Introduction to a review series on chronic GVHD: from pathogenic B-cell receptor signaling to novel therapeutic targets

Robert Zeiser and Robert S. Negrin

Chronic graft-versus-host disease (cGVHD) remains a major complication after allogeneic hematopoietic cell transplantation. Over the last decade, clinical success in patients with cGVHD has been hampered by the lack of insight into the complex pathobiological mechanisms of the disease, the paucity of specific therapeutic targets, and the need for a commonly accepted diagnostic staging system for response assessment.

In this review series, leading authors in the field present and discuss novel findings in basic T- and B-cell biology research that have led to novel therapeutic targets in cGVHD,1 mechanistic approaches for prevention and treatment of cGVHD,2 and a summary of the National Institutes of Health (NIH) Consensus Development Projects on Criteria for Clinical Trials in cGVHD; they then put these concepts into the clinical context.3

The articles in this review series, “Chronic graft-versus-host disease,” include the following:

Fundamental steps toward an understanding of the pathophysiology of cGVHD presented in this review series are (1) that a defect in thymic deletion of self-reactive T cells leads to autoreactive T cells and (2) that naive T cells that differentiate into Th17/Tc17 and T-follicular helper cells promote aberrant B-cell activation in cGVHD. Articles in this review series explore the biology of B cells that produce antibodies to polymorphic recipient antigens or nonpolymorphic antigens common to both recipient and donor.1,2 Of the different antigens recognized by B cells, H-Y antigens were found in male recipients of female hematopoietic cells.4 Control mechanisms that counteract abnormal B-cell activation, such as interleukin-10 (IL-10)–producing regulatory B cells,5 appear to be impaired under conditions of cGVHD.6-8 Further mechanistic insight into the pathogenesis of cGVHD discussed by MacDonald et al1 is the role of B-cell activating factor, a cytokine critical for the survival and maturation of B cells, which is found to be increased in patients with cGVHD.9,10

New directions of research discussed in this review series aim at targeting signaling pathways that are operational in B cells during cGVHD, including Bruton’s tyrosine kinase (BTK), spleen tyrosine kinase (SYK), and Janus kinases (JAKs), among others. A major novel concept for targeting B cells that promote cGVHD is based on the observation that animals lacking BTK in B cells do not develop cGVHD, indicating that BTK plays a central role in the pathophysiology of cGVHD. In addition, activation of T and B cells from patients with active cGVHD was inhibited by BTK and IL-2 inducible T-cell kinase blockade by the BTK inhibitor ibrutinib. Based on these data, a multicenter open-label phase 1b/2 study of ibrutinib in steroid-dependent/refractory cGVHD has been performed (registered at as #NCT02611063) and showed substantial response rates leading to the breakthrough therapy designation granted by the US Food and Drug Administration. SYK inhibitors, which were shown to reduce disease severity in mouse models of acute GVHD and cGVHD,11-13 are currently being studied in a clinical trial (#NCT02611063) and are discussed in this review series.1,2 While these approaches directly target the B-cell–mediated component of cGVHD, the T-cell cytokine-mediated component may be effectively targeted by JAK1/2 inhibition, as multiple cytokines relevant for B-cell activation signal via JAK1/2. Consistently, murine cGVHD and human cGVHD responded to JAK1/2 inhibition by ruxolitinib.14

Besides these approaches, multiple mechanistic interventions for cGVHD are summarized in elegant fashion in the review by Cutler et al.2 These approaches include stem cell graft engineering, inhibition of T-cell signaling, regulatory T cell (Treg)–related therapies (Treg sparing, Treg transfer, and in vivo Treg expansion), and depletion or inhibition of B cells.2 The authors highlight studies focused on in vivo Treg expansion showing that low-dose IL-2 increases Treg numbers in patients with cGVHD, which opens a new therapeutic option besides adoptive Treg transfer.

Another therapeutic approach discussed in the review series is the B-cell–depleting antibody rituximab, which has been successfully applied to patients with cGVHD, with high response rates.2 These findings are consistent with the central role of autoreactive B cells for cGVHD maintenance, forming the basis for phase 3 testing that is currently underway.

The need to assess and monitor cGVHD responses in patients using a reliable disease severity scoring system is required, and this is discussed by Lee in the review series.3 The initially proposed NIH criteria were based on expert opinion, and therefore, empirical studies were needed to assess their validity. A major pitfall for clinicians in scoring cGVHD severity is that patients with cGVHD have many concurrent medical conditions that may trigger a score on the cGVHD assessment form, even though there is no pathogenetic connection to cGVHD. In particular, skin rashes due to drug toxicity or infection can be misunderstood for chronic skin GVHD, and chronic infectious diarrhea is sometimes hard to distinguish from intestinal cGVHD. In the review by Lee,3 diagnostic criteria of cGVHD, assessments of organ involvement, and methods to document improvement or worsening during treatment based on the currently available classification and response assessment systems of cGVHD are presented and critically discussed.

Overall, this review series presents important novel insights into the pathogenesis of cGVHD and novel therapeutic strategies that have evolved over the past 5 years. With this information in mind, major advances in the prevention and treatment of cGVHD are eagerly awaited.

  • Submitted October 17, 2016.
  • Accepted October 31, 2016.


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