Stimulating results with stimulatory antibodies

Graft-versus-host disease (GVHD) is one of the major causes of morbidity and mortality in allogeneic hematopoietic stem cell transplantation. In acute GVHD, tremendous progress has been made in recent years with a better understanding of the underlying pathophysiologic events. In contrast, the pathogenesis of chronic GVHD (cGVHD) is still a largely unknown territory with more questions than answers regarding the underlying mechanisms leading to this very complex and clinically challenging disease. The study by Svegliati and colleagues in this issue of Blood provides interesting new insights into the mechanistic aspects of cGVHD development bearing potential therapeutic implications. Based on the clinical presentation of cGVHD with sclerodermatous and lichenoid lesions, Sjogren-like symptoms, or polymyositis to name a few, it has been suggested for a long time that cGVHD is an autoimmune disease with a striking resemblance particularly to systemic sclerosis. Recently, the same group published a study in the New England Journal of Medicine¹  describing the presence of stimulatory autoantibodies against the platelet-derived growth factor receptor (PDGF-R) in patients with systemic sclerosis. These antibodies activate Ha-Ras–extracellular-signal-regulated kinases 1 and 2 (ERK 1/2)–reactive oxygen species (Ha-Ras–ERK <½–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.

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.