Abnormalities in Th17 T cells in aplastic anemia

In this issue of Blood, Peffault de Latour et al demonstrate that interleukin-17 (IL-17)–producing Th17 T cells are increased in the peripheral blood and bone marrow of patients with aplastic anemia, compared with healthy controls. They also provide evidence that IL-17 contributes to the severity of marrow failure at an early stage. This work advances our overall understanding of the mechanisms of immune-mediated hematopoietic suppression and may ultimately have important clinical implications for the treatment of aplastic anemia.

Idiopathic aplastic anemia is characterized by pancytopenia and bone marrow hypoplasia, resulting from immune-mediated suppression of hematopoiesis.¹  Although the management of aplastic anemia is challenging and the outcome frequently fatal, advances in our understanding of the immune pathophysiology of the disease over the years have led to improvements in the immunosuppressive regimens used for its treatment and, in some cases, improved outcomes and survival.^1,2 

Over the past 3 decades, extensive work has established that cytokines play key roles in the suppression of hematopoiesis seen in aplastic anemia.²  Observations made first in the 1980s suggested a disease model in which overproduction of myelosuppressive cytokines by activated cytotoxic T cells results in immune-mediated hematopoietic destruction.^3,4  The principles established by such original observations remain essentially unchanged, but subsequent work has expanded on them and defined the mechanisms of immune deregulation seen in aplastic patients. An important observation in recent years was the demonstration that the T-bet transcription factor, which binds to the promoter of the IFNγ gene, is up-regulated in T cells from aplastic anemia patients, resulting in enhanced gene expression and overproduction of myelosuppressive cytokines.⁵  Other recent studies have shown that regulatory T cells (Treg) are decreased in the peripheral blood of aplastic anemia patients at diagnosis,⁶  suggesting a mechanism of escape of autoreactive T cells during the development of the disease.

Th17 immune responses play important roles in the pathogenesis of several autoimmune disorders and syndromes,⁷  but their roles in the pathogenesis and pathophysiology of aplastic anemia have been unclear and undefined. There had been some clues that Th17 cells may have been involved in the pathogenesis of aplastic anemia. From previous work we know that Tregs are suppressed in aplastic anemia,⁶  and a dichotomy in the development of pathogenic Th17 cells and regulatory (Foxp3⁺) Treg cells has been shown.⁸  In addition, there has been some recent evidence for increased expression of IL17A mRNA in bone marrow and peripheral blood mononuclear cells of aplastic anemia patients.⁹ 

In this issue, Peffault de Latour et al examined the patterns of expression of Th17 cells in patients with aplastic anemia and compared them to those seen in normal controls.¹⁰  Increased numbers of IL-17⁺ cells were found in aplastic bone marrows, while the percentage and overall absolute numbers of CD3⁺CD8⁻IL-17⁺ T cells were elevated in the peripheral blood of 21 newly diagnosed patients with aplastic anemia, compared with 10 healthy donors. Although the numbers of Th17 cells were not predictive of response to immunosuppression, patients in complete remission after treatment had lower numbers and percentages of Th17 cells than newly diagnosed patients and an inverse relationship with Treg cells in such patients was documented. To further define the role of Th17 cells in the pathophysiology of aplastic, the authors used an experimental mouse model of bone marrow failure involving infusion of allogeneic lymph node cells into sublethally irradiated recipients. Their data demonstrate that, in addition to the classical Th1 response, CD4⁺ and CD8⁺ IL-17–producing T cells were present—albeit to a lesser extent—in such mice. Remarkably, early treatment of such mice with an anti–IL-17 antibody resulted in reduced areas of hemorrhage in the marrow and improved overall bone marrow cellularity.

Altogether, the findings of this study provide evidence for an important role of Th17-mediated responses in the development and/or progression of early stages of aplastic anemia. They also suggest a synchronized Th1/Th17 response during development of marrow failure, associated with Treg deficiency. Beyond advancing our understanding of the immune pathophysiology of marrow failure, this work raises the prospect of future approaches to optimize immunosuppression regimens for the treatment of aplastic anemia patients, by targeting the Th17 response. There are already clinical trials aiming to block the Th17 response using anti–IL-17 monoclonal antibodies for autoimmune diseases. Efforts to incorporate monoclonal anti–IL-17 antibodies or other means to target Th17 T cells in current immunosuppressive regimens, such antithymocyte globulin and cyclosporine A, may provide a nonoverlapping approach to enhance responses and optimize immunosuppression. Such an approach may be particularly relevant for the treatment of patients with moderate aplastic anemia and efforts in that direction are warranted.