Vol. 110, No. 1, pp. 6-7.
Stimulating results with stimulatory antibodiesUNIVERSITY OF PITTSBURGH CANCER INSTITUTE
In this issue of Blood, Svegliati and colleagues provide new insights into the mechanisms of chronic GVHD development by demonstrating the presence and functional activity of stimulatory anti–PDGF-R autoantibodies in patients with extensive chronic GVHD.
Based on the hypothesis that there might be a common underlying pathogenetic mechanism between extensive cGVHD and systemic sclerosis, Svegliati and colleagues studied a cohort of patients with extensive cGVHD for the presence of stimulatory PDGF-R antibodies. Indeed, the authors were able to identify functionally active autoantibodies against the PDGF-R in the serum of patients with extensive cGVHD. These findings have several implications: (1) The nature of the target antigens (ie, allogeneic minor antigens versus autoantigens) in cGVHD is still subject to intense investigation. The results from the Svegliati et al study provide evidence that the presence of antibodies to autoantigens is not a pure epiphenomenon in cGVHD, but rather is directly contributing to disease manifestation. (2) Similar to acute GVHD, it has been assumed that cGVHD is primarily caused by alloreactive or autoreactive (due to impaired negative selection) donor T cells. Recent evidence also supports the direct role of B cells in cGVHD. Thus, it has been shown that the presence of minor antigen-reactive antibodies correlated with the presence of cGVHD.2 Furthermore, treatment of cGVHD patients with the humanized anti-CD20 monoclonal antibody rituxan resulted in significant improvement of the disease.3 In this light, the findings of Svegliati and colleagues are direct proof that auto-antibodies may play a pivotal role in cGVHD, and underscore the notion that anti–B-cell–directed treatment strategies may be of potential benefit for the treatment of cGVHD by depleting auto- or alloreactive B cells. (3) The finding that stimulatory autoantibodies against the anti-PDGF receptor may be directly responsible for the sclerotic/fibrotic changes in cGVHD and involve tyrosine kinase–dependent/Ha-Ras–Erk-1/2–ROS signaling could provide the rationale for molecular targeted treatment of cGVHD (eg, tyrosine kinase inhibitors, farnesyltransferase inhibitors). In this context, it is of interest that the tyrosine kinase inhibitor imatinib has already been used successfully in preclinical models of dermal and pulmonary fibrosis.4 Despite the fact that these results still require confirmation and validation in a larger number of patients, the study by Svegliati and colleagues sheds new light on the pathogenesis of cGVHD. Most importantly, these findings could provide the basis for novel treatment strategies, which are desperately needed for a complex and frequently debilitating disease.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
–ROS), leading to increased collagen gene expression and myofibroblast phenotype conversion of normal human primary fibroblasts. These findings suggest that stimulatory autoantibodies against the PDGF-R might play a significant role in contributing to the development of sclerodermatous lesions and development of fibrosis. 
